論文ID: CJ-23-0223
Background: Carpal tunnel syndrome (CTS) is considered an early sign of cardiac amyloidosis (CA) because amyloid deposition is often confirmed in the tenosynovium removed during carpal tunnel release (CTR); however, the prevalence of concomitant CA is unclear.
Methods and Results: We prospectively examined 700 patients who underwent CTR and evaluated amyloid deposition after tenosynovium removal. Amyloid deposition was observed in 261 (37%) patients, who were significantly older and predominantly male (P<0.05). Of them, 120 agreed to cardiac screening. We performed 99 mTc-labeled pyrophosphate (99 mTc-PYP) scintigraphy in 12 patients who met either of the following criteria: (1) interventricular septal diameter (IVSd) ≥14 mm or (2) 12 mm ≤ IVSd < 14 mm with above-normal limits in high-sensitivity cardiac troponin T (hs-cTnT). Six patients (50%) had positive findings on 99 mTc-PYP scintigraphy and were diagnosed with wild-type transthyretin CA. Concomitant CA was observed in 6/120 (5%) CTR patients with amyloid deposition and 50% (6/12) in patients with left ventricular hypertrophy (≥12 mm) with increased hs-cTnT levels.
Conclusions: Amyloid deposition was frequently observed in the removed tenosynovium of elderly men with CTS. Cardiac screening may be useful for early diagnosis of CA in patients undergoing CTR with amyloid deposition.
Amyloidosis is a systemic disorder that results from the deposition of insoluble amyloid fibrils in various organs. Cardiac amyloidosis (CA) is a progressive and infiltrative form of cardiomyopathy characterized by increased ventricular wall thickness, diastolic dysfunction, and cardiac conduction system diseases caused by the deposition of amyloid fibrils in the extracellular space of the myocardium. Immunoglobulin light-chain and transthyretin (TTR) are the 2 main types of precursor proteins in CA.1,2 Until recently, CA was underdiagnosed and considered rare, but it is now recognized as a hidden cause of heart failure and coexisting with several heart diseases.3,4 Furthermore, noninvasive diagnostic algorithms5 and emerging therapies have become available, improving the early diagnosis of CA.6–8
Several guidelines report “red flags” for CA,9–11 one of which is carpal tunnel syndrome (CTS) as a preceding symptom and an important diagnostic indicator for CA, especially the TTR form (ATTR-CA). Approximately 30–50% of individuals with wild-type TTR-CA (ATTRwt-CA) have a history of CTS that precedes the diagnosis by 5–10 years.2,12 The risks of amyloidosis and heart failure are higher among patients undergoing carpal tunnel release (CTR) than among matched control subjects.13 Amyloid deposition in the tenosynovium removed during CTR is often confirmed (10–37%).14–16 Taken together, the evidence suggests that CTS patients with amyloid deposition in the removed tenosynovium are high-risk patients for CA.
There are some reports on the prevalence of CA among patients undergoing CTR;15,17–20 however, the prevalence of concomitant CA in a sufficient number of patients with amyloid deposition in the removed tenosynovium has not been reported and to avoid unnecessary pathologic inspection, it is clinically important to select patients with a high possibility of CA. Thus, we aimed to evaluate the prevalence of amyloid deposition in the removed tenosynovium in patients who underwent CTR to clarify the prevalence of concomitant CA.
This prospective study was conducted at Kumamoto University between June 2019 and February 2023. The study conformed to the principles outlined in the Declaration of Helsinki and was approved by the review board and ethics committee of Kumamoto University (approval no. 1648). All patients who underwent cardiac screening provided written informed consent.
Study PopulationDiagnosis of CTS and CTR with the removal of the tenosynovium was performed in 3 orthopedic institutes in Kumamoto (Kato Orthopedics Clinic, Kumamoto Orthopaedic Hospital, and Kumamoto University). Pathological evaluation of amyloid deposition in the tenosynovium was performed at the Division of Cell Pathology, Kumamoto University. Congo red staining was performed at K. I. Stainer Inc. (Kumamoto, Japan). Two investigators (S.T. and Y.K.), one of whom was a pathologist (Y.K.), blinded to the clinical characteristics, independently determined the dichotomous presence or absence of amyloid deposition in the removed tenosynovium. Among the patients who underwent bilateral CTR during the study period, amyloid positivity was determined if amyloid deposits were found in at least one of the samples. Invitation and proposal letters for screening for CA were sent to patients who had amyloid deposition. Immunohistochemical staining was conducted to identify the precursor proteins in patients who consented to the study. We excluded patients with known CA prior to CTR.
