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Diagnosing and Treating ATTR-CM
Empowering NPs and PAs With Frontline Strategies to Recognize and Treat ATTR-CM

Released: December 30, 2025

Jill S. Waldron
Jill S. Waldron, APRN, GNP-BC
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Key Takeaways
  • Early and accurate diagnosis is essential to avoid missed or late diagnoses and enable timely disease-modifying therapy.
  • Patients with ATTR-CM are preload dependent and often poorly tolerate standard heart failure therapies.
  • ATTR-CM is progressive even with treatment, necessitating structured long-term follow-up with biomarkers and symptom assessment, early referral to experienced centers, and shared-care models to manage disease progression effectively.

In this commentary, Jill S. Waldron, APRN, GNP-BC, answers questions posed by healthcare professionals (HCPs) during a live symposium titled “First to See, First to Act: Empowering NPs and PAs With Frontline Strategies to Recognize and Treat ATTR-CM.” Many patients with transthyretin amyloid cardiomyopathy (ATTR-CM) experience delays between symptom onset and diagnosis. This is important, because current therapies can slow the progression of the disease, but they cannot reverse damage that has already occurred. Learn about important topics for patients with ATTR-CM in this activity, which addresses questions from HCPs in a recent symposium on ATTR-CM.

What is the currently recommended diagnostic algorithm for patients with ATTR-CM?

There is not 1 specific diagnostic algorithm for ATTR-CM, but each of the currently used algorithms are very similar. The main goal across all algorithms is to rule out light chain amyloidosis first, given its aggressive course and urgent treatment implications.

Evaluation begins with serum and urine immunofixation testing to assess for monoclonal light chains.  Once AL amyloidosis has been ruled out, HCPs usually proceed with noninvasive imaging, usually a technetium-based pyrophosphate (PYP) scan, although the specific tracer may vary by institution. Sometimes it is a slightly different scan depending on the tracer that is available. A positive scan in the appropriate clinical context establishes the diagnosis of ATTR-CM. If a scan is negative but clinical suspicion remains high, endomyocardial biopsy should be considered. Once ATTR-CM is confirmed, genetic testing is essential to determine whether the disease is hereditary or wild-type, as this has implications for prognosis, counseling, and family screening.

Of importance, PYP scanning should not be performed in patients with abnormal light chain studies, even if elevations are mild. In these cases, referral directly to hematology is preferred, as additional imaging may complicate interpretation. Tissue biopsy, from the heart or another involved organ, can also establish the diagnosis, but genetic testing remains a required final step to define the amyloid subtype.

What are some of the pitfalls that delay diagnosis for patients with ATTR-CM?

One of the most common causes of delayed diagnosis is incomplete execution of the diagnostic algorithm. Failing to order all appropriate tests, particularly light chain studies, can postpone both diagnosis and treatment. This is especially concerning for patients with AL amyloidosis, which constitutes a medical emergency and can be fatal within months if untreated. Although ATTR-CM generally progresses more slowly than AL amyloidosis, it remains a progressive disease, and delays still carry meaningful consequences. Missing the diagnosis may not result in immediate harm, but it does allow continued amyloid deposition and loss of functional reserve.

Additional pitfalls arise after diagnosis. Inappropriate application of standard guideline-directed medical therapy can lead to hypotension, falls, and worsening quality of life when HCPs are unfamiliar with the unique physiology of amyloid cardiomyopathy. Delayed referral to specialized centers and failure to complete genetic testing further undermine optimal care, even when the diagnosis itself has already been established.

What are the clinical red flags that should prompt an HCP to suspect ATTR-CM in the first place? How do these differ between hereditary and wild-type disease?

Heart failure is often the initial clinical signal that raises concern for ATTR-CM, particularly when symptoms are disproportionate to traditional risk factors. Atrial fibrillation is another key red flag and is more commonly encountered than other conduction abnormalities such as sinus node dysfunction or atrioventricular block. These rhythm disturbances frequently lead to pacemaker implantation, which itself should heighten suspicion. Other important clues include orthostatic symptoms, reflecting autonomic involvement, as well as extracardiac manifestations such as carpal tunnel syndrome and lumbar spinal stenosis. These orthopedic features often precede cardiac symptoms by years and are frequently overlooked.

Patients with wild-type ATTR-CM typically exhibit many or all of these red flags. Hereditary ATTR-CM, however, is more heterogeneous and mutation dependent. Some patients develop a mixed phenotype with both cardiomyopathy and polyneuropathy, whereas others experience isolated neuropathy for years before cardiac involvement becomes apparent. In these cases, peripheral neuropathy may be the earliest and most important warning sign.

