Rethinking Disease Progression in Transthyretin Amyloid Cardiomyopathy

Abstract and IntroductionAbstractThe 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 remodeling, 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. (JACC. 2026;88:1440–1449) © 2026 Published by Elsevier on behalf of the American College of Cardiology Foundation.IntroductionThe therapeutic landscape of transthyretin amyloid cardiomyopathy (ATTR-CM) has undergone a remarkable transformation. Within a decade, the field has evolved from having no disease-modifying therapies to a rapidly expanding therapeutic pipeline encompassing approved transthyretin stabilizers and gene-silencing therapies, together with investigational genome-editing approaches and amyloid-depleting therapies.[1]In parallel, there has been evolution of the conceptual framework used to assess disease progression. Recently proposed multidomain criteria define progression through deterioration across clinical, biomarker, and functional domains.[2-4] Although current progression criteria remain highly valuable because they are simple, widely available, and readily applicable in routine clinical practice, these measures predominantly reflect downstream consequences of disease rather than the underlying biological processes driving it.A complementary perspective is therefore to consider disease progression according to the biological mechanisms driving it. These mechanisms may operate simultaneously, emerge sequentially, or vary in importance across disease stages and between individuals. Importantly, these biological pathways are now the targets of distinct therapeutic approaches.[1] As a result, similar clinical trajectories may arise from fundamentally different pathophysiological processes, whereas therapies with markedly different mechanisms of action may influence the same clinical endpoints. This disconnect between biological activity and clinical manifestations highlights the need for a more mechanistic framework for understanding disease progression in ATTR-CM.The emergence of multiple therapeutic classes has made this distinction increasingly relevant. Treatments that target the transthyretin (TTR) protein itself (through stabilization, gene silencing, or genome editing), amyloid-depleting therapies, and conventional heart failure treatments each target different components of the disease cascade and may therefore exert fundamentally different biological effects. Yet, current definitions of disease progression largely rely on common downstream clinical, biomarker, and functional endpoints. As therapeutic strategies become increasingly mechanism-specific, a more nuanced framework that explicitly links disease biology, therapeutic mechanisms, and disease monitoring is needed.Three Domains of Disease Progression. We propose that progression in cardiac amyloidosis can be understood as the interaction of 3 interconnected but biologically distinct domains: amyloid precursor protein biology; amyloid burden; and organ response, the latter encompassing myocardial remodeling, neurohormonal activation, cardiorenal dysfunction, and the clinical manifestations of heart failure (Figure 1). Although these domains are closely linked, they may evolve at different rates within the same patient. Importantly, each domain can now be targeted by distinct therapeutic strategies.FIGURE 1 3 Biological Domains of Disease Monitoring in Cardiac AmyloidosisProposed framework linking disease monitoring to the biological target being treated in cardiac amyloidosis. Domain 1 (precursor protein biology) focuses on transthyretin (TTR) production, stability, and clearance and is directly linked to therapies that modify TTR availability. Domain 2 (amyloid burden) focuses on quantification of tissue amyloid and is directly linked to amyloid-depleting therapies. Domain 3 (downstream organ response) captures the consequences of amyloid deposition, including heart failure, symptoms, functional capacity, and cardiorenal dysfunction, and remains essential for clinical management and risk stratification. As therapies become increasingly mechanism-specific, monitoring strategies should increasingly align with the biological target being treated. 6MWT = 6-minute walking test; ANP = atrial natriuretic peptide; BNP = B-type natriuretic peptide; CMR = cardiac magnetic resonance; eGFR = estimated glomerular filtration rate; EQ-5D = EuroQol 5-Dimension; KCCQ = Kansas City Cardiomyopathy Questionnaire; NT-proBNP = N-terminal pro–B-type natriuretic peptide; PET = positron emission tomography; SNS–RAAS = Sympathetic Nervous System and Renin–Angiotensin–Aldosterone System.Domain 1: Amyloid Precursor Protein Biology. The first domain is the biology of the amyloid precursor protein itself, including its production, circulation, stability, and fibrillogeneicity. This represents the initiating and propagating matter in all forms of systemic amyloidosis and is a biological process shared across the entire amyloid spectrum.In AL, AA, and transthyretin amyloidosis (ATTR), the precursor proteins are immunoglobulin light chains, serum amyloid A protein, and transthyretin, respectively. The therapeutic principle across all forms of amyloidosis is remarkably consistent: reducing production of the amyloidogenic precursor protein improves outcomes.[5] In AA amyloidosis, survival strongly correlates with the degree of suppression of serum amyloid A protein concentration. In AL amyloidosis, the depth of free light chain reduction following chemotherapy is the key modifiable determinant of prognosis, with progressively better outcomes observed as patients move to deeper degrees of free light chain suppression. The central lesson from both diseases is that disease progression is fundamentally driven by ongoing amyloid production.This paradigm now underpins the modern treatment landscape of ATTR amyloidosis.