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Carpal tunnel syndrome may be an early warning sign of amyloidosis and heart failure, a Danish study showed.

Matched by age and sex to the general population, people who got carpal tunnel surgery had higher risks of developing amyloidosis (0.10% vs 0.006%, adjusted HR 12.12, 95% CI 4.37-33.60) and heart failure over the next 10 years (5.3% vs 3.2%, adjusted HR 1.54, 95% CI 1.45-1.64).

These patients also experienced significantly more of other adverse cardiovascular outcomes -- such as atrial fibrillation, atrioventricular heart block, and pacemaker implantation -- according to a group led by Emil Fosbøl, MD, PhD, of the University Hospital of Copenhagen, Rigshospitalet, reporting in the July 9 issue of the .

Given that the absolute incidence of diagnosed amyloidosis was still low for either group, carpal tunnel syndrome by itself "may not merit direct referral for further evaluation for amyloidosis, but could rather be considered a red flag and an opportunity for early disease detection," Fosbøl and colleagues said.

"Transthyretin cardiac amyloidosis is still usually found too late, when severe left ventricular thickening, restrictive cardiomyopathy, and depressed systolic function can lead to orthostasis, hypotension, conduction disease, dyspnea, and death. To improve outcomes and start drugs when they can be of benefit, early diagnosis of transthyretin cardiac amyloidosis is imperative," commented Van-Khue Ton, MD, PhD, and colleagues, all from the University of Maryland School of Medicine in Baltimore, in an .

Study investigators also found that the subgroup with heart failure and a history of carpal tunnel syndrome showed lower short-term but higher long-term mortality risk than peers with heart failure but not the latter -- consistent with the development of wild-type transthyretin cardiac amyloidosis, they said.

Their study was based on Danish registry data spanning from 1996 to 2012 (total of 56,032 patients). Median age was 53.9 years and 67.9% of the cohort were women.

Carpal tunnel syndrome is known to be common in transthyretin amyloidosis (ATTR), and the two may be linked by systemic amyloid accumulation. On top of that, ATTR has been found to be one of the causes of heart failure with preserved ejection fraction (HFpEF), according to the authors.

"It would be highly interesting to determine the importance of HFrEF [heart failure with reduced ejection fraction] versus HFpEF in the current study, but unfortunately, these data were not available in the registry," Fosbøl's group acknowledged. "It is crucial that future studies phenotype the HF syndrome associated with CTS [carpal tunnel syndrome]."

Other limitations of the study include its observational nature and the lack of certain clinical variables in the files (for example, hereditary amyloid cardiomyopathy and wild-type ATTR could not be distinguished from the dataset).

Moreover, people who got surgery for carpal tunnel syndrome had more comorbidities than controls and were on more medications, especially anti-inflammatory drugs, at baseline.

"[C]arpal tunnel syndrome often predates clinical amyloidosis by decades. Thus, a 10-year study, while admirable, might still miss many patients with amyloidosis. Furthermore, amyloidosis is still , and true rates might be much higher," Ton and colleagues added.

ATTR cardiomyopathy also presents more commonly in men and non-Caucasians, suggesting that the Danish population may not be the best group in which to study this, the editorialists wrote.

With such low absolute event rates in patients with carpal tunnel syndrome in the present study, the question is whether it would only predict relatively few amyloidosis patients, the editorialists said.

Nevertheless, they agreed that carpal tunnel syndrome could be considered a "red flag" of possible amyloidosis down the road.