Screening for CAData on each patient’s characteristics and comorbidities were obtained. ECG, echocardiography, and biomarkers were evaluated to assess the likelihood of CA. On ECG, a prolonged PR interval was defined as 200 ms, and wide QRS was defined as ≥120 ms. Low voltage in the limb leads was defined as QRS amplitude <5 mm in height in all limb leads. Echocardiography was performed using an Epiq 7G (Philips, Bothell, WA, USA). Cardiac chamber size and wall thickness were measured via the transthoracic view. Left ventricular hypertrophy was defined as an interventricular septal diameter (IVSd) ≥12 mm. Left ventricular ejection fraction was calculated using the modified Simpson’s method. All echocardiographic images were stored in the Digital Imaging and Communications in Medicine format on the Echo Management Information System and retrieved later for offline global longitudinal strain (LS) analysis. Apical sparing was evaluated using the relative apical LS index (apical LS / basal LS + mid-LS) >1.04.21
We evaluated the following biomarkers: (1) serum high-sensitivity cardiac troponin T (hs-cTnT), (2) N-terminal pro-B-type natriuretic peptide (NT-proBNP) or B-type natriuretic peptide (BNP), (3) estimated glomerular filtration rate (eGFR), and (4) serum free light-chain (FLC). Serum hs-cTnT levels (normal cutoff value 0.014 pg/mL) were measured using the Elecsys 2010 Troponin T HS kit (Roche Diagnostics, Indianapolis, IN, USA). Serum NT-proBNP levels (normal cutoff value 125 pg/mL) were measured using the Elecsys NT-proBNP II (Roche Diagnostics) and plasma BNP levels (normal cutoff value 18.4 pg/mL) were measured using the MI02 Shionogi BNP kit (Abbott Japan, Matsudo, Japan). The GFR was calculated using the Modification of Diet in Renal Disease Study equation, level-modified for Japanese individuals. The normal range of the FLC ratio was 0.26–1.65; however, it is well known that the FLC ratio increases as eGFR decreases. Hence, we decided to consider an FLC ratio up to 2.0 as normal if the eGFR was <45 mL/min/1.73 m2.11
We recommended further screening by 99 mTc-labeled pyrophosphate (99 mTc-PYP) scintigraphy in patients who met the following criteria: (1) IVSd ≥14 mm, or (2) 12 mm ≤ IVSd < 14 mm with above-normal limits in hs-cTnT (≥0.014 ng/mL).9–11,18,22 If amyloid light-chain (AL) deposition in the removed tenosynovium or an abnormal FLC ratio was observed, we consulted a hematologist. Patients who did not fall into these categories were recommended to undergo annual cardiac screening tests.
99 mTc-PYP Scintigraphy99 mTc-PYP scintigraphy was performed using GE Discovery 670 dual-headed single-photon emission computed tomography (SPECT) with low-energy, high-resolution collimators (GE Healthcare, Waukesha, WI, USA). Anterior and lateral planar views of the heart were obtained 3 h after radiotracer administration. Radiotracer accumulation in the myocardium was assessed using both planar and SPECT to rule out false-positive results secondary to radiotracer retention in the left ventricular blood pool.23 99 mTc-PYP positivity was defined as a visual score of 2 or 3. Quantitative analysis of cardiac retention was assessed by the heart-to-contralateral ratio, which was calculated as the total counts in a region of interest over the heart divided by the background counts in a region of identical size over the contralateral chest, including the soft tissue, ribs, and blood pool.
Diagnosis of CAATTR-CA was diagnosed by (1) the presence of TTR deposits in the removed tenosynovium, (2) absence of monoclonal protein, and (3) positive findings on 99 mTc-PYP scintigraphy. We diagnosed ATTRwt-CA based on the absence of TTR mutations. AL-CA was diagnosed based on AL deposits in the removed tenosynovium with left ventricular hypertrophy.