[1] Transthyretin silencers and genome-editing approaches reduce precursor protein production, whereas transthyretin stabilizers inhibit tetramer dissociation and subsequent fibrillogenesis.[1] Although these therapies act through different mechanisms, they ultimately target the same biological domain, ie, reduction of new amyloid production. However, precursor protein biology in ATTR-CM is determined not only by circulating transthyretin concentration but also by factors intrinsic to transthyretin itself, including variant-specific amyloidogenicity, tissue tropism, fibril composition, and the propensity to generate toxic prefibrillar species. These biological characteristics influence the efficiency with which transthyretin is converted into amyloid and contribute to the marked heterogeneity in disease progression observed across ATTR genotypes compared with wild-type ATTR-CM.DOMAIN 2: AMYLOID BURDEN. The second domain is the burden of deposited amyloid within tissues. Unlike precursor protein biology, which reflects ongoing amyloidogenic activity, amyloid burden reflects cumulative disease, the net result of sustained precursor protein production, misfolding, aggregation, and extracellular deposition over time.[1]Suppression of precursor protein production reduces future fibril formation but does not directly reverse established tissue infiltration. Consequently, disease activity and disease burden represent related but distinct dimensions of amyloid pathobiology. And, although conceptually distinct, precursor protein biology directly influences tissue amyloid burden by determining the rate of ongoing amyloid formation, illustrating the close biological interaction between these domains.This principle is evident across both AL and ATTR amyloidosis. In AL amyloidosis, the depth of hematological response remains the dominant therapeutic determinant of outcome. However, recent data demonstrate that the prognostic impact of a given hematological response is strongly modulated by the extent of preexisting cardiac amyloid infiltration.[6] Patients with limited myocardial amyloid burden derive favorable outcomes even when deep hematological responses are achieved later, whereas those with more extensive infiltration require earlier and more profound suppression of circulating free light chains to achieve comparable survival.[6] Thus, the burden of deposited amyloid modifies the relationship between precursor protein suppression and outcome, highlighting its independent biological and prognostic significance.A similar paradigm is increasingly apparent in ATTR cardiomyopathy.[7] Across the full spectrum of disease, myocardial amyloid burden demonstrates a strong, continuous, and independent association with mortality. Risk increases progressively with increasing infiltration, even after adjustment for established biomarkers, functional status, and conventional measures of disease severity. Importantly, this relationship persists in the contemporary therapeutic era, suggesting that prognosis is not determined solely by ongoing transthyretin amyloidogenesis but also by the burden of preexisting myocardial amyloid deposition.Taken together, observations from AL and ATTR amyloidosis support a unifying biological concept: precursor protein biology and tissue amyloid burden represent complementary but distinct determinants of disease progression. Whereas precursor protein availability governs future fibrillogenesis, accumulated amyloid burden reflects the established pathological substrate upon which subsequent disease evolution occurs.The therapeutic implications are substantial. Historically, disease-modifying therapies in both AL and ATTR amyloidosis have primarily targeted precursor protein biology and therefore acted by reducing ongoing and future amyloid accumulation.[1] The development of investigational amyloiddepleting therapies introduces a potentially different therapeutic paradigm in which the deposited fibril burden itself becomes the principal therapeutic target.[1]Domain 3: Neurohormonal and Myocardial Response. The third domain encompasses the myocardial and systemic consequences of amyloid deposition, including ventricular dysfunction, neurohormonal activation, cardiorenal dysfunction, and the clinical manifestations of heart failure. Neurohormonal activation may begin early during disease evolution and is likely influenced by both precursor protein biology and tissue amyloid deposition. However, its relative contribution to disease progression generally increases as myocardial injury, remodeling, and heart failure become established.The third domain should therefore not be viewed simply as a consequence of amyloid accumulation, but as an increasingly important determinant of disease progression and clinical outcome. Although initially triggered by precursor protein biology and tissue amyloid deposition, myocardial dysfunction, neurohormonal activation, and cardiorenal impairment may subsequently contribute independently to disease progression and represent important therapeutic targets in their own right. This concept becomes increasingly relevant as the relative contribution of the 3 biological domains evolves across the disease course and different therapeutic strategies target different mechanisms. Accordingly, therapeutic strategies targeting organ response have become an increasingly important component of patient management, complementing therapies directed at precursor protein biology and amyloid burden. A patient may achieve profound suppression of