Novel blood-based biomarkers for transthyretin amyloidosis with cardiomyopathy (ATTR-CM) in patients heart failure with preserved ejection fraction

Background Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, life-threatening disease. Recent evidence suggests that ATTR-CM may be found in up to 17% of persons affected by heart failure with preserved ejection fraction (HFpEF). Early and accurate diagnosis of ATTR-CM remains challenging with missed, delayed, or incorrect diagnosis. Lack of simple blood tests to diagnose ATTR-CM likely contribute to under- and misdiagnosis. Purpose To identify candidate biomarkers in blood that could aid in the diagnosis of ATTR-CM in HFpEF patients without a diagnosis of ATTR-CM. Methods We analyzed plasma samples from 307 participants (mean age 80.0 years, 87.6% male) belonging to the PREFER-HF study (ATTR-CM n=103; age- and sex-matched HFpEF (n=105) and non-HF control groups (n=99)) using two proteomic platforms (Olink 5K and SomaScan 11K) for biomarker discovery. Proteins capable of discriminating ATTR-CM from HFpEF cases with area under the curve (AUC) ≥0.80 in receiver operator characteristic analysis were considered candidates. Top-performing candidates were subsequently evaluated using target-specific immunoassays. Results Two proteins displayed high diagnostic performance across both proteomic platforms. Both proteins were significantly increased in ATTR-CM compared with HFpEF and non-HF controls (P<0.001 for all comparisons) and showed high accuracy for discriminating ATTR-CM from HFpEF: AUC [CI95%]: biomarker candidate 1, 0.93 [0.90-0.97] and 0.88 [0.83-0.93]; biomarker candidate 2, 0.88 [0.83-0.93] and 0.89 [0.84-0.93]; data for SomaScan and Olink, respectively. These findings were subsequently validated using immunoassays that yielded an AUC [CI95%] of 0.99 (0.95-1.0) for biomarker candidate 1, and 0.98 (0.93-1.0) for biomarker candidate 2 (Figure 1). Conclusions Blood-based proteomic analysis has revealed candidate biomarkers with the potential to aid in the diagnosis of ATTR-CM. While further validation in well-characterized research cohorts and real-world clinical populations is ongoing, the immunoassay results indicate the potential for simple blood testing with biomarker candidate 1 and 2 to assist clinical diagnosis of ATTR-CM. Such tests could substantially shorten time to diagnosis and increase detection rates, enabling earlier therapy and improved outcomes.