A Reliable Baton Passing From Orthopedic Surgeon to Cardiologist　― Cardiac Screening in Patients With Carpal Tunnel Syndrome for Early Diagnosis of Transthyretin Amyloid Cardiomyopathy ―

Wild-type transthyretin amyloidosis (ATTRwt) may actually be a common heart disease. ATTRwt-cardiomyopathy (CM) is more prevalent in older individuals and reported to account for approximately 10% of cases of heart failure with preserved ejection fraction (HFpEF), which constitute about half of HF patients,¹ yet many remain undiagnosed. Recently, a transthyretin (TTR) tetramer stabilizer, tafamidis, has become available in Japan for clinical use in treating ATTR-CM.² Subgroup analysis of the Phase 3 trial, ATTR-ACT, demonstrated that tafamidis is more effective when administered in the early stages of HF.² In other words, there are still numerous untreated ATTR-CM patients within the HF population, and early detection and diagnosis have significant therapeutic value.

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However, early diagnosis of ATTR is unexpectedly difficult because there are few imaging tests or biomarkers that can detect the subtle changes in early cardiac involvement. Therefore, carpal tunnel syndrome (CTS), which is a typical extracardiac symptom of ATTR, is recognized as an important trigger for early diagnosis of ATTR.^3,4

ATTRwt is known to deposit amyloid not only in the heart but also in tendons and ligaments, with a particularly high tendency to deposit in the wrist ligaments and synovium, leading to the development of CTS at a significant rate.⁵ CTS associated with ATTRwt is characterized by occurring in elderly males, exhibiting bilateral symptoms, and an earlier onset compared with cardiac involvement by 5–10 years. Therefore, when bilateral CTS is observed in elderly males, it is recommended to consider the possibility of ATTR and perform screening for cardiac involvement.⁶

However, as CTS is primarily managed by orthopedic surgeons rather than cardiologists, effective collaboration between these disciplines is crucial for the early diagnosis of ATTR-CM. To facilitate referrals from orthopedic surgeons to cardiologists when ATTR-CM is suspected, it is important to share sufficient knowledge and information about this condition and propose convenient screening methods. In fact, some orthopedic surgeons already have the impression that although amyloid deposition is often observed in the tenosynovium sampled during carpal tunnel release (CTR), ATTR-CM is less frequent. Therefore, accurate information regarding the positive rate of ATTR-CM in CTS patients and efficient screening approaches are considered as unmet clinical needs.

The study by Takashio et al⁷ in this issue of the Journal provides a clear answer to this issue. Although several studies have already reported the frequency of ATTR-CM among patients with CTS,^8–11 this study stands out as the largest prospective study to date, involving pathological examination of >700 consecutive biopsy specimens obtained during CTR. Surprisingly, the present study shows that amyloid deposits were observed in the tenosynovium tissue in a higher percentage (37%) than expected, and that while the majority of patients did not exhibit concurrent cardiac involvement, a certain number of patients did present with CM (5%, 6/120).

Given the high morbidity of CTS in the general population, it would be inefficient in terms of effort and cost to examine the presence of ATTR in all patients undergoing CTR surgery. The authors propose that by confirming left ventricular hypertrophy and abnormalities in biomarkers such as troponin, it is possible to narrow down, to some extent, the group of patients with ATTR-CM. However, it should be noted that pre-referral screening and assessment for cardiac involvement in practice are conducted by orthopedic surgeons. In Japan, orthopedic surgeons who specialize in CTS and its surgery often operate their own clinics as a standalone specialty. Because conducting echocardiography to assess cardiac hypertrophy is not feasible everywhere, it may be sufficient to examine the troponin level and/or B-type natriuretic peptide, which can be assessed simply through blood tests. And it is highly valuable to ensure that the red flags mentioned in the discussion section (age ≥60, bilateral CTS, history of HF, atrial fibrillation or conduction disorders) are checked.

This study⁷ revealed that the majority of patients with TTR amyloid fibers in the tenosynovium of the hand had localized ATTR without cardiac involvement.¹² However, it remains unclear whether these localized ATTR cases will progress to cardiac involvement in the future. Particularly for patients who exhibit cardiac hypertrophy, abnormal biomarkers, or meet some of the relevant red flags, follow-up is essential even if ATTR-CM is not detected at the time of examination. The duration of follow-up needs to be considered on a case-by-case basis. Careful consideration should be given to how to manage and follow up cases of early diagnosis of ATTR-CM in which the patient is not exhibiting HF or cardiac symptoms. It has been reported that the patients with mild HF related to cardiac transthyretin amyloidosis have a prognosis similar to that of the general population if diagnosed at an extremely early stage.¹³

Takashio et al⁷ have elucidated the rate of amyloid deposition in the tenosynovium of CTS patients and the incidence of ATTR-CM among them, making theirs a valuable study for promoting multidisciplinary collaboration on early diagnosis of ATTR-CM. In the future, this study is expected to shed light on the backgrounds of CTS patients who are at risk of developing cardiac involvement.

Competing Interests / Sources of Funding

None.

References

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