Article ID: CR-21-0046
Background: Wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) is a life-threatening progressive disease. Recent studies have shown that the detection of transthyretin (TTR) amyloid in tenosynovial tissue may play an important role in the diagnosis of cardiac amyloidosis. The aim of this study was to determine the prevalence of TTR amyloid deposits in surgical tissue of patients undergoing carpal tunnel surgery and to clarify the clinical significance of concomitant cardiac examination with 99 mTc-labeled pyrophosphate (99 mTc-PYP) scintigraphy in those patients with TTR deposition.
Methods and Results: We evaluated 79 consecutive patients undergoing carpal tunnel release surgery and biopsy of tenosynovial tissue. The mean (±SD) age of the patients at surgery was 71.6±12.5 years (range 30–95 years); 32 patients (41%) were male. TTR amyloid deposition in tenosynovial tissue was observed in 27 patients (34%). Sixteen of those 27 patients underwent 99 mTc-PYP scintigraphy. Of those 16 patients, 3 (19%) had Grade 2 uptake on 99 mTc-PYP scintigraphy. None of the 3 patients with a diagnosis of ATTRwt-CA had apparent cardiac symptoms and left ventricular wall thickness >13 mm.
Conclusions: Concomitant cardiac examination with 99 mTc-PYP scintigraphy in patients who had TTR amyloid deposition in tenosynovial tissue resulted in the identification of 19% of patients with a diagnosis of ATTRwt-CA. This diagnostic approach seems to be useful for the early diagnosis of the disease.
Wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) is a life-threatening progressive disease characterized by infiltrative cardiomyopathy caused by deposition of transthyretin (TTR) amyloid in the myocardium.1–3 It has been perceived as a rare disease and is often undiagnosed in clinical practice, especially in elderly patients with heart failure. Diagnosis of ATTRwt-CA often takes more than 1 year from the appearance of cardiac symptoms.3,4 However, with the introduction of the therapeutic agent tafamidis, early diagnosis of ATTRwt-CA has become increasingly important.5
Carpal tunnel syndrome is one of the symptoms of systemic amyloidosis. The reported prevalence of TTR deposition in tenosynovial tissue in Japanese patients with idiopathic carpal tunnel syndrome was 34.0%.6 Recent studies have revealed that a history of carpal tunnel syndrome was associated with a diagnosis of amyloidosis and heart failure.7,8 In addition, it has been shown that carpal tunnel syndrome precedes the diagnosis of ATTRwt-CA by 5–10 years.9 Therefore, carpal tunnel syndrome is an important red flag in the diagnosis of ATTRwt-CA.
However, there are very few reports of systematic efforts to detect ATTRwt-CA in collaboration with orthopedic surgeons and cardiologists. Recently, we have built a cooperative system including cardiac evaluations by technetium-99 m pyrophosphate (99 mTc-PYP) scintigraphy examination for patients undergoing carpal tunnel release surgery with detection of amyloid deposits in the tenosynovial tissue. To the best of our knowledge, there have been no reports of the prevalence of cardiac involvement at the time of carpal tunnel surgery in Japanese patients with evidence of TTR deposition in tenosynovial tissue.
The aims of this study were to determine the prevalence of TTR amyloid deposits in surgical tissues of patients undergoing carpal tunnel surgery and to clarify the clinical significance of concomitant examination with 99 mTc-PYP scintigraphy in those patients with evidence of TTR deposition.
We retrospectively evaluated 79 consecutive patients who underwent carpal tunnel release surgery and biopsy of tenosynovial tissue between August 2017 and October 2020 at Kochi Medical School Hospital. Data for these patients were obtained from medical records.
This study was approved by the Ethics Committee on Medical Research of Kochi Medical School and was conducted in accordance with the Declaration of Helsinki and the ethical standards of the responsible committee on human experimentation.
Surgical Procedure and Clinical EvaluationAfter transection of the transverse carpal ligament, the median nerve and flexor tendons were protected, and a small sample of synovial tissue was excised. The tenosynovial tissue was then formalin fixed and subsequently evaluated by hematoxylin-eosin and Congo red staining by pathologists. Biopsy specimens with confirmed amyloid deposits by Congo red staining were further analyzed using immunohistochemistry for subtyping.
