Cardiac amyloidosis (CA) is a progressive, underrecognized disease caused by the deposition of misfolded proteins in the heart and other organs. Despite growing clinical awareness and the availability of disease-modifying therapies, diagnosis is often missed or delayed.1
CA is a known but frequently missed cause of heart failure, particularly in patients with preserved ejection fraction (HFpEF). Its symptoms often mimic more common cardiovascular conditions, leading to misclassification, prolonged investigations, and missed opportunities for treatment. Studies suggest that up to two-thirds of CA cases go undiagnosed in clinical practice.2-4 Earlier identification is critical, as treatments are most effective when initiated before significant disease progression.
A Heterogeneous and Underdiagnosed Disease
The two most common types of CA, transthyretin (ATTR) and light chain (AL) amyloidosis, have distinct pathophysiologies but share a progressive course that leads to restrictive cardiomyopathy and heart failure.
ATTR, especially its wild-type form, is underrecognized in older adults due to gradual progression and overlap with age-related cardiac changes. AL amyloidosis progresses more rapidly and is often fatal if not diagnosed early. Median survival in stage I AL is 55 months, but drops to just 5 months in stage IV.5 In ATTR, median survival falls from 5.8 years in early stages to 2 years in advanced disease.6
Symptoms often mimic more common cardiac conditions such as hypertensive heart disease, hypertrophic cardiomyopathy, or diastolic dysfunction, complicating detection. Moreover, CA frequently affects multiple systems, including the kidneys and nervous system, leading to diagnostic confusion. Many patients undergo numerous consultations and tests, involving burdensome hospitalizations and interventions, before CA is even considered.7-8
Current Diagnostic Tools – and Their Limitations
Broadly recommended diagnostic approaches for cardiac amyloidosis involve a combination of imaging, laboratory testing, and, when appropriate, tissue confirmation. Consensus guidelines typically suggest the following steps:
- Echocardiography to identify features such as increased wall thickness, biatrial enlargement, diastolic dysfunction, or abnormal longitudinal strain.9
- Bone scintigraphy (e.g., 99mTc-PYP) to detect transthyretin (ATTR) amyloid deposits in the myocardium.10
- Serum and urine testing for monoclonal proteins to evaluate for light chain (AL) amyloidosis¹¹.11
- Genetic testing, if ATTR is confirmed, to identify hereditary variants.12
These tools are often used in combination to confirm cardiac involvement and distinguish between subtypes, as no single test is definitive.
In more complex or inconclusive cases, additional modalities may be required:
- Cardiac MRI to detect extracellular expansion and diffuse fibrosis using late gadolinium enhancement.13
- Endomyocardial biopsy, still considered the gold standard when diagnosis is uncertain.14
- Scoring systems like the Increased Wall Thickness (IWT) and Transthyretin Cardiac Amyloidosis Score (TCAS) can help stratify risk, but many patients fall into indeterminate zones that may not trigger follow-up testing.15
Despite the availability of diagnostic pathways, real-world implementation is inconsistent. Echocardiography, while widely accessible, has limitations: its findings, such as increased wall thickness, impaired diastolic function, or reduced longitudinal strain, are often non-specific and overlap with other cardiac conditions such as hypertensive heart disease or hypertrophic cardiomyopathy. 16-18
Even when these features raise suspicion, echocardiography is not definitive. Interpretation depends heavily on operator expertise and institutional experience, with significant variability in image acquisition and quality.19 This can lead to different conclusions from the same data, especially in under-resourced settings with limited access.
HFpEF: A High-Risk Population Often Overlooked
One of the most significant gaps in detection lies within the HFpEF population. Studies estimate that on average 15% of patients with HFpEF have underlying cardiac amyloidosis.20 More than half are misclassified, often as having hypertensive cardiomyopathy or unexplained left ventricular hypertrophy.21-22
Symptoms like exercise intolerance, thickened LV walls, or persistent edema are frequently attributed to more common causes of heart failure. Surveys suggest fewer than 10% of clinicians routinely screen HFpEF patients for CA, while many remain unaware of its true prevalence in this group.23
Linking HFpEF findings to amyloidosis investigations could dramatically improve early detection, giving more patients access to therapies that are most effective when initiated in early stages.
Earlier Detection is Critical
Disease-modifying treatments (DMTs), such as transthyretin stabilizers, are now available and can meaningfully improve survival, function, and quality of life, but only when started early¹. Delayed diagnosis often results in irreversible organ damage, limited therapeutic windows, and increased healthcare costs due to repeat hospitalizations and unnecessary interventions.
The greatest impact will come from recognizing the signs of CA earlier, and ensuring every patient has the chance to benefit from timely diagnosis and treatment.
Screening high-risk groups, particularly patients with unexplained HFpEF, should become standard clinical practice. At the same time, embedding structured pathways and reducing variability in diagnostic assessment can support more consistent and equitable care.
References:
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2. González-López E, Gallego-Delgado M, Guzzo-Merello G, et al. Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. European Heart Journal. 2015;36(38):2585–2594. doi:10.1093/eurheartj/ehv338
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17. 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.
