Imaging Replaces Biopsy in U.S. Cardiac Amyloidosis Diagnosis

Between 2017 and 2025, the way U.S. clinicians diagnose cardiac transthyretin amyloidosis, or ATTR-CM, changed dramatically. A retrospective, descriptive analysis of the TriNetX U.S. Collaborative Network, published in EJNMMI Reports, found that the annual number of patients diagnosed with the condition rose from 59 to 2,221, while technetium-99m bone scintigraphy and cardiac magnetic resonance imaging expanded substantially in absolute terms and biopsy use steadily declined. The findings document a decisive shift toward noninvasive, imaging-based diagnosis of a disease that once required tissue sampling to confirm.

Cardiac ATTR-CM is a form of amyloidosis in which misfolded transthyretin protein deposits in the heart, causing cardiomyopathy and heart failure. It exists in wild-type and hereditary forms, and it disproportionately affects older adults. Because its symptoms overlap with common cardiac conditions, diagnosis has historically been difficult, and for many years definitive confirmation depended on biopsy demonstrating amyloid deposits in tissue. That paradigm began to change after landmark research established that bone-avid scintigraphy, when combined with the exclusion of monoclonal protein disorders, could identify the disease noninvasively with high accuracy.

The study team, led by researchers including Issam Motairek, Mazen Hanna, and Wael A. Jaber, identified patients diagnosed with wild-type or hereditary ATTR-CM between January 2017 and November 2025. They combined ATTR-specific ICD-10 codes, E85.82 and E85.2, with evidence of cardiac involvement defined by concurrent codes for cardiomyopathy or heart failure, including I43, I42.5, I42.9, and I50.x. To minimize diagnostic misclassification, they excluded patients with light-chain amyloidosis or plasma cell dyscrasias, using codes such as E85.81, C90.x, C88.x, D47.2, and D47.9, since these conditions require entirely different diagnostic and therapeutic pathways.

One methodological challenge the investigators faced is that ATTR-CM codes are frequently assigned only after confirmatory testing, entered following care at outside institutions, or applied provisionally before subtype confirmation. To address this, they used an extended diagnostic ascertainment window spanning 24 months before and 12 months after the index date, defined as the first qualifying ATTR diagnosis code. This approach was designed to reflect real-world diagnostic workflows and capture testing performed during evaluation as well as testing that preceded formal coding within the health system. Diagnostic modalities assessed included Tc-99m pyrophosphate scintigraphy, cardiac magnetic resonance imaging, and biopsy, with trends evaluated by year of diagnosis and reported as absolute counts and proportions.

The overall cohort had a mean age of 77 years and was 81 percent male. Seventy percent of patients were White, 22 percent Black, 2 percent Asian, and 2 percent Hispanic. The burden of comorbid conditions was high: 53 percent had atrial fibrillation, 38 percent chronic kidney disease, 68 percent hypertension, 49 percent chronic ischemic heart disease, 28 percent diabetes mellitus, and 26 percent obesity. The analysis drew on a growing network, with contributing U.S. health systems increasing from 17 in 2017 to 46 by 2025, which itself reflects broader recognition of the disease across the country.

Use of Tc-99m scintigraphy, the noninvasive nuclear imaging test central to current diagnostic guidelines, increased from 19 patients in 2017 to 468 in 2024 and 420 in 2025. Yet as a proportion of diagnosed patients, its use told a more complicated story: it rose from 32.2 percent in 2017 to a peak of 41.5 percent in 2019, then declined to 18.9 percent in 2025. The authors attribute this paradox primarily to a denominator effect. The number of newly diagnosed patients expanded far more rapidly than imaging capacity or access could accommodate, so even as absolute imaging volume grew, a shrinking share of patients received the test.

Cardiac MRI followed a similar absolute pattern. Use increased from 10 patients in 2017 to 341 in 2024 and 354 in 2025, while proportional use remained relatively stable at 16.9 percent in 2017, 15.6 percent in 2024, and 15.9 percent in 2025. The authors interpret this stability as growth consistent with broader increases in CMR availability rather than disproportionate adoption specific to ATTR diagnosis. Dual-modality imaging, defined as concurrent use of both Tc-99m scintigraphy and CMR within the ascertainment window, increased from 10 patients, or 16.9 percent, in 2017 to 129 patients, or 5.9 percent, in 2024 and 110 patients, or 5.0 percent, in 2025, a modest rise in absolute numbers that nonetheless represents a shrinking fraction of the growing diagnosed population.