In accordance with the Japanese Circulation Society 2020 Guideline on Diagnosis and Treatment of Cardiac Amyloidosis,10 the diagnosis of ATTRwt-CA was established by tenosynovial tissue biopsy-proven TTR amyloid deposition and Grade 2 or 3 positive uptake on 99 mTc-PYP scintigraphy accompanied by clinical and laboratory findings suggesting cardiac amyloidosis, with normal free light chain ratio and serum immunofixation. The subtype of wild-type TTR amyloid was established on the basis of the absence of TTR mutations.
Evaluation of patients included a medical history, clinical examination, 12-lead electrocardiogram (ECG), laboratory variables, B-type natriuretic peptide (BNP), high-sensitivity cardiac troponin T (hs-cTnT), echocardiography, and 99 mTc-PYP scintigraphy. BNP was measured using an enzyme immunoassay (TOSOH, Tokyo, Japan) and hs-cTnT was measured using an Elecsys troponin T high-sensitivity immunoassay (Roche Diagnostics, Rotkreuz, Switzerland). A standard 12-lead ECG was performed for each patient and was reviewed retrospectively. Low voltage was assessed by limb criteria (QRS amplitude ≤0.5 mV in all limb leads). A pseudo-infarction pattern was defined as pathological Q waves or QS waves in at least 2 consecutive leads in the absence of evidence of akinetic/dyskinetic wall segments. Echocardiographic parameters were measured in a standard manner as recommended by the American Society of Echocardiography guidelines.11 Apical sparing was evaluated by using a systolic longitudinal base-to-apex strain gradient (average apical to average basal longitudinal peak systolic strain ratio >2.1).12 In the present study, 99 mTc-PYP scintigraphy was defined as significant for a definite diagnosis of cardiac TTR amyloidosis when there was Grade 2 or 3 uptake of 99 mTc-PYP in the left ventricle (LV) according to previously reported grading systems.10,13,14 Visual and quantitative assessments were established in the 3-h imaging. In patients undergoing 99 mTc-PYP scintigraphy, we assessed the following 3 factors in the ‘Kumamoto criteria’: QRS width ≥120 ms, LV posterior wall thickness (LVPWT) ≥13.6 mm, and hs-cTnT ≥0.0308ng/mL. The Kumamoto criteria were introduced for good performance to predict 99 mTc-PYP scintigraphy positivity.15,16
Statistical AnalysisCategorical variables are expressed as numbers (percentages) and continuous variables are presented as the mean±SD. The significance of differences between the 2 groups was assessed using unpaired t-tests for continuous variables and the χ2 test for categorical variables. All analyses were performed using IBM SPSS version 21.0.0.0 (IBM Corp., Armonk, NY, USA).
Figure 1 shows the study patient flow chart. All patients underwent biopsy of tenosynovial tissue. The clinical characteristics of the 79 patients who underwent carpal tunnel release surgery are summarized in Table 1. The mean age of the patients at surgery was 71.6±12.5 years (range 30–95 years), and 32 patients (41%) were male. Forty-three patients (54%) had bilateral carpal tunnel syndrome.
Study flow chart. CTR, carpal tunnel release surgery; TTR, transthyretin; 99 mTc-PYP, 99 mTc-labeled pyrophosphate.
