Rethinking Disease Progression in Transthyretin Amyloid Cardiomyopathy

The therapeutic landscape of transthyretin amyloid cardiomyopathy has evolved rapidly, with the introduction of transthyretin stabilizers and gene-silencing therapies, together with the development of investigational genome-editing approaches and amyloid-depleting therapies. These therapeutic classes target distinct biological mechanisms underlying disease progression. However, current definitions of disease progression continue to rely predominantly on clinical, biomarker, and functional measures that reflect downstream manifestations of disease rather than the specific biological processes targeted by these therapies. As therapies become increasingly mechanism-specific, a more biologically informed framework for understanding disease progression and treatment response is needed. We propose that disease progression in transthyretin amyloid cardiomyopathy can be understood as the interaction of 3 biologically distinct, yet highly interconnected, domains: amyloid precursor protein biology, amyloid burden, and organ response. These domains continuously influence one another throughout the disease course; however, distinguishing them conceptually provides a biological framework that aligns disease progression with therapeutic mechanism and biomarker development. The first domain encompasses production, stability, and amyloidogenicity of the precursor protein and represents the fundamental driver of ongoing amyloid formation. The second reflects the cumulative burden of deposited amyloid within tissues, which serves as both a determinant of prognosis and a direct therapeutic target. The third comprises the consequences of amyloid deposition, including myocardial remodelling, neurohormonal activation, cardiorenal dysfunction, and the clinical manifestations of heart failure. These domains may evolve independently, contribute differently to prognosis, and respond differently to therapy. Ultimately, the future of disease monitoring in cardiac amyloidosis lies in both measuring disease severity more precisely and defining disease biology more accurately. Together, these complementary approaches have the potential to enable mechanism-specific therapeutic guidance and truly personalized care. As treatments become increasingly mechanism-specific, monitoring strategies must evolve from tracking the consequences of disease to measuring the biological processes being targeted. The greatest advances are likely to come from biomarkers that quantify precursor protein biology, amyloid burden, and organ response. This forward-looking conceptual framework provides a conceptual foundation for aligning disease biology, therapeutic mechanisms, and monitoring strategies with the ultimate goal of enabling precision therapeutic guidance for patients with cardiac amyloidosis.