precursor protein production and even reductions in amyloid burden while continuing to experience persistent heart failure, atrial dysfunction, renal impairment, or advanced neurohormonal activation. Conversely, therapies targeting downstream organ response, including diuretic agents, sodium-glucose cotransporter 2 inhibitors, and selected heart failure therapies, may improve symptoms and clinical outcomes without directly altering precursor protein biology or amyloid burden. This concept is supported by emerging observational evidence that supports the use of sodium-glucose cotransporter 2 inhibitors[5] in ATTR-CM and mineralocorticoid receptor antagonists, whereas the role of other conventional heart failure therapies, β-blockers and renin-angiotensin system inhibitors, remains less well established and may vary according to disease stage and patient phenotype.Together, these observations suggest that disease progression in cardiac amyloidosis is not a single process but the result of dynamic interactions among precursor protein biology, accumulated amyloid burden, and the myocardial and systemic response to both. Although presented separately for conceptual clarity, these domains should not be considered independent biological entities. Rather, they evolve dynamically, they interact continuously, and their relative contribution to disease progression changes over time and between patients.Aligning Monitoring With MechanismAligning Monitoring With MechanismDomain 1: Monitoring Precursor Protein Biology.The strongest precedent for mechanismspecific monitoring comes from the history of systemic amyloidosis itself. In both AA and AL amyloidosis, some of the greatest improvements in patient outcomes were not driven solely by the development of effective therapies, but by the ability to measure the biological effect of those therapies and use that information to guide treatment decisions.[8]In AA amyloidosis, the recognition that ongoing serum amyloid A protein (SAA) production was the fundamental driver of amyloid deposition transformed disease management.[8] As therapies capable of suppressing inflammation became available, it became increasingly apparent that the magnitude of SAA reduction was tightly linked to outcome. Patients who achieved normalization of SAA concentrations experienced the best survival, whereas progressively higher levels of residual SAA were associated with progressively worse outcomes. Importantly, measuring SAA did not simply provide prognostic information; it provided a therapeutic target. Treatment strategies evolved from controlling symptoms to those achieving maximal suppression of SAA, the precursor protein responsible for amyloid formation.A remarkably similar story unfolded in AL amyloidosis.[8] Initially, treatment success was judged largely by clinical changes. However, as the biology of the disease became better understood, assays developed to measure concentration of circulating free immunoglobulin light chains emerged as a highly meaningful indicator of disease activity. It subsequently became apparent that survival improved incrementally in proportion to the depth of free light chain reduction, establishing suppression of the amyloid precursor protein as the principal therapeutic target. The depth of precursor suppression became the major determinant of prognosis and therapeutic decision-making, and serial free light chain measurement is now central to the management of AL amyloidosis.Historically, circulating transthyretin concentrations received relatively little attention because therapeutic options were limited. However, contemporary therapies differ substantially in their effects on serum transthyretin levels, both between therapeutic classes and between individual patients.[1] As a result, the changes may become an increasingly important biological variable to consider when evaluating disease activity and treatment response.Similar to the evolution seen in AL and AA amyloidosis, where progressively deeper suppression of amyloid precursor protein production translated into improved outcomes, the expanding therapeutic landscape in ATTR amyloidosis raises the possibility that circulating transthyretin concentrations may also carry important biological and clinical information. Unlike AL and AA amyloidosis, however, ATTR therapies exert different effects on circulating precursor protein levels.[1] Whereas genesilencing and genome-editing therapies reduce circulating transthyretin concentration by suppressing hepatic production, TTR stabilizers increase it by stabilizing the protein in the native conformation. Consequently, changes in circulating transthyretin concentration cannot be interpreted in isolation but rather in the context of the therapeutic mechanism being employed.Recent data demonstrate an association between treatment-related changes in circulating transthyretin and prognosis in ATTR-CM, supporting its potential as a biomarker of biological response. However, whether these changes should be used to guide treatment decisions in individual patients remains unknown and requires prospective validation.Domain 2: Monitoring Amyloid Burden. The second domain concerns the direct quantification of amyloid burden itself. Here, perhaps the most informative precedent comes not from amyloidosis but from transfusion-dependent thalassemia, where the ability to measure the pathological substrate targeted by therapy fundamentally transformed clinical care.