Statistical AnalysisNormally distributed parameters are expressed as mean±standard deviation, and non-normally distributed parameters are expressed as median with interquartile range (IQR). Categorical values are presented as number (percentage) and were compared using the chi-square test or Fisher’s exact test. Differences between groups were examined using Student’s t-test or the Mann-Whitney U test for unpaired data. Univariate logistic regression analysis was performed to identify significant parameters for amyloid positivity in the removed tenosynovium. Multivariate logistic regression analysis was performed using a forced inclusion model. A two-tailed value of P<0.05 was considered significant. All statistical analyses were performed using IBM SPSS Statistics for Windows, version 19.0 (IBM Corp., Armonk, NY, USA).
Figure 1 is a flowchart of participant selection. In total, 702 patients with CTS underwent CTR, with exclusion of 2 patients diagnosed with ATTR-CA preoperatively. Among the remaining 700 patients, amyloid deposition in the removed tenosynovium was confirmed in 261 patients (37%) and their characteristics are presented in Table 1. Amyloid-positive patients were significantly older (P<0.001) and mostly male (P<0.001) compared with amyloid-negative patients. The amyloid-positive rate was significantly higher in males (61%; mean age: 66.4±10.9 years) than in females (24%; mean age: 62.4±12.8 years) (P<0.001). The amyloid-positivity rate of each age group (per 10 years) in the overall cohort, and in the male and female patients is shown in Figure 2. Among the 107 patients who underwent bilateral CTR during the study period and were evaluated for amyloid deposition in each sample, pathological results for both tenosynovium were consistent in 100 patients (93%).
Flowchart of participant selection and cardiac evaluation. 99 mTc-PYP, 99 mTc-labeled pyrophosphate; ATTR, transthyretin amyloid; CMR, cardiac magnetic resonance.
| Variables | All cases (n=700) |
Amyloid-positive (n=261) |
Amyloid-negative (n=439) |
P value |
|---|---|---|---|---|
| Age, years | 63.9±12.3 | 71.1±8.2 | 59.5±12.3 | <0.001 |
| Men, n (%) | 253 (36%) | 153 (59%) | 100 (23%) | <0.001 |
| Past medical history (n=233) | ||||
| Bilateral CTS, n/total (%) | 182/233 (78%) | 123/147 (84%) | 59/86 (69%) | <0.001 |
| Rotator cuff tear, n/total (%) | 37/233 (16%) | 28/147 (19%) | 9/86 (11%) | 0.08 |
| Lumbar spinal canal stenosis, n/total (%) | 55/233 (24%) | 43/147 (29%) | 12/86 (14%) | 0.008 |
| Hypertension, n/total (%) | 127/233 (55%) | 88/147 (60%) | 39/86 (45%) | 0.03 |
| Heart failure, n/total (%) | 3/233 (1%) | 2/147 (1%) | 1/86 (1%) | 0.89 |
Data are mean±standard deviation or n (%). CTS, carpal tunnel syndrome.
Amyloid-positive rate in each age group in the overall cohort (A), men (B), and women (C). The rate increased with age, and men had a higher amyloid-positive rate than women.
Among the 233 patients whose prior medical history we were able to obtain, bilateral CTS, lumbar spinal canal stenosis, and hypertension were more frequently observed in amyloid-positive patients. In the univariate logistic regression analyses, age, male sex, bilateral CTS, and lumbar spinal canal stenosis were significantly associated with amyloid positivity (P<0.001). The multivariate analysis, including these 4 parameters, identified age (odds ratio [OR]: 1.08, 95% confidence interval [CI]: 1.04–1.11; P<0.001), male sex (OR: 3.00, 95% CI: 1.60–5.61; P=0.001), and bilateral CTS (OR: 2.01, 95% CI: 1.00–4.03; P=0.049) as independent predictors of amyloid positivity in the removed tenosynovium.