| Total cohort (n=79) |
TTR amyloid positive (n=27) |
TTR amyloid negative (n=52) |
P value | |
|---|---|---|---|---|
| Age (years) | 71.6±12.5 | 79.4±6.1 | 67.5±13.0 | <0.001 |
| BMI (kg/m2) | 24.2±4.3 | 23.7±3.0 | 24.6±4.9 | 0.368 |
| Male sex | 32 (41) | 16 (59) | 16 (31) | 0.017 |
| Bilateral CTS | 43 (54) | 18 (67) | 25 (48) | 0.239 |
| Hypertension | 43 (54) | 20 (74) | 23 (44) | 0.017 |
| Dyslipidemia | 29 (37) | 15 (56) | 14 (27) | 0.015 |
| Diabetes | 19 (15) | 4 (15) | 11 (21) | 0.561 |
| Coronary artery disease | 7 (9) | 2 (7) | 5 (10) | 1.000 |
| Atrial fibrillation | 9 (11) | 3 (11) | 6 (11) | 1.000 |
| Dialysis | 15 (19) | 3 (11) | 12 (23) | 0.241 |
| Sodium (mmol/L) | 140.5±2.6 | 140.2±3.0 | 140.7±2.3 | 0.407 |
| Potassium (mmol/L) | 4.2±0.4 | 4.2±0.4 | 4.2±0.4 | 0.490 |
| Creatinine (mg/dL) | 1.9±2.5 | 1.6±1.9 | 2.0±2.7 | 0.406 |
| eGFR (mL/min/1.73 m2) | 56.7±30.2 | 51.8±25.1 | 59.3±32.4 | 0.294 |
| Albumin (g/dL) | 4.1±0.4 | 4.1±0.5 | 4.1±0.4 | 0.811 |
Unless indicated otherwise, data are given as the mean±SD or n (%). BMI, body mass index; CTS, carpal tunnel syndrome; eGFR, estimated glomerular filtration rate, determined using the Modification of Diet in Renal Disease study equation; TTR, transthyretin.
TTR amyloid in the tenosynovial biopsy was found in 27 patients (34%). TTR amyloid-positive patients were significantly older and there was a significantly larger proportion of male patients in this group. Regarding comorbidities, hypertension and dyslipidemia were more frequent in TTR amyloid-positive patients. No differences were found in other parameters.
Cardiac InvolvementOf the 27 TTR amyloid-positive patients, 1 with a prior diagnosis of ATTRwt-CA, 6 who refused to be referred by cardiologists, and 4 who did not want to have a 99 mTc-PYP scintigraphy examination were excluded (Figure 1). This left 16 patients who underwent 99 mTc-PYP scintigraphy after the biopsy for assessment in the present study.
Table 2 presents the findings of cardiac evaluation in the 16 patients undergoing 99 mTc-PYP scintigraphy. Most patients had cardiac evaluation within 1 year after carpal tunnel release surgery. Of these 16 patients, 3 had Grade 2 uptake and 2 had Grade 1 uptake on 99 mTc-PYP scintigraphy. Figure 2 shows 3-h planar imaging and the heart-to-contralateral ratio of the 3 patients with Grade 2 uptake. These 3 patients (Patients #1, #2, and #3) with Grade 2 uptake on 99 mTc-PYP scintigraphy showed a normal free light chain ratio and serum immunofixation, and TTR mutations were not identified. Patients #1 and #3 had no symptoms (New York Heart Association [NYHA] functional class I). Patient #2 had very mild dyspnea (NYHA functional class II). The ECG showed a pseudo-infarction pattern in Patients #2 and #3. Low voltage in limb leads was observed in Patient #2. Echocardiography showed an interventricular septal thickness (IVST) of 11 mm in Patients #1 and #2 and an IVST of 12 mm in Patient #3. Positive apical sparing was confirmed in 1 patient. BNP concentrations in Patients #1, 2, and 3 ranged from 62 to 105pg/mL. According to the current Japanese guideline,10 the 3 patients with Grade 2 uptake on 99 mTc-PYP scintigraphy were finally diagnosed as having ATTRwt-CA; that is, a diagnosis of ATTRwt-CA at the time of carpal tunnel surgery was obtained in 3 (19%) of the 16 patients.