[9,10]In transfusion-dependent thalassemia, effective iron chelation therapies were available long before clinicians could reliably quantify myocardial iron burden. Treatment was therefore guided by imperfect surrogates such as serum ferritin and hepatic iron concentration, neither of which accurately reflected cardiac iron loading.The introduction of T2* cardiovascular magnetic resonance fundamentally changed this paradigm. For the first time, clinicians could directly quantify myocardial iron burden noninvasively, and T2* measurements rapidly proved to be much more than a diagnostic tool. Myocardial T2* demonstrated a strong and graded relationship with prognosis, with progressively lower T2* values associated with increasing risks of heart failure, ventricular arrhythmias, and death. Equally important, myocardial iron burden was shown to be modifiable. Intensification of chelation therapy resulted in improvements in T2*, recovery of ventricular function, and improved outcomes. The field therefore evolved from administering chelation therapy according to standardized protocols to individualizing treatment according to the amount of myocardial iron present. In retrospect, the major advance was not simply the availability of chelation therapy, but the combination of effective therapy with a quantitative biomarker capable of measuring its biological target.Cardiac amyloidosis may now be approaching a similar inflection point. For many years, therapies in both AL and ATTR amyloidosis primarily targeted precursor protein biology, making suppression of amyloid production the principal therapeutic objective. However, the emergence of amyloid-depleting therapies fundamentally changes the therapeutic landscape. If therapies capable of safely and effectively removing existing amyloid deposits prove beneficial in ongoing clinical trials, the burden of deposited amyloid itself will become a critical therapeutic target.Extracellular volume (ECV) mapping by cardiovascular magnetic resonance currently represents the most mature quantitative approach for assessing myocardial amyloid burden. As occurred with T2* imaging in thalassemia, the greatest value of these techniques may ultimately lie not simply in diagnosis, but in identifying patients most likely to benefit from amyloid-depleting therapies, monitoring biological response, guiding treatment intensity, and individualizing long-term management. The lesson from thalassemia is clear: once effective therapies become available, the ability to quantify the therapeutic target becomes central to optimizing their use.Domain 3: Monitoring myocardial response. The third domain encompasses the consequences of amyloid deposition, including myocardial dysfunction, chamber remodeling, neurohormonal activation, heart failure progression, arrhythmias, and symptoms. This is currently the domain most familiar to clinicians because it represents the HF-related mechanisms.However, this domain differs fundamentally from the previous two because it reflects biological consequences rather than the primary disease substrate itself. Unlike precursor protein biology and amyloid burden, there is currently no direct method for quantifying the entirety of this downstream response. Instead, clinicians monitor individual components, such as natriuretic peptide levels, functional capacity, and quality of life, of a large pathological cascade. Management largely relies on optimization of heart failure with preserved ejection fraction therapies together with careful management of congestion and rhythm disturbances.Consequently, monitoring within this domain remains focused on clinical optimization rather than precise biological targeting. These measures remain critically important because they reflect how patients feel and function, but they provide only a partial view of the broader myocardial response to amyloid deposition. At present, this remains the least biologically specific of the 3 domains.Toward Biomarkers That Improve Clinical OutcomesToward Biomarkers That Improve Clinical OutcomesBiomarker development follows a hierarchy of evidence, progressing from technical validation and biological plausibility to demonstration of prognostic value and, ultimately, evidence that biomarkerguided treatment improves patient outcomes (Figure 2). Although many biomarkers achieve early stages of development, relatively few demonstrate true clinical impact by changing management. A biomarker may correlate with disease severity, track progression, or predict prognosis yet still fail to influence therapeutic decision-making. The ultimate value of a biomarker therefore lies in its ability to identify actionable biology and guide intervention. An illustrative example is the serum free light chain assay in AL amyloidosis, which serves as a diagnostic biomarker, provides prognostic information, and directly guides therapy by quantifying the biological target of treatment.FIGURE 2 From Biomarker Discovery to Clinical Impact: A Hierarchy of Evidence for Biomarker Development and Clinical AdoptionProposed hierarchy of evidence required for biomarkers to achieve their principal clinical aims: diagnosis, prognosis, and guiding therapy through monitoring treatment response. Biomarkers progress from analytical development and biological validation to demonstration of diagnostic performance, prognostic value, and the ability to monitor disease and treatment (Rx)-related changes. The highest level of evidence is reached when biomarker-guided treatment decisions improve patient outcomes.Within this framework, circulating transthyretin currently represents the leading candidate biomarker of precursor protein biology, whereas ECV mapping is the most mature quantitative biomarker of amyloid burden. Biomarkers of organ response, including natriuretic peptides, functional capacity, and patient-reported outcomes, remain indispensable for clinical management but primarily reflect