What are the best practices for managing heart failure symptoms in patients with ATTR-CM? How do the management strategies differ from patients with heart failure who do not have ATTR-CM?

Patients with ATTR-CM and heart failure are preload dependent and often require higher filling pressures to maintain cardiac output. As a result, diuresis must be approached cautiously, and hypotension frequently limits standard heart failure therapies. HCPs may be tempted to reduce or stop diuretics due to low blood pressure, allowing patients to tolerate chronic congestion. However, persistent fluid overload increases hospitalization risk and may ultimately necessitate intravenous diuretics or inotropic support. Supporting blood pressure, including with agents such as midodrine when appropriate, can allow safer and more effective volume management.

Patients with ATTR-CM often do not tolerate conventional guideline-directed medical therapy well. Beta-blockers and ACE inhibitors frequently need to be reduced or discontinued. In contrast, SGLT2 inhibitors are generally well tolerated and may be particularly beneficial given the restrictive physiology of amyloid cardiomyopathy.

Arrhythmia management also differs from typical heart failure care. Atrial fibrillation tends to be persistent and recurrent, and early, aggressive treatment is often warranted. Conduction disease is common, and in patients with high pacing burdens, consideration of biventricular pacing is emerging, supported by newer directives such as the 2025 European Society of Cardiology guidelines.

How should HCPs structure long-term follow-up and monitoring for patients with ATTR-CM?

Because ATTR-CM is a progressive disease, close longitudinal follow-up is essential. In clinically stable patients, reassessment every 6 months is reasonable, with repeat measurement of NT-proBNP and high-sensitivity troponin to monitor disease trajectory. Additional laboratory testing may be performed as needed, but these biomarkers provide critical insight into progression.

Echocardiography is typically repeated 6-12 months after initiation of therapy to assess early response. Beyond that point, routine imaging is not required unless symptoms change or there is concern for complications such as valvular disease. Repeat PYP scanning is generally not recommended.

Patients with more advanced or unstable disease require closer monitoring, often every 3 months or more frequently during periods of decompensation. Shared-care models that integrate centers of excellence with local cardiologists can be particularly effective, ensuring access to specialized expertise while maintaining continuity and rapid response to acute issues.

If a monoclonal antibody is used to target amyloid beta plaques in Alzheimer's disease, what is the likelihood that this may work for cardiac and peripheral deposits of amyloid?

ATTR-CM is fundamentally different from Alzheimer’s disease and other amyloid disorders. Amyloid is not a single entity but a broad category encompassing more than 35 distinct proteins, each with unique structure and pathophysiology. Beta-amyloid plaques in Alzheimer’s disease are biologically distinct from transthyretin fibrils. Although advances in 1 amyloid field may offer conceptual insights, therapies targeting beta-amyloid are unlikely to translate directly to ATTR-CM. These conditions are best understood as biologically separate, requiring disease-specific therapeutic strategies.

Do you find that patients with ATTR-CM have symptom progression that develops over 1-5 years, or is it even slower?

The rate of progression in ATTR-CM depends heavily on whether patients are receiving disease-modifying therapy. Without treatment, decline can be rapid and dramatic, with significant loss of function occurring over as little as 12-18 months. With therapy, progression often slows substantially and may unfold over several years. Historical survival estimates of 2-5 years after diagnosis are based on older data from the early treatment era. Contemporary experience suggests that many patients now live significantly longer, with some maintaining relative stability for 8 years or more. Despite this, progression continues, and clinically meaningful worsening often becomes apparent around 3 years, even in treated patients.

Is there a specific beta-blocker that is better for patients with ATTR who have arrhythmias and also particular diuretics that are better for these patients?

When beta-blockers are necessary, metoprolol is generally preferred due to better tolerability and once-daily dosing, but at times even this is not tolerated. Carvedilol is typically avoided because of its higher risk of hypotension and twice-daily administration. Even metoprolol may need to be discontinued in patients with low blood pressure, and alternatives such as bisoprolol are used selectively.

Diuretic management is similarly individualized. SGLT2 inhibitors are often introduced first, with loop diuretics added as needed. Furosemide is commonly used initially, but many patients ultimately benefit from switching to torsemide or bumetanide due to improved bioavailability. Torsemide, in particular, is effective in patients with gut edema and can be used at relatively low doses, making it a practical option as amyloid disease advances.

Overall, successful management hinges on flexibility, close monitoring, and an appreciation for how profoundly ATTR-CM differs from conventional heart failure.

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