Cardiac Screening for CAAmong 261 patients with amyloid deposition in the removed tenosynovium, 120 (46%) consented to cardiac screening and thier characteristics are shown in Table 2. There were no significant differences in age (70.4±7.4 vs. 71.7±8.9 years; P=0.19) and sex (male; 57% vs. 60%; P=0.55) between participants and non-participants. All patients who consented to cardiac screening underwent immunohistochemical assessment, and 116 had TTR deposits (4 were unable to be typed because of a tiny amount of amyloid deposition). No patient had evidence of AL amyloid deposits. An abnormal FLC ratio was not observed in patients in whom a precursor protein could not be identified by immunohistochemical staining. The median time from CTR to the screening test was 4.0 months (IQR: 2.6–5.6 months). In the laboratory tests, the median hs-cTnT level was 0.010 (0.006–0.015) ng/mL, and the median NT-proBNP level was 77 (41–151) pg/mL. Elevated hs-cTnT levels (≥0.014 ng/mL) were observed in 36 patients (30%). On echocardiography, the mean IVSd was 10.2±1.8 mm. IVSd ≥12 mm was observed in 17 patients (14%) and IVSd ≥14 mm was observed in 5 patients (3%). The distributions of IVSd, hs-cTnT, and NT-proBNP levels are shown in Figure 3.
| Variables | (n=120) |
|---|---|
| Age at cardiac screening test, years | 70.4±7.4 |
| Age at diagnosis of CTS, years | 68.8±7.9 |
| Men, n (%) | 68 (57%) |
| Bilateral CTS, n (%) | 98 (82%) |
| Immunohistochemical staining | |
| Transthyretin | 116 (97%) |
| Light-chain amyloid | 0 (0%) |
| Undetermined | 4 (3%) |
| Past medical history | |
| Rotator cuff tear, n (%) | 22 (18%) |
| Lumbar spinal canal stenosis, n (%) | 40 (33%) |
| Hypertension, n (%) | 68 (57%) |
| Heart failure, n (%) | 0 (0%) |
| Laboratory parameters | |
| hs-cTnT, ng/mL | 0.010 (0.006–0.015) |
| hs-cTnT ≥0.014 ng/mL | 36 (30%) |
| NT-proBNP, pg/mL (n=112) | 77 (41–151) |
| NT-proBNP ≥125 pg/mL, n/total (%) | 36/112 (32%) |
| BNP, pg/mL (n=8) | 28 (15–51) |
| BNP ≥40 pg/mL, n/total (%) | 3/8 (38%) |
| Creatinine, mg/dL | 0.81±0.24 |
| eGFR, mL/min/1.73 m2 | 68±16 |
| Free light-chain ratio | 1.30±0.59 |
| Abnormal free light-chain ratio | 14 (12%) |
| ECG parameters | |
| Atrial fibrillation, n (%) | 1 (1%) |
| Heart rate, beats/min | 65±10 |
| PR duration, ms | 170±28 |
| Prolonged PR interval, n (%) | 14 (11%) |
| QRS duration, ms | 94±15 |
| Wide QRS, n (%) | 7 (6%) |
| CLBBB, n (%) | 2 (2%) |
| CRBBB, n (%) | 4 (3%) |
| Interventricular conduction, n (%) | 1 (1%) |
| Low QRS voltage in limb leads, n (%) | 6 (5%) |
| Poor R wave progression in precordial leads, n (%) | 0 (0%) |
| Echocardiographic parameters | |
| LVDd, mm | 44.1±5.3 |
| LVDs, mm | 28.9±5.6 |
| IVSd, mm | 10.2±1.8 |
| IVSd ≥12 mm, n (%) | 17 (14%) |
| LVPWd, mm | 10.0±1.7 |
| LAD, mm | 37.5±5.8 |
| LVEF, % | 63.3±5.8 |
| LV-GLS (n=111) | −15.7±3.0 |
| RapLSI (n=111) | 0.74±0.35 |
| E/A | 0.92±0.35 |
| E/e’ | 11.5±4.1 |
Data are median (interquartile range), mean±standard deviation, or n (%). BNP, B-type natriuretic peptide; CLBBB, complete left bundle branch block; CRBBB, complete right bundle branch block; CTS, carpal tunnel syndrome; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; hs-cTnT, high-sensitivity cardiac troponin T; IVSd, interventricular septal diameter; LVDd, left ventricular diastolic diameter; LVDs, left ventricular systolic diameter; LVEF, left ventricular ejection fraction; LVPWd, left ventricular posterior wall diameter; LV-GLS, left ventricular global longitudinal strain; NT-proBNP, N-terminal pro-B-type natriuretic peptide; RapLSI, relative apical longitudinal strain index.