the downstream consequences of disease. Analogous to the role of serum free light chains in AL amyloidosis, biomarkers of precursor protein biology and amyloid burden have the potential to directly inform mechanism-specific therapeutic strategies by quantifying the biological processes targeted by different therapeutic classes. In contrast, biomarkers of organ response principally reflect the clinical consequences of disease and provide information on whether a patient is improving or deteriorating, but offer limited insight into the underlying biological mechanisms or adequacy of target engagement.Importantly, biomarkers should not be viewed as belonging exclusively to a single biological domain. For example, although ECV primarily reflects myocardial amyloid burden, the extent of amyloid infiltration is itself a major determinant of subsequent myocardial remodeling, dysfunction, and neurohormonal activation, such that ECV also has important prognostic implications for organ response.Future advances are likely to refine biomarkers across all 3 domains. Within the precursor protein domain, measurements of misfolded transthyretin species, oligomeric intermediates, or other prefibrillar aggregates may provide a more direct assessment of amyloidogenic activity. An important unmet need is the development of biomarkers that quantify the conversion of circulating transthyretin into deposited amyloid, because the relationship between precursor protein levels and tissue amyloid burden remains incompletely understood and may vary substantially across disease stages, genotypes, and individual patients. Within the amyloid burden domain, extracellular volume by CT, amyloid positron emission tomography imaging, and artificial intelligence–enabled echocardiographic techniques that generate surrogate estimates of ECV may provide scalable alternatives. Equally important will be the continued development of biomarkers capable of characterizing fibrosis, inflammation, myocardial recovery, neurohormonal activation, and cardiorenal dysfunction within the organ response domain.An important implication of this framework is that disease progression is not only mechanism-specific, but also treatment-modifiable and stage-dependent (Figure 3). As the relative contribution of precursor protein biology, accumulated amyloid burden, and downstream organ response changes throughout the disease course, the biological process driving progression, and therefore the process most amenable to therapeutic modification, is also likely to evolve. In earlier disease, when ongoing ATTR production contributes proportionally more to overall risk, therapies targeting precursor protein biology, including transthyretin stabilizers and genesilencing therapies, would be expected to exert their greatest relative impact. Conversely, as disease progresses and the burden of established amyloid deposition and downstream organ dysfunction become increasingly dominant, reducing further ATTR production alone may have a more limited influence on overall disease progression. In this setting, therapies capable of removing existing amyloid deposits may become increasingly important, particularly when combined with continued suppression of ATTR production. Although this hypothesis requires prospective validation, it provides a biological framework that is broadly consistent with observations from contemporary ATTR-CM clinical trials, including ATTR-ACT (Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy), HELIOS-B (A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy), ATTRibute-CM (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy) and CARDIO-TTRansform (a phase 3 study evaluating eplontersen in patients with transthyretin-mediated amyloid cardiomyopathy), in which treatment effects appear consistent with the concept that the dominant biological drivers of disease progression evolve across the disease course.FIGURE 3 Mechanistic Drivers of Disease Progression and Stage-Dependent Impact of Disease-Modifying Therapy in Transthyretin AmyloidosisConceptual framework illustrating how the relative contribution of ATTR production (blue), existing amyloid deposits (green), and downstream organ response (purple) changes across the disease course. The red arrow represents overall disease progression (overall risk). The figure illustrates the hypothesis that disease progression is mechanism-specific, treatment-modifiable, and stage-dependent: production-lowering therapies have their greatest impact earlier in the disease course, whereas amyloid-depleting therapies are expected to become increasingly important as established amyloid burden drives progression. Arrow lengths are illustrative only.Ultimately, the future of disease monitoring in cardiac amyloidosis lies not in measuring disease severity more precisely, but in defining disease biology more accurately. As therapeutic options expand, the central question will no longer be whether a patient is progressing, but which biological process is driving that progression and whether it is being adequately targeted by therapy. Biomarkers will therefore need to evolve from tools of diagnosis and prognostication to tools that characterize biological activity, identify the dominant drivers of disease, and guide mechanism-specific intervention. The greatest advances are likely to arise from integrating biomarkers of precursor protein biology, amyloid burden, and organ response into a unified framework that enables personalized disease monitoring and therapeutic decision-making. In this paradigm, the ultimate goal is not simply to predict outcomes, but to improve them and enable more rational, biologically informed therapeutic decisionmaking.