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Diagnosing Cardiac Amyloidosis: Challenges and Current Gaps in Detection

Despite the early detection of Cardiac Amyloidosis being critical for extending survival and improving quality of life (QoL), delayed and misdiagnoses are common.1 In one survey of 500 patients, for example, the average time from symptom onset to diagnosis was two years, and 31.8% reported seeing at least five healthcare professionals during this period.2 

There is no denying that the condition, which often mimics other heart diseases, is challenging to detect. But with more accessible, standardized screening and diagnostic approaches, the healthcare community could ensure more people access the right interventions at the right time. 

A Complex Diagnostic Pathway

Cardiac Amyloidosis is an infiltrative cardiomyopathy characterized by the deposition of amyloid fibrils within the myocardial extracellular matrix.3 While the two primary forms, transthyretin amyloidosis (ATTR) and light chain amyloidosis (AL), have distinct pathophysiologies, both are progressive, leading to restrictive cardiomyopathy and, ultimately, heart failure (HF). The median survival time for early-stage ATTR amyloidosis is approximately 5.8 years, compared to just 2 years in advanced stages.4 In AL, the median survival drops from 55 months at stage I, to five months at stage IV.5 

Disease modifying treatments (DMTs), such as transthyretin stabilizers, are now available, but they are most effective when initiated in the early stages of the disease.1 Early detection, then, is key to increasing survival, reducing the risk of sudden death, and improving cardiac function and QoL. But it is fraught with challenges.  

CA affects multiple systems, from cardiac to renal and neurological. This can result in symptoms that mimic other conditions, and confound initial clinical assessments. Many patients undergo numerous consultations and tests, involving burdensome hospitalizations and interventions, before CA is even considered.6,7 

The difficulties do not end once the clinical suspicion has been raised. Diagnosis is often based on echocardiographic assessment, yet common CA features, such as diastolic dysfunction, left ventricular thickening, atrial enlargement, and abnormal longitudinal strain,8,9,10 are non-specific. They often overlap with other forms of heart disease, and this can lead to mistaken diagnoses. Echocardiography remains a critical diagnostic tool but faces limitations. Lack of skilled cardiac sonographers, particularly in under-resourced areas, contributes to diagnostic inconsistencies. Additionally, there is significant variability in image acquisition, measurement, and interpretation, leading different clinicians to draw different conclusions from the same scan data. 

It is also important to remember that echocardiography itself is a highly complex, and often subjective modality. Worldwide, there is a lack of skilled cardiac sonographers to carry out and interpret the tests, particularly in under-resourced areas. What’s more, variability in image acquisition, measurement, and interpretation, is common,11 and different clinicians can draw different conclusions from the same scan data.  

CA and HFpEF

Another barrier to the early detection of CA is a lack of awareness around the link between the condition and HF with preserved ejection fraction (HFpEF). 

An estimated 14% of people with HFpEF have CA, but around two thirds remain undiagnosed.12,13,14 More than half (57%) are misclassified, often as having hypertensive cardiomyopathy or unexplained left ventricular hypertrophy, which results in delayed diagnosis, delayed treatment, and, in turn, worsening outcomes.15,16 Given that two-thirds of CA cases are estimated to go undiagnosed in HFpEF populations, systematic screening could prevent delays in intervention.  

Linking HFpEF findings to amyloidosis investigations could help identify those with CA. Yet a global survey of cardiologists found just 10% of physicians conduct systematic screening of HFpEF patients for the condition, while 24% do not consider screening for it at all.17 

Given that DMTs are now available and have shown improved outcomes when initiated early, raising awareness of CA as a potential diagnosis in people with HFpEF is essential.18,19

Towards a Solution

The lack of reliable, accessible diagnostic pathways for CA directly impacts patient outcomes. Delayed and missed diagnoses lead to frequent hospitalizations, increased symptom burden, and reduced quality of life, and advanced-stage diagnosis limits treatment options and undermines the potential efficacy of emerging therapies.7,20 Financially, delayed and missed diagnoses lead to added patient and healthcare costs due to frequent hospitalizations, repeated consultations, and invasive diagnostic procedures. 

There is a clear need for improved screening tools that can facilitate timely, accurate detection across various clinical settings, particularly in those with limited access to echocardiography expertise.  

