Carpal tunnel syndrome as an early warning sign for cardiac amyloidosis

Physician-scientists from the University of Alabama at Birmingham Marnix E. Heersink School of Medicine led a nationwide study to examine the role of carpal tunnel syndrome in predicting the risk of cardiac amyloidosis. 

In their study published in the Mayo Clinic Proceedings, UAB researchers collaborated with researchers from Weill Cornell Medicine and Columbia University to show that carpal tunnel syndrome preceded the development of cardiac amyloidosis by 10-15 years and individuals with carpal tunnel syndrome were at a high risk of developing cardiac amyloidosis.

Cardiac amyloidosis is an underdiagnosed condition that may be responsible for up to one in 10 cases of heart failure. At the time of diagnosis, individuals with cardiac amyloidosis have developed severe heart failure and are at a high risk of death. Early identification of cardiac amyloidosis may allow the initiation of disease-modifying therapeutic agents that halt the progression of disease and delay the development of heart failure. Therefore, early identification of cardiac amyloidosis is essential to prevent the mortality and morbidity associated with the disease."

Naman S. Shetty, M.D., research fellow in the UAB Division of Cardiovascular Disease and the first author of this manuscript

Shetty and his team utilized nationwide data from the All of Us Research Program to study approximately 150,000 individuals across the United States. The study unveiled a significant association between carpal tunnel syndrome and the risk of developing heart failure and amyloidosis. 

"We found that individuals with carpal tunnel syndrome exhibited a 13 percent higher risk of developing heart failure and a threefold higher risk of amyloidosis compared to those without carpal tunnel syndrome," Shetty said. "Therefore, the findings of this study point toward carpal tunnel syndrome as a potential early indicator of cardiac amyloidosis."

Shetty says the development of carpal tunnel syndrome before developing cardiac amyloidosis may be attributed to the disease process in amyloidosis. Amyloidosis is characterized by the destabilization of the transthyretin protein, which leads to the breakdown of this protein into fragments. The deposition of these protein fragments in various tissues leads to the manifestations of amyloidosis. 

Shetty notes that the carpal tunnel is a tight space in the wrist and the deposition of even a small amount of protein fragments leads to the development of symptoms. However, a large amount of protein deposition in the heart is required for the alteration of the function of the heart and the development of cardiac symptoms. These differences may explain why carpal tunnel syndrome precedes cardiac amyloidosis by 10-15 years. 

Pankaj Arora, M.D., the senior author of the manuscript and an associate professor in the UAB Division of Cardiovascular Disease, explains that cardiac amyloidosis is broadly classified as wild-type, meaning it has no identifiable genetic mutation, or hereditary, meaning it is caused by a genetic mutation in the TTR gene. 

"The All of Us Research Program provided the unique opportunity to examine whether carrying a TTR mutation was associated with a higher risk of developing carpal tunnel syndrome," Arora said. "The study found that carriers of a TTR mutation have a roughly 40 percent higher risk of developing carpal tunnel syndrome, with the risk increasing notably around the age of 50-60 years. Our previous work showed that the risk of heart failure in individuals carrying a TTR mutation increased at nearly 75 years of age. Putting these findings together, individuals with a genetic mutation for cardiac amyloidosis develop carpal tunnel syndrome about 10-15 years prior to the development of heart failure." 

Arora, who also serves as the director of the UAB Cardiogenomics Clinic, is routinely involved in caring for patients with hereditary cardiac amyloidosis. 

"The findings of this study have several implications for the detection of cardiac amyloidosis," Arora said. "Cardiac amyloidosis screening programs targeting individuals with CTS between the ages of 50 and 60 years may facilitate early identification of ATTR amyloidosis." 

Arora notes that genetic testing for TTR variants may prove to be a feasible strategy for screening. Considering that about 3 percent to 4 percent of Black individuals carry a genetic variant, implementation of genetic testing in individuals with carpal tunnel syndrome may allow early identification of carriers of genetic mutation and permit preventive strategies. These efforts may ultimately contribute to decreasing racial disparities in cardiovascular disease.