| Patient no. |
Age (years) |
Sex | Bilateral CTS |
99 mTc-PYP scintigraphy | Laboratory findings | ECG findings | Echocardiographic findings | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Grade | Time from surgery (months) |
BNP (ng/mL) |
hs-cTnT (ng/mL) |
eGFR (mL/min/1.73 m2) |
Albumin (mg/dL) |
QRS width (ms) |
Low voltage in limb leads |
Pseudo-infarction pattern |
LVEF (%) |
IVST (mm) |
PWT (mm) |
Mean E/e´ | Apical sparing |
||||
| 1 | 69 | M | + | 2 | 1 | 62.3 | 0.040 | 47.1 | 3.9 | 112 | − | − | 59 | 11 | 11 | 9.4 | − |
| 2 | 85 | M | − | 2 | 3 | 105.2 | 0.039 | 35.3 | 3.9 | 90 | + | + | 61 | 11 | 11 | 10.4 | − |
| 3 | 78 | F | + | 2 | 1 | 75.0 | 0.018 | 85.8 | 4.1 | 113 | − | + | 67 | 12 | 12 | 20.9 | + |
| 4 | 78 | F | + | 1 | 13 | 59.7 | 0.015 | 80.6 | 4.7 | 110 | − | + | 58 | 11 | 8 | 23.0 | − |
| 5 | 80 | M | + | 1 | 1 | 291.0 | 0.029 | 57.7 | 3.8 | 100 | − | + | 48 | 10 | 11 | 26.3 | + |
| 6 | 86 | F | − | 0 | 2 | 76.2 | 0.032 | 53.1 | 4.2 | 88 | − | − | 65 | 10 | 8 | 6.0 | − |
| 7 | 78 | M | + | 0 | 5 | 37.7 | 0.012 | 34.2 | 3.5 | 97 | − | − | 66 | 9 | 8 | 13.0 | − |
| 8 | 84 | F | + | 0 | 6 | 55.3 | 0.015 | 49.9 | 4.3 | 88 | − | − | 65 | 9 | 9 | 14.2 | − |
| 9 | 79 | F | + | 0 | 5 | 36.5 | 0.013 | 59.7 | 4.0 | 98 | − | − | 67 | 9 | 10 | 12.1 | − |
| 10 | 93 | F | − | 0 | 10 | 57.7 | 0.020 | 56.8 | 4.4 | 95 | − | − | 67 | 8 | 9 | 17.4 | − |
| 11 | 82 | M | + | 0 | 1 | 13.4 | 0.012 | 72.9 | 4.3 | 122 | − | − | 52 | 10 | 9 | 8.1 | − |
| 12 | 78 | M | + | 0 | 2 | 36.1 | 0.386 | 4.7 | 3.9 | 90 | − | − | 62 | 9 | 8 | 7.9 | − |
| 13 | 68 | M | − | 0 | 2 | 76.7 | 0.013 | 61.1 | 3.8 | 89 | − | − | 66 | 10 | 10 | 8.5 | − |
| 14 | 89 | F | − | 0 | 1 | NA | NA | 38.8 | 3.0 | 133 | − | − | 79 | 14 | 12 | NA | NA |
| 15 | 81 | F | − | 0 | 33 | 41.0 | 0.031 | 36.6 | 4.0 | 102 | − | − | 68 | 10 | 10 | 8.7 | − |
| 16 | 68 | M | + | 0 | 23 | 31.0 | 0.010 | 85.4 | 4.5 | 107 | − | − | 82 | 13 | 11 | 14.9 | − |
99 mTc-PYP, 99 mTc-labeled pyrophosphate; BNP, B-type natriuretic peptide; CTS, carpal tunnel syndrome; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate, determined using the Modification of Diet in Renal Disease study equation; F, female; hs-cTnT, high-sensitivity cardiac troponin T; IVST, interventricular septal thickness; LVEF, left ventricular ejection fraction; M, male; NA, not available; PWT, posterior wall thickness.
Three-hour planar imaging of patients with Grade 2 uptake on 99 mTc-labeled pyrophosphate scintigraphy. H/CL, heart-to-contralateral ratio.
Table 3 presents the 3 factors in the ‘Kumamoto criteria’ and apical sparing on echocardiography in patients with Grade 2 uptake on 99 mTc-PYP scintigraphy. None of these patients fulfilled the criteria of QRS width ≥120 ms and LVPWT ≥13.6 mm. Regarding hs-cTnT values, 2 of the 3 patients with Grade 2 uptake on 99 mTc-PYP scintigraphy had hs-cTnT ≥0.0308 ng/mL.
| Patient no. | 99 mTc-PYP scintigraphy grade |
Wide QRS ≥120 ms | LVPWT ≥13.6 mm | hs-cTnT ≥0.0308 ng/mL | Apical sparing on echocardiography |
|---|---|---|---|---|---|
| 1 | 2 | − | − | + | − |
| 2 | 2 | − | − | + | − |
| 3 | 2 | − | − | − | + |
99 mTc-PYP, 99 mTc-labeled pyrophosphate; hs-cTnT, high sensitivity cardiac troponin T; LVPWT, left ventricular posterior wall thickness.