AI-powered echocardiography can meet these needs, while integrating easily into clinical workflows, requiring minimal clinical information, and providing consistent diagnostic outcomes regardless of the site or operator. It can also perform reliably in high-risk populations, such as older HF patients, and streamline the clinical pathway, from suspicion to diagnosis, by supporting standardized diagnostic outputs.  

Harnessing the power of such solutions, then, could help the healthcare community enhance the detection, management, and care of this debilitating condition. In time, as more data on CA prevalence and AI device efficacy is gathered, it is hoped that the regulatory landscape will adapt to support broader screening capabilities. 

 

References:

  1. Wechalekar, A. D., Fontana, M., et al. (2022). AL amyloidosis for cardiologists: awareness, diagnosis, and future prospects: JACC: cardiooncology state-of-the-art review. Cardio Oncology, 4(4), 427-441.
  2. Maurer, M. S., Elliott, P., et al. (2017). Addressing common questions encountered in the diagnosis and management of cardiac amyloidosis. Circulation, 135(14), 1357-1377.
  3. Martinez-Naharro, A., Hawkins, P. N., et al (2018). Cardiac amyloidosis. Clinical Medicine, 18(2), s30-s35.
  4. Gillmore, J. D., Damy, T., et al. (2018). A new staging system for cardiac transthyretin amyloidosis. European heart journal, 39(30), 2799-2806.
  5. Kumar, S., Dispenzieri, A., et al. (2012). Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. Journal of Clinical Oncology, 30(9), 989-995
  6. Dang, D., Fournier, P., et al. (2020). Gateway and journey of patients with cardiac amyloidosis. ESC Heart Failure, 7(5), 2418-2430.
  7. Ney, S., Ihle, P., Ruhnke, T., et al. (2023). Epidemiology of cardiac amyloidosis in Germany: a retrospective analysis from 2009 to 2018. Clinical Research in Cardiology, 112(3), 401-408.
  8. Falk, R. H., Alexander, K. M., et al. (2016). AL (light-chain) cardiac amyloidosis: a review of diagnosis and therapy. Journal of the American College of Cardiology, 68(12), 1323-1341.
  9. Dorbala, S., Ando, Y., et al (2021). ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: part 1 of 2—evidence base and standardized methods of imaging. Circulation: Cardiovascular Imaging, 14(7), e000029.
  10. Kittleson, M. M., Ruberg, F. L., et al. (2023). 2023 ACC expert consensus decision pathway on comprehensive multidisciplinary care for the patient with cardiac amyloidosis: a report of the American College of Cardiology Solution Set Oversight Committee. Journal of the American College of Cardiology, 81(11), 1076-1126.
  11. Nitsche, C., Mascherbauer, K., et al. (2022). Prevalence and outcomes of cardiac amyloidosis in all-comer referrals for bone scintigraphy. Journal of Nuclear Medicine, 63(12), 1906-1911.
  12. González-López, E., Gallego-Delgado, M., (2015). Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. European heart journal, 36(38), 2585-2594.
  13. Hahn, V. S., Yanek, L. R., et al. (2020). Endomyocardial biopsy characterization of heart failure with preserved ejection fraction and prevalence of cardiac amyloidosis. Heart failure, 8(9), 712-724.
  14. AbouEzzeddine, O. F., Davies, et al. (2021). Prevalence of transthyretin amyloid cardiomyopathy in heart failure with preserved ejection fraction. JAMA cardiology, 6(11), 1267-1274.
  15. Ruberg FL, Grogan M, et al. Transthyretin Amyloid Cardiomyopathy. JACC State-of-the-Art Review. J Am Coll Cardiol. 2019;73:2872-91.
  16. Maurer, M. S., Elliott, P., et al. (2017). Addressing common questions encountered in the diagnosis and management of cardiac amyloidosis. Circulation, 135(14), 1357-1377.
  17. Shchendrygina, A., Mewton, N., et al. (2024). Cardiac Amyloidosis Screening and Management in Heart Failure with Preserved Ejection Fraction patients: an International Survey. The American journal of cardiology.
  18. Tana, M., Piccinini, R., et al. (2024). Heart Failure with Preserved Ejection Fraction and Cardiac Amyloidosis in the Aging Heart. International Journal of Molecular Sciences, 25(21), 11519.
  19. EchoGo Amyloidosis 510K FDA submission data
  20. AbouEzzeddine, O. F., Davies, D. R., et al. (2021). Prevalence of transthyretin amyloid cardiomyopathy in heart failure with preserved ejection fraction. JAMA cardiology, 6(11), 1267-1274. 

     

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