Carpal Tunnel Syndrome as a Warning Sign of Cardiomyopathy Caused by Transthyretin Amyloidosis

Nerve Compression as a Precursor of Heart Disease?

Cardiomyopathy caused by transthyretin amyloidosis (ATTR-CM) is often diagnosed very late, contributing to the high mortality of this disease. It is well known that the development of ATTR-CM can be preceded by carpal tunnel syndrome, approximately 5–15 years before the manifestation of cardiac symptoms. In patients with hereditary or wild-type (wt) ATTR-CM, the prevalence of this relatively common compression syndrome reaches 39–46%.

Studies evaluating the link between carpal tunnel syndrome and ATTR-CM are insufficient; it is not clear what proportion of patients with carpal tunnel syndrome are at subsequent risk of developing heart failure. The aim of the Danish authors' study was to better elucidate this association by analyzing an extensive population registry.

Evaluated Population

Data from the Danish population registry for the period from January 1, 1996, to December 31, 2012, were used for the analysis. All patients who underwent surgery for carpal tunnel syndrome during this period were included. Patients with already documented heart failure or amyloidosis were excluded. For control, a cohort of the Danish population matched by age and sex was selected in a 1:1 ratio. A total of 56,032 patients and an equal number of control subjects were included in the study. The median age in both groups was 53.9 years (interquartile range [IQR] 43.3–65.9 years), with women predominating at 67.9%.

Patients were followed until the occurrence of a target event. The primary endpoints were the diagnosis of amyloidosis (outpatient or during hospitalization) and hospitalization for heart failure (as the final diagnosis upon discharge). Secondary endpoints included other forms of cardiac manifestation such as atrial fibrillation, atrioventricular blocks, and implantation of a pacemaker or cardioverter-defibrillator. Sensitivity analysis included a comparison with a cohort of patients with heart failure without carpal tunnel syndrome matched in a 1:4 ratio by age and sex.

Results

Among patients with carpal tunnel syndrome, a higher incidence of comorbidities and concomitant pharmacotherapy was noted, especially higher rates of nonsteroidal anti-inflammatory drug use (32 vs. 12.2%; p < 0.0001). A total of 29.5% of patients underwent more than one surgery, and 29.8% underwent bilateral surgery for carpal tunnel syndrome.

Carpal tunnel syndrome was associated with a higher cumulative incidence of amyloidosis diagnosis compared to the control group (hazard ratio [HR] 12.12; 95% confidence interval [CI] 4.37–33.60). However, the absolute risk was low, with a cumulative incidence of 0.10% (47 cases) over 10 years for patients with carpal tunnel syndrome compared to 0.006% (3 cases) in the control group. The median time from surgery to diagnosis of amyloidosis was 3.1 years.

Carpal tunnel syndrome was also associated with a higher risk of heart failure compared to the control group. The cumulative incidence over 10 years was 5.3% compared to 3.2% in the control group. The median time from surgery to the diagnosis of heart failure was 3.7 years. The cumulative incidence of mortality did not differ between the groups during the follow-up. The risk of secondary cardiovascular endpoints was also higher for patients with carpal tunnel syndrome compared to the control group.

Further sensitivity analysis indicated that patients undergoing bilateral surgery were at even greater risk of developing amyloidosis (HR 30.68; 95% CI 4.17–225.52) and the occurrence of secondary cardiovascular endpoints. There was no significant interaction based on sex (p = 0.5).

Another interesting finding emerged from the sensitivity analysis in the cohort of patients with heart failure without carpal tunnel syndrome. It was found that patients with heart failure and carpal tunnel syndrome have a lower risk of death within 0–7 years from the onset of heart failure and a higher risk after 7 years compared to patients with heart failure without a history of carpal tunnel syndrome.

Summary, Conclusion, and Discussion

The analysis of the population registry revealed three key findings:

• Patients with a history of surgery for carpal tunnel syndrome are at up to a 12× higher risk of being diagnosed with ATTR-CM compared to the general population, although this risk was small in absolute numbers in the cited study.
• Patients with carpal tunnel syndrome also have a higher risk of heart failure, rhythm disorders, and a higher likelihood of pacemaker or cardioverter-defibrillator implantation.
• The mortality of patients with developed heart failure and carpal tunnel syndrome is lower in the short term compared to patients with heart failure without a history of carpal tunnel syndrome but higher in the long term, consistent with the development of wtATTR-CM.

Some limitations of the cited analysis should also be noted:

• The data include only patients who underwent surgical treatment for carpal tunnel syndrome and not those who were only registered with the diagnosis.
• These were observational studies.
• Patients diagnosed with amyloidosis could only be identified through hospital systems, which may have led to a conservative estimate of the results—lower than what actually corresponds to reality.

(holi)

Source: Fosbøl E. L., Rørth R., Leicht B. P. et al. Association of carpal tunnel syndrome with amyloidosis, heart failure, and adverse cardiovascular outcomes. J Am Coll Cardiol 2019; 74 (1): 15–23, doi: 10.1016/j.jacc.2019.04.054.