Next, we focused on the 16 patients who underwent 99 mTc-PYP scintigraphy in order to identify the clinical markers providing better pretest probability for a positive uptake (Grade 2 uptake) on 99 mTc-PYP scintigraphy. Table 4 presents the 4 factors suggestive of ATTRwt-CA that can be easily obtained in routine examination: hs-cTnT ≥0.0308 ng/mL, the presence of low voltage in limb leads, the presence of a pseudo-infarction pattern, and the presence of apical sparing. There were 8 patients with 1 or more positive findings for these 4 factors: the sensitivity, specificity, positive predictive value, and negative predictive value for 99 mTc-PYP scintigraphy positivity were 100%, 62%, 38%, and 100%, respectively.
| Patient no. | 99 mTc-PYP scintigraphy grade |
hs-cTnT ≥0.0308 ng/mL |
Low voltage in limb leads |
Pseudo-infarction pattern |
Apical sparing |
No. positive findings |
|---|---|---|---|---|---|---|
| 1 | 2 | + | − | − | − | 1 |
| 2 | 2 | + | + | + | − | 3 |
| 3 | 2 | − | − | + | + | 2 |
| 4 | 1 | − | − | + | − | 1 |
| 5 | 1 | − | − | + | + | 2 |
| 6 | 0 | + | − | − | − | 1 |
| 7 | 0 | − | − | − | − | 0 |
| 8 | 0 | − | − | − | − | 0 |
| 9 | 0 | − | − | − | − | 0 |
| 10 | 0 | − | − | − | − | 0 |
| 11 | 0 | − | − | − | − | 0 |
| 12 | 0 | + | − | − | − | 1 |
| 13 | 0 | − | − | − | − | 0 |
| 14 | 0 | NA | − | − | NA | 0 |
| 15 | 0 | + | − | − | − | 1 |
| 16 | 0 | − | − | − | − | 0 |
99 mTc-PYP, 99 mTc-labeled pyrophosphate; hs-cTnT, high sensitivity cardiac troponin T; NA, not available.
In this study we found that 34% of patients who underwent carpal tunnel release surgery for carpal tunnel syndrome had TTR amyloid deposition in tenosynovial tissue. Of the 16 patients with TTR deposition who underwent 99 mTc-PYP scintigraphy for concomitant cardiac examination, 3 patients (19%) were diagnosed with ATTRwt-CA. Notably, none of these 3 patients had obvious heart failure symptoms or septal and posterior wall thicknesses of more than 13 mm. ATTRwt-CA could be diagnosed at an early stage in these patients. Our diagnostic approach, conducted by a collaboration between orthopedic surgeons and cardiologists, could lead to an opportunity for the early diagnosis of ATTRwt-CA.
Sperry et al reported the prevalence of amyloid deposition in 98 patients who underwent carpal tunnel surgery.17 Ten patients (10%) had a positive biopsy for amyloid (8 patients with TTR amyloid and 2 patients with AL amyloid). Of these 10 patients, cardiac involvement was found in 2 (1 patient with AL amyloidosis and 1 patient with ATTRwt-CA).17 Compared with the results of Sperry et al,17 the reported prevalence of TTR amyloid deposition in tenosynovial tissue in Japanese patients is relatively high (34.0%),6 and is similar to the results in the present cohort. Although the deposition of amyloid fibers has been noted to increase with aging,18–20 the mean age of patients in these studies (68.0, 67.3, and 71.6 years old) was equivalent to that in the present study. Racial differences may affect the prevalence of amyloid deposition.
