Cardiac amyloidosis is becoming increasingly recognized as an etiology for heart failure (HF). Most cases of amyloid cardiomyopathy will fall into one of two categories: light-chain amyloid (AL) amyloidosis resulting from misfolding of monoclonal immunoglobulin light chains or transthyretin amyloidosis with cardiomyopathy (ATTR-CM), due to misfolding of the transthyretin protein.¹

The rise of newer imaging techniques over the last few years have allowed for accurate noninvasive diagnosis of ATTR-CM. This is incredibly important given the development of multiple therapeutic agents that can improve outcomes in these patients if they are diagnosed in an early stage of disease.

A Clinical Case

Imagine you're seeing Mr. M in clinic. He's a 75-year-old man who has had multiple recent hospitalizations for heart failure with preserved ejection fraction (HFpEF). He also has a history of atrial fibrillation (AFib) on apixaban and chronic kidney disease (CKD).

His blood pressure is 100/60 mm Hg with a pulse of 70 bpm. His medical history also includes bilateral carpal tunnel syndrome. A 12-lead echocardiogram shows AFib with slow ventricular response and a right bundle branch block. His recent echocardiogram confirms a normal EF with left ventricular hypertrophy (LVH).

Pathway to Diagnosis

Many patients will see multiple providers before receiving a diagnosis of cardiac amyloidosis. In one survey, less than 50% of patients received a diagnosis within six months of experiencing symptoms and some studies estimate that patients see more than five doctors before this diagnosis is reached.^1-3

One may imagine that many older patients with HFpEF are comorbid with AFib and CKD. While this is true, it's important to keep one's eyes open for any red flags or clinical clues for cardiac amyloidosis. Some such clues are depicted in the Table. Our patient has evidence of conduction disease and has signs of LVH on his echocardiogram without systemic hypertension.

Cardiac Amyloidosis Suspected? What's Next?

Although cardiomyopathy due to AL amyloidosis is much rarer, it's essential that this be ruled out first, checking for monoclonal proteins, as the treatment pathway is significantly different and involves chemotherapeutic agents. This should include serum kappa/lambda free light chains as well as serum and urine immunofluorescence. If there's concern for a plasma cell disorder, hematology should be consulted for further diagnostic testing.

Next, cardiac scintigraphy with Tc-PYP should be performed to look for uptake. Planar imaging should be performed with SPECT to increase diagnostic performance.¹ A diagnostic algorithm from the 2023 ACC Expert Consensus Decision Pathway on Comprehensive Multidisciplinary Care for the Patient With Cardiac Amyloidosis guides next steps (Figure).

The screening for monoclonal protein ordered for Mr. M returns negative. Next, the Tc-99m PYP scan you ordered shows Grade 2/3 uptake, which is highly suggestive of a diagnosis of ATTR-CM. Then, you perform genetic testing to determine if he has a hereditary or variant ATTR or wild-type ATTR.

Exciting Treatments For ATTR-CM

When discussing the diagnosis with Mr. M, there are multiple emerging therapies in this area to highlight.

Tafamadis stabilizes the transthyretin protein and is approved for the treatment of ATTR-CM by the U.S. Food and Drug Administration (FDA). In the ATTR-ACT trial, 441 patients with ATTR-CM were randomized to tafamadis or placebo.

Patients who received tafamadis had reduced all-cause mortality (hazard ratio, 0.70) and rates of cardiovascular hospitalizations (relative risk ratio, 0.68).⁴ As such, prescription of tafamadis is a Class I recommendation in the 2022 ACC/AHA Heart Failure Guideline.⁵ Unfortunately, challenges remain with access to these medications as out-of-pocket costs can be high.

Patisiran, a TTR silencer, was studied in the setting of ATTR-CA in the Apollo B trial. Although administration of patisiran showed preserved functional capacity compared with placebo, it was not granted approval by the FDA for treatment of cardiomyopathy, although it is approved for treatment of polyneuropathy.⁶

Recently, primary results of the HELIOS-B trial evaluating the use of vutrisiran in ATTR-CM showed a 28% lower risk of all-cause mortality and recurrent cardiovascular events at 36 months compared with placebo. (Click here for more results from HELIOS-B presented at ESC Congress 2024.)

New therapeutic classes in the pipeline include antibodies and CRISPR gene editing therapies (NTLA-2001).

Heart Transplantation in Patients With Cardiac Amyloidosis

Despite new and emerging disease-modifying therapies, some patients may progress to advanced disease and select individuals with AL cardiac amyloidosis or ATTR-CA may be considered for heart transplantation.

As amyloidosis is a multisystemic disease, it's essential to investigate all extra-cardiac manifestations of disease and consider their potential impact on candidacy for heart transplantation.

For example, frailty, symptomatic orthostasis and nephrotic range proteinuria may be likely barriers to eligibility for heart transplantation.

Single-center as well as large national registry analyses have shown similar post-transplant outcomes for patients with amyloid cardiomyopathy as compared with those who received transplant for another indication. However, careful patient selection is paramount.^7-9

After heart transplantation, consideration should be given to continuation of disease-directed therapies particularly for management of extracardiac manifestations.^9,10

References

1. Kittleson MM, Ruberg FL, Ambardekar AV, et al. 2023 ACC Expert Consensus Decision Pathway on Comprehensive Multidisciplinary Care for the Patient With Cardiac Amyloidosis. J Am Coll Cardiol 2023;81:1076-1126.
2. Lousada I, Comenzo RL, Landau H, et al. Patient experience with hereditary and senile systemic amyloidoses: a survey from the Amyloidosis Research Consortium. Orphanet J Rare Dis 2015;10(Suppl 1):P22.
3. Lane T, Fontana M, Martinez-Naharro A, et al. Natural history, quality of life, and outcome in cardiac transthyretin amyloidosis. Circulation 2019;140:16-26.
4. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med 2018;379:1007-16.
5. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure. J Am Coll Cardiol 2022;79:e263-421.
6. Maurer MS, Kale P, Fontana M, et al. Patisiran Treatment in patients with transthyretin cardiac amyloidosis. N Engl J Med 2023;389:1553-65.
7. Barrett CD, Alexander KM, Zhao H, et al. Outcomes in patients with cardiac amyloidosis undergoing heart transplantation. JACC Heart Fail 2020;8:461-8.
8. Vaidya GN, Patel JK, Kittleson M, et al. Intermediate-term outcomes of heart transplantation for cardiac amyloidosis in the current era. Clin Transplant 2021;35:e14308.
9. Griffin JM, Baughan E, Rosenblum H, et al. Surveillance for disease progression of transthyretin amyloidosis after heart transplantation in the era of novel disease modifying therapies. J Heart Lung Transplant 2022;41:199-207.
10. Ambardekar AV, Fontana M, Maurer MS, et al. How to identify cardiac amyloidosis patients who might benefit from cardiac transplantation. JACC Heart Fail 2023;11:115-20.

Clinical Topics: Arrhythmias and Clinical EP, Cardiovascular Care Team, Heart Failure and Cardiomyopathies, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure

Keywords: Cardiology Magazine, ACC Publications, Heart Failure, Amyloidosis, Familial, Immunoglobulin Light-chain Amyloidosis, Cardiomyopathies, Atrial Fibrillation