Distribution of IVSd (A), and the NT-proBNP (B), and hs-cTnT (C) levels. hs-cTnT, high-sensitivity cardiac troponin T; IVSd, interventricular septal diameter; NT-proBNP, N-terminal pro-B-type natriuretic peptide.
A total of 14 patients (12%) underwent further investigation based on their echocardiographic and biomarker findings. One patient declined 99 mTc-PYP scintigraphy (72-year-old male, IVSd: 12.4 mm, hs-cTnT: 0.017 ng/mL, NT-proBNP: 94 pg/mL), and 1 was evaluated by contrast-enhanced cardiac magnetic resonance imaging because of the high possibility of hypertrophic cardiomyopathy; that patient was diagnosed with hypertrophic cardiomyopathy without the typical findings of CA. Finally, 12 patients underwent 99 mTc-PYP scintigraphy. Their results and detailed characteristics are shown in Table 3. A visual score ≥2 was observed in 6 male patients, who all had TTR deposition in the removed tenosynovium, normal FLC ratio, and no TTR mutation; thus, they were diagnosed with ATTRwt-CA in Mayo prognosis stage I.24 Among them, patient 4 had New York Heart Association functional class II symptoms with increased NT-proBNP level (1,450 pg/mL), and was prescribed loop diuretics (furosemide 10 mg) and tafamidis meglumine (80 mg). The remaining patients had no signs of heart failure and had low biomarker levels, so they were assigned to regular follow-up (National Amyloidosis Center ATTR stage Ia).25 The prevalence of concomitant CA was 6/120 (5%) in patients with amyloid deposition in the removed tenosynovium, 6/68 (9%) in male patients, and 6/12 (50%) in patients with left ventricular hypertrophy and hs-cTnT levels above the normal limit.
| Case no. | Age at screening (years) |
Age at diagnosis (years) |
Sex | NYHA | Bilateral CTS |
LSCS | hs-cTnT (ng/mL) |
NT-proBNP (pg/mL) |
eGFR (mL/min/ 1.73 m2) |
Wide QRS | IVSd (mm) | LVEF (%) | LV-GLS | Apical sparing |
Visual score |
H/CL (3 h) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 72 | 72 | M | I | + | + | 0.018 | 259 | 58 | − | 12.9 | 67.8 | −10.4 | − | 2 | 1.46 |
| 2 | 70 | 65 | M | I | + | + | 0.014 | 76 | 62 | − | 12.0 | 63.6 | −18.0 | + | 2 | 1.49 |
| 3 | 69 | 66 | M | I | − | − | 0.023 | 311 | 48 | − | 12.8 | 49.0 | −11.8 | − | 3 | 1.89 |
| 4 | 74 | 74 | M | II | + | − | 0.030 | 1,450 | 73 | − | 13.6 | 56.1 | −12.1 | − | 3 | 1.88 |
| 5 | 72 | 72 | M | I | + | − | 0.026 | 81 | 67 | + | 13.9 | 67.8 | −17.5 | − | 3 | 1.75 |
| 6 | 73 | 73 | M | I | + | − | 0.029 | 194 | 67 | + | 15.1 | 57.2 | −15.5 | − | 2 | 1.57 |
| 7 | 78 | 77 | M | I | + | − | 0.015 | 557 | 71 | − | 14.2 | 58.2 | −12.0 | − | 1 | 1.32 |
| 8 | 72 | 72 | M | I | + | + | 0.023 | 507 | 43 | − | 13.8 | 57.5 | −14.1 | − | 0 | 1.24 |
| 9 | 67 | 67 | M | I | + | + | 0.025 | 47 | 69 | − | 12.0 | 68.8 | −17.8 | − | 0 | 1.23 |
| 10 | 65 | 65 | M | I | + | + | 0.010 | 353 | 79 | − | 15.2 | 63.0 | −17.5 | − | 0 | 1.20 |
| 11 | 75 | 74 | M | I | + | + | 0.011 | 50 | 77 | − | 14.0 | 60.0 | −14.2 | − | 0 | 1.15 |
| 12 | 65 | 64 | F | I | + | − | 0.020 | 77 | 29 | − | 12.2 | 60.0 | NA | NA | 0 | 1.10 |
99 mTc-PYP, 99 mTc-labeled pyrophosphate; F, female; H/CL, heart-to-contralateral ratio; LSCS, lumbar spinal canal stenosis; M, male; NA, not available; NYHA, New York Heart Association. Other abbreviations as in Table 2.