Regarding the diagnostic approach to ATTRwt-CA, concomitant cardiac evaluation with 99 mTc-PYP scintigraphy resulted in the identification of patients with cardiac involvement among patients with TTR deposition in tenosynovial tissue. A definite diagnosis was made in 19% of patients in the present study. According to the Kumamoto criteria, 3 factors, namely wide QRS (QRS ≥120 ms), LVPWT ≥13.6 mm and hs-cTnT ≥0.0308 ng/mL, are useful predictors of positive 99 mTc-PYP scintigraphy findings in the elderly.15,16 However, none of the 3 patients diagnosed with ATTRwt-CA in our study fulfilled the criteria for QRS width on ECG or LVPWT on echocardiography (Table 3). These findings suggest that wide QRS (QRS ≥120 ms) and LVPWT ≥13.6 mm are useful markers for patients with heart failure or arrhythmic symptoms, but are not sufficient to diagnose a very early stage of ATTRwt-CA in patients without cardiac symptoms. With regard to hs-cTnT, 2 of the 3 patients with Grade 2 uptake fulfilled this criterion. Although apical sparing on echocardiography was shown to contribute to the diagnosis of ATTRwt-CA in a previous study,12 there were 2 patients in the present study in whom apical sparing was not shown. Conversely, 99 mTc-PYP scintigraphy may play an important role even in very early diagnosis of ATTRwt-CA.
Based on the findings presented in Table 4, hs-cTnT ≥0.0308ng/mL, the presence of low voltage in limb leads or a pseudo-infarction pattern on ECG, as well as apical sparing in echocardiographic findings, may be useful determinants to narrow down candidates for 99 mTc-PYP scintigraphy. Patients having at least 1 factor had a negative predictive value of 100% for Grade 2 uptake in 99 mTc-PYP scintigraphy. Based on our results, patients in whom TTR amyloid is detected in tenosynovial tissue and who have at least 1 of the 4 factors should undergo 99 mTc-PYP scintigraphy.
With the introduction of tafamidis as a therapeutic agent for ATTRwt-CA amyloidosis, the importance of early diagnosis of the disease has increased further.5,21 A beneficial effect of tafamidis on mortality has been reported to appear after 18 months of treatment. Thus, it is important to start tafamidis treatment as early as possible for those who are expected to survive for a long time. In the present study, we were able to diagnose ATTRwt-CA in 3 patients at the time of carpal tunnel surgery. These patients were considered to have a favorable long-term prognosis according to proposed prognostic factors, including BNP or hs-cTnT values and echocardiographic findings.22–24 Although none of the patients diagnosed with ATTRwt-CA in this study satisfied current patient requirements for treatment with tafamidis for ATTRwt-CA because of the early diagnosis, they could be eligible for timely treatment with tafamidis as soon as they satisfy the patient requirements.
Carpal tunnel syndrome has been reported to precede the diagnosis of ATTRwt-CA by 5–10 years.9 For that reason, patients with no evidence of cardiac amyloidosis in the present study could also develop prospective cardiac involvement. Therefore, they need to be followed-up from the viewpoint of having a risk of developing cardiac amyloidosis.
Study LimitationsThis study has several limitations that need to be considered. First, this study was a single-center retrospective study. Second, the number of patients in the study was relatively small. Third, 99 mTc-PYP scintigraphy was not performed for all TTR amyloid-positive patients. This was due to the retrospective nature of the investigation. Some patients did not want to be referred by cardiologists and to have a 99 mTc-PYP scintigraphy examination. Fourth, cardiac biopsy was not performed in patients who had Grade 2 uptake on 99 mTc-PYP scintigraphy, although these patients had a definite diagnosis of ATTRwt-CA according to the current guidelines.10 Fifth, the prognosis of patients with an early diagnosis of ATTRwt-CA is still incompletely understood. We need to investigate the clinical relevance of an early diagnosis with this protocol.
In a cohort of Japanese patients undergoing carpal tunnel release surgery, TTR amyloid deposition in tenosynovial tissue was observed in 34% of patients. Concomitant cardiac examination with 99 mTc-PYP scintigraphy in those patients with evidence of TTR deposition resulted in the identification of a considerable number of patients with a definite diagnosis of ATTRwt-CA. This diagnostic approach seems to be useful for the early diagnosis of this progressive disease.
This work was supported, in part, by a research grant from the Japan Society for the Promotion of Science (18k08078) to H. Kitaoka.
T.K. and H. Kitaoka have received remuneration from Pfizer. H. Kitaoka is a member of Circulation Reports’ Editorial Team. The remaining authors have no conflicts of interest to declare.
This study was approved by the Ethics Committee on Medical Research of Kochi Medical School (Reference no. ERB-002378).
