ATTR-CM outcomes differ by sex, but biology may not explain why
Women were older, more symptomatic and at higher early risk after diagnosis
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Women with transthyretin amyloid cardiomyopathy (ATTR-CM) had worse outcomes than men in a new study, but the gap may reflect differences in age and disease severity at diagnosis rather than biological sex alone.
Researchers found that women with ATTR-CM were generally older and had more severe disease when they were diagnosed. Valvular heart disease also was more common in women. These differences may help explain why women had worse outcomes than men.
Study examines why outcomes differ by sex
“After adjustment for major [influencing factors], sex was not independently associated with outcomes in [statistical] analyses,” the researchers wrote. “Taking into account the limited number of women included, this finding supports the hypothesis that once differences in age and disease severity at the time of diagnosis are accounted for the subsequent clinical course of ATTR-CM appears similar regardless of sex.”
The findings underscore the importance of diagnosing ATTR-CM in women early and accurately, the researchers noted in the study, “Sex Differences in Presentation and Outcomes of Transthyretin Amyloid Cardiomyopathy,” published in JACC: Advances.
ATTR-CM is a disorder in which abnormal clumps of the protein transthyretin build up in and damage heart tissue, which can eventually cause heart failure.
ATTR-CM is diagnosed much more often in men than in women, but the reasons for this disparity remain unclear. Biological differences may play a role, but ATTR-CM also may be underdiagnosed in women.
Although ATTR-CM is diagnosed more often in men, less is known about whether disease outcomes differ between women and men. To investigate, researchers analyzed prospectively collected data from a multicenter Swiss registry involving 515 men and 52 women with ATTR-CM.
“As both disease awareness and the availability of specific therapies have increased, understanding sex-specific differences has become increasingly important,” the scientists wrote. “Such insights are paramount to ensure timely and equitable diagnosis, risk stratification, and initiation of disease-specific therapy, for both men and women.”
Women were older and sicker at diagnosis
At the time of ATTR-CM diagnosis, women were significantly older than men, with a mean age of 80.3 vs. 76.9 years. Women also had a significantly higher New York Heart Association functional class, indicating greater physical limitations and more severe heart failure symptoms.
Women also had significantly lower exercise capacity, walking an average of 320 meters on the 6-minute walk test vs. 411 meters for men. Their median blood level of NT-proBNP, a marker of heart stress, also was significantly higher: 2,574 vs. 1,632 picograms/mL.
While rates of co-occurring conditions were generally comparable between sexes, valvular heart disease was significantly more common in women (28.8% vs. 17.5%). Kidney-related blood tests generally favored women: they had lower creatinine and slightly higher estimated kidney filtration, although chronic kidney disease stages were similar between sexes.
Women were significantly less likely than men to be prescribed Vyndamax (tafamidis), an ATTR-CM treatment.
To evaluate outcomes, the researchers looked at rates of major adverse cardiac events (MACE), a composite measure that includes hospitalization for heart failure and death from any cause.
Statistical analyses showed that, over a median follow-up of about two years, women were significantly more likely, by 86%, to experience MACE than men.
Analyses of the individual MACE components showed that “women experienced a significantly higher incidence of [heart failure] hospitalization and a trend toward higher mortality compared with men, particularly within the first 2 years of follow-up,” the researchers wrote.
Sex was not an independent predictor of outcomes
Further statistical analyses that adjusted for potential influencing factors identified several independent predictors of MACE, including older age at diagnosis, higher NT-proBNP, poorer kidney function, and a lower proportion of blood pumped from the heart with each contraction. However, “female sex was not independently associated with MACE,” the team wrote.
In other words, the data suggest that women with ATTR-CM tend to have worse outcomes, but their early disadvantage appears to be driven mainly by their older age and more advanced disease at diagnosis, rather than by sex itself.
“Our data suggest that sex-related differences in ATTR-CM may be, at least partly, related to delayed diagnosis and more advanced disease stages in women, rather than purely reflecting intrinsic biological differences,” the researchers wrote. This finding “is consistent with existing evidence and reflects patterns observed across a broad spectrum of cardiovascular diseases, in which women tend to seek medical care later, are older at presentation, and present with more advanced disease at the time of initial evaluation compared with men.”
These data highlight the importance of efforts to diagnose ATTR-CM earlier in women. The researchers called for more studies to define sex-specific diagnostic thresholds and imaging red flags and to better understand disease patterns in women.
“Our findings underscore the importance of early diagnosis, comprehensive [management of co-occurring conditions], and the investigation of sex-specific diagnostic thresholds and imaging red flags,” the team wrote. “Enhancing representation of women in clinical trials remains essential to better understand sex-specific disease patterns and optimize outcomes in cardiac amyloidosis.”
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