Our study prospectively evaluated the prevalence of concomitant CA in patients who underwent CTR and showed amyloid deposition in the removed tenosynovium, as well as the utility of a cardiac screening strategy using echocardiography and biomarkers. The major findings were: (1) a 37% positive rate of amyloid deposition in tenosynovium in patients who underwent CTR, particularly elderly men; (2) concomitant CA in 6/120 (5%) patients with amyloid deposition in the removed tenosynovium, in 6/68 (9%) of male patients, and in 6/12 (50%) patients with left ventricular hypertrophy and hs-cTnT above the normal limit (Figure 4); (3) all of the diagnosed patients were ATTRwt-CA and mainly in the preclinical Mayo prognostic stage I. To the best of our knowledge, this is the largest prospective study to evaluate the prevalence of concomitant CA in CTS patients with amyloid deposition in the removed tenosynovium after CTR.
Positive rate of amyloid deposition in removed tenosynovium in patients who underwent carpal tunnel release, especially in elderly men: 37%. Concomitant cardiac amyloidosis observed in 6/120 (5%) patients with amyloid deposition in the removed tenosynovium, in 6/68 (9%) male patients, and in 6/12 (50%) patients with left ventricular hypertrophy with hs-cTnT levels above the normal limit. ATTRwt-CA, wild-type transthyretin cardiac amyloidosis; CTS, carpal tunnel syndrome; hs-cTnT, high-sensitivity cardiac troponin T; IVSd, interventricular septal diameter; LVH, left ventricular hypertension.
It has been reported that the positive rate of amyloid deposition in tissue samples obtained by CTR varies widely from 10% to 37%.14–16,19,26,27 Compared with reports from other Western countries, the positive rate was higher in reports from Japan (>30%), which is consistent with our results (37%). Similar to those previous reports, the positive rate in our study increased with age and positive patients were predominantly male, which is consistent with the patient characteristics of ATTRwt-CA.12 The coexistence of rotator cuff tears and lumbar spinal canal stenosis tended to be more common in amyloid-positive cases, and the concordance rate of amyloid deposition in bilateral CTR samples was high. These results suggest that amyloid deposition is a common pathology in these orthopedic diseases.
Aimo et al4 reported a CA prevalence of 7% in patients who underwent surgery for CTS by meta-analysis including 3 studies.15,17,18 However, there were several differences, such as patient selection, screening process, and evaluation timing. Table 4 is a summary of the studies on the prevalence of CA in patients who underwent CTR, including our study and previous studies.15,17–20 Sperry et al,15 Sugiura et al,19 and our study evaluated amyloid deposition in the removed samples, and cardiac evaluation was performed at the time of CTR. Vianello et al,17 Zegri-Reiriz et al,18 and our study selected patients with left ventricular hypertrophy on echocardiography, and in all studies the prevalence of CA was consistent (1%–5%). Each study screened using echocardiography, cardiac biomarkers, or pathological findings to increase the pretest probability before bone scintigraphy and sought a high-risk patient group (e.g., male, no occupational risk factors for CTS). The prevalence of CTS in the general population is reported to be 2.7%,28 which is higher than the prevalence of CA (0.05%),29 so routinely screening patients with CTS for CA by bone scintigraphy would be labor-intensive and costly.