The most striking trend was the steady decline of biopsy. Invasive histologic confirmation fell from 11 patients, or 18.6 percent of those diagnosed, in 2017 to 155 patients, or 7.1 percent, in 2024 and 124 patients, or 5.6 percent, in 2025. Combined scintigraphy and biopsy remained uncommon throughout. Collectively, the authors conclude, these findings indicate a sustained shift away from invasive histologic confirmation toward noninvasive imaging-based evaluation of cardiac ATTR-CM, a transformation they describe as major in the diagnostic approach to the disease.

The authors place these changes in scientific and clinical context. Gillmore and colleagues established the specificity of bone-avid scintigraphy when monoclonal protein disorders are excluded, showing that grade 2 to 3 myocardial uptake on Tc-99m imaging in the absence of a monoclonal protein carries 100 percent positive predictive value for ATTR-CM. The ATTR-ACT trial later confirmed tafamidis as the first disease-modifying therapy, accelerating recognition and screening. ASNC CARI guidelines now endorse imaging-based diagnosis, reducing reliance on biopsy. The authors view the shift from invasive to noninvasive diagnosis as scientifically justified and clinically appropriate, noting that eliminating the need for biopsy reduces procedural risk, improves patient access, enables earlier initiation of disease-modifying therapy, and is particularly important in an elderly, comorbid population.

The rapid expansion in case identification likely reflects a combination of increased disease awareness, earlier echocardiographic recognition of infiltrative cardiomyopathy phenotypes, and heightened clinical index of suspicion following tafamidis approval. The authors also suggest that a proportion of newly diagnosed patients may have been identified through a clinical-only diagnostic pathway, particularly in frail or elderly individuals, in which pre-test probability is sufficiently high and the therapeutic decision already made, rendering confirmatory scintigraphy less likely to alter management. Their findings align with claims-based Medicare analyses showing increased scintigraphy use and declining biopsy rates, and extend those observations through 2025, demonstrating that although absolute imaging utilization continues to increase, proportional adoption has not kept pace with rapidly expanding case identification, highlighting persistent dissemination gaps.

The study has important limitations. TriNetX data are de-identified and do not permit confirmation of imaging results, biopsy site, or diagnostic intent. Diagnostic pathways such as non-cardiac biopsy with cardiac involvement inferred by imaging may not be fully captured. Imaging or biopsy performed outside participating institutions or prior to network entry may also be underrepresented, and coding practices may vary across health systems. Furthermore, TriNetX procedure code granularity does not permit differentiation between planar scintigraphy, SPECT, and SPECT/CT acquisitions. As SPECT/CT is increasingly recognized as important for reducing false positives by distinguishing myocardial from blood-pool uptake, this distinction has implications for the interpreted diagnostic accuracy of scintigraphy in real-world practice and represents an important area for future investigation. Despite these constraints, the consistency of observed trends across a growing number of institutions supports a genuine nationwide shift in diagnostic practice.

The authors conclude that between 2017 and 2025, diagnostic evaluation of cardiac ATTR-CM shifted decisively toward noninvasive imaging, with substantial growth in Tc-99m scintigraphy and CMR accompanied by declining biopsy use. They emphasize that continued efforts are needed to ensure consistent implementation of guideline-recommended diagnostic pathways as disease recognition expands, and that targeted quality improvement initiatives will be essential to ensure that guideline-adherent imaging-based diagnosis is applied broadly and equitably across health systems. As ATTR-CM becomes an increasingly recognized cause of heart failure in older adults, the infrastructure for confirming the diagnosis will need to grow at least as fast as the population being identified.

Subject of Research: Temporal trends in diagnostic testing for cardiac transthyretin amyloidosis across U.S. health systems

Article Title: Temporal shifts in diagnostic testing for cardiac amyloidosis across U.S. health systems

Article References: Motairek, I., Abadie, B., Higgins, A., Jawad, Z. N., Bhat, P., Rubio, A. C., Hanna, M., & Jaber, W. A. (2026). Temporal shifts in diagnostic testing for cardiac amyloidosis across U.S. health systems. EJNMMI Reports, 10(1), Article 29. https://doi.org/10.1186/s41824-026-00316-5

Image Credits: AI Generated

DOI: 10.1186/s41824-026-00316-5

Keywords: cardiac amyloidosis, ATTR-CM, transthyretin amyloidosis, technetium-99m scintigraphy, cardiac MRI, biopsy, TriNetX, diagnostic imaging, health systems, retrospective analysis, heart failure, guidelines