| Present study (n=120) |
Sperry et al (n=98)15 |
Vianello et al (n=53)17 |
Zegri-Reiriz et al (n=233)18 |
Sugiura et al (n=79)19 |
Westin et al (n=250)20 |
|
|---|---|---|---|---|---|---|
| Patient selection criteria | CTR + amyloid deposition |
CTR | Bilateral CTR + male |
CTR | CTR | Bilateral CTR |
| Age (years) | 70.4±7.4 | 68 (IQR 61–74) |
72.0±12.2 | 69 (IQR 64–77)# |
71.6±12.5 | 70.4 (IQR 65.2–75.2) |
| Men | 57% | 18% | 100% | 32%# | 41% | 50% |
| Bilateral CTS | 82% | 45% | 100% | 54%# | 54% | 100% |
| Time from surgery to evaluation |
4.0 months (IQR: 2.6–5.6) |
Same time (detailed data not shown) |
4.4±2.3 years | 6 years (IQR 3.2–9.7)# |
Within 1 year | 9.0 years (IQR 7.6–11.5) |
| Evaluation of cardiac biomarkers |
NT-proBNP hs-cTnT |
NT-proBNP TnT |
(−) | NT-proBNP hs-cTnI |
BNP hs-cTnT |
NT-proBNP hs-cTnT |
| Second-screening criteria before bone scintigraphy |
(1) IVSd ≥14 mm or (2) 12 mm ≤ IVSd < 14 mm with above-normal limits in hs-cTnT |
Amyloid deposition in removal sample |
Unexplained LVH (IVSd >12 mm) |
LVH (IVSd ≥12 mm) |
Amyloid deposition in removal sample |
(−) |
| No. of patients undergoing bone scintigraphy |
12 | 10 | 4 | 101 | 16 | 250 |
| Cardiac involvement | ATTRwt-CA: 6 | ATTRwt-CA: 1 AL-CA: 1 |
ATTRwt-CA: 2 | ATTRwt-CA: 2 AL-CA: 1 |
ATTRwt-CA: 3 | ATTRwt-CA: 12 |
| Prevalence of cardiac amyloidosis |
6/120 (5.0%) | 2/98 (2.0%) | 2/53 (3.8%) | 3 /233 (1.2%) | 3/79 (3.8%) | 12/250 (4.8%) |
| Prevalence of cardiac amyloidosis among second-screening cases |
6/12 (50%) | 2/10 (20%) | 2/4 (50%) | 3 /101 (3%) | 3/16 (19%) | (−) |
#Clinical data for patients with LVH (n=101). ATTRwt-CA, wild-type transthyretin cardiac amyloidosis; AL-CA, light-chain cardiac amyloidosis; CTR, carpal tunnel release; hs-cTnI, high-sensitivity cardiac troponin I; IQR, interquartile range. Other abbreviations as in Table 2.
Based on our results and those of previous reports, the characteristics of CTS patients who should be considered for screening for CA are: 1) elderly men (≥70 years), (2) amyloid deposits in the removed tenosynovium, (3) left ventricular hypertrophy, (4) bilateral CTS without occupational risk factors,15,17–20 and (5) increased cardiac troponin levels. ATTRwt-CA is known to be predominantly in elderly men. A Japanese cohort study reported that the average age at diagnosis of ATTRwt-CA was 78.5±6.4 years, and 85% of the cases were male.12 In our study, the amyloid-positive rate in the removed tenosynovium was 76% in men aged ≥70 years, and Westin et al also concluded that men aged ≥70 years was a factor that increased the prevalence.20 Therefore, it may be reasonable to assume that men aged ≥70 years with bilateral CTS are candidates for cardiac screening. Although there are no data on the prevalence of CA in CTS patients with amyloid-negative samples, it was reported that the rate of amyloid deposition in samples from CTS patients diagnosed with ATTR-CA by preoperative non-biopsy criteria was 100%.30 Therefore, we speculate that there is a high probability that amyloid deposits will be found in the tenosynovium of ATTR-CA patients who undergo CTR. Sugiura et al reported that the prevalence of CA by 99 mTc-PYP scintigraphy was 19% in patients with CTS and amyloid deposition in the removed tenosynovium.19 We clarified that combining the results of pathological examination with echocardiography and biomarkers increased the positivity rate (50%).
There is significant attention being paid to determining which patients with CTS should undergo pathological evaluation of the removed tenosynovium. However, it can be challenging for orthopedic surgeons to evaluate echocardiography and cardiac biomarkers as part of routine care before CTR. Based on the “red flags” of CA and findings from previous research, including our own,9–11,15,17–20 we recommend that clinicians consult with cardiologists to discuss the possibility of CA and the necessity of pathological evaluation in patients with the following clinical history: (1) bilateral CTS, (2) male aged ≥60 years, (3) history of heart failure (e.g., history of hospitalization for heart failure, taking diuretics), (4) history of atrial fibrillation or cardiac conduction system diseases, and (5) history of lumbar spinal canal stenosis and tendon rupture. We believe that these patients have a high risk of concomitant or future CA. It is important to share clinical information among healthcare providers for the early diagnosis of CA.
Left ventricular hypertrophy is a characteristic finding in CA, although the cutoff value for cardiac screening tests needs further discussion. IVSd ≥14 mm is a proposed cutoff value for suspicious CA.22 IVSd ≥12 mm was selected in our study and previous reports; however, Sugiura et al confirmed some cases of ATTR-CA with IVSd <12 mm.19 Therefore, echocardiographic findings in addition to left ventricular hypertrophy are desired. Apical sparing, which is another characteristic of CA, was not observed in many cases in our study, so as a marker it may not contribute to increasing the pretest probability of CA in the early phase. Increased levels of cardiac troponin (hs-cTnT >0.03ng/mL) have been reported as a clue to CA in patients with left ventricular hypertrophy.31 We added hs-cTnT values to differentiate CA from hypertensive hypertrophy, because the positive rate of bone scintigraphy in patients with IVSd ≥12 mm is low (2%), as reported by Zegri-Reiriz et al.18 Empirically, early-stage CA may be overlooked if hs-cTnT >0.03 ng/mL is selected as the cutoff value, so we selected the normal limit in hs-cTnT (≥0.014 ng/mL) as the cutoff value in this study. The utility and optimal cutoff values of hs-cTnT cannot be discussed because bone scintigraphy was not performed in all cases; however, the objectivity and reproducibility of biomarkers make it easy to evaluate the probability of CA and institute serial follow-up.
In our study, all diagnosed cases were ATTRwt-CA in Mayo prognostic stage I with low levels of natriuretic peptide and cardiac troponin. There were some cases of a slight elevation in biomarker levels without left ventricular hypertrophy (≥12 mm). Therefore, the possibility of CA cannot be ruled out in those patients. However, even if they did have CA, ATTR-CA is a slowly progressive disease, with an estimated survival that is comparable to that of the general population with low levels of NT-proBNP and on a low dose of loop diuretics.25 Early diagnosis is possible by conducting annual follow-up.
Study LimitationsFirst, this was a single-center study with a relatively small number of cases. Nonetheless, this is a large-scale prospective study of CTS patients with amyloid deposits in the removed tenosynovium. Second, 141 (54%) amyloid-positive patients declined to participate in cardiac screening. Previous reports have also reported on declined participation in 15–49% of cases, which is fewer than in our study. We speculate that many patients were hesitant to participate during the COVID-19 pandemic response with imposed movement restrictions that occurred in Japan during the study period. Although there were no significant differences in age or sex between participants and non-participants, the possibility of differences in detailed health conditions cannot be ruled out. Third, bone scintigraphy was not performed for all of the study patients. There is no evidence that CA was absent in patients with no amyloid deposition in the removed tenosynovium. Therefore, there may be undiagnosed cases of CA among the study patients. Finally, the long-term clinical course of the study patients was unclear. Further studies evaluating changes in cardiac findings and trends in the diagnosis of CA are warranted.
Amyloid deposition in the removed tenosynovium was observed in 39% of patients undergoing CTR, especially in elderly men with CTS. Concomitant CA was found in 6/120 (5%) patients. The prevalence increased to 50% (6/12) in patients with left ventricular hypertrophy and high hs-cTnT levels. Most of the diagnosed patients were preclinical ATTRwt-CA and difficult to diagnose without cardiac screening and pathological evaluation. This strategy may be useful for the early diagnosis of CA in patients undergoing CTR, and the findings should be shared with the consulting orthopedic surgeons and cardiologists.
This research was supported by the Japan Intractable Diseases (Nanbyo) Research Foundation and JSPS KAKENHI [grant number: 21K08131]. The authors are grateful to Megumi Nagahiro and Saeko Tokunaga from the Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, and Naomi Akizuki from Kumamoto Orthopaedic Hospital for their skillful technical assistance. We thank Editage (www.editage.com) for English language editing.
S.T. and K.T. have received remuneration for lectures from Pfizer Japan Inc. M.U. has received remuneration for lectures from Pfizer Japan Inc. and Alnylam, and research funding from Pfizer Japan Inc. K.T. is a member of Circulation Journal’s Editorial Team. The remaining authors declare they have no conflicts of interest.
Name of the Ethics Committee: Kumamoto University Hospital. Reference number: 1648.
The deidentified participant data will not be shared.
