Cardiac Amyloidosis: Expanding Awareness to Optimize Diagnosis (2024)

Corresponding Author

Cardiac Amyloidosis: Expanding Awareness to Optimize Diagnosis (1)

Open in a separate window

Key words: cardiac amyloidosis, heart failure

Cardiac amyloidosis results in a restrictive cardiomyopathy caused by extracellular deposition of proteins in the myocardium. The proteins have an unstable structure that causes them to misfold, aggregate, and deposit as amyloid fibrils. The origin of the misfolded protein in cardiac amyloidosis is typically either monoclonal immunoglobulin light chains (AL) from an abnormal clonalproliferation of plasma cells, or transthyretin amyloidosis (ATTR), a liver-synthesized protein that is normally involved in the transportation of the hormone thyroxine and retinol-binding protein.

ATTR amyloidosis is more common than AL amyloidosis and can be inherited as an autosomal dominant trait caused by pathogenic variants in the transthyretin gene TTR (ATTRv) or by the deposition of wild-type transthyretin protein (ATTRwt). Historically, median survival after diagnosis in untreated patients is poor: 2.5years for ATTRv caused by the TTR Val122Ile (or pV142I) mutation, and 3.6years for ATTRwt.1, 2, 3

Several critical advances in the diagnostic approach, coupled with approval of effective therapies, have elevated cardiac amyloidosis to a position of diagnostic prominence.4 First, imaging techniques and monoclonal protein testing now allow for accurate noninvasive diagnosis of ATTR cardiac amyloidosis5 without the need for confirmatory endomyocardial biopsies. Second, observational studies indicate that ATTR cardiac amyloidosis may be under-recognized in a significant proportion of patients with heart failure.6,7 Third, prompt implementation of therapeutic interventions, namely tafamidis, can improve survival, physical function, and/or quality of life.8,9

With these advances over the past decade, there has been a substantial increase in diagnosis of ATTR cardiac amyloidosis, with more patients diagnosed at an earlier stage of the disease with substantially lower mortality over time.10 The impact of increased awareness on prompt recognition, appropriate diagnosis, and timely treatment also can be inferred from comparison of outcomes in the 2 landmark clinical trials in ATTR cardiac amyloidosis. The Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT) enrolled patients from December 2013 through August 2015.9 After 30months, 42.9% of patients receiving placebo had died, compared with 29.5% of patients receiving tafamidis. In contrast, the Efficacy and Safety of AG10 in Subjects with Transthyretin Amyloid Cardiomyopathy (ATTRibute-CM) trial enrolled patients from April 2019 through October 2020 and, after 30months, 24.2% of patients in the placebo group had died, compared with 17.8% of patients receiving acoramidis.8 The fact that patients in the placebo group in ATTRibute-CM had 30-month mortality that was lower than that of patients in the treatment group in the ATTR-ACT trial suggests improvements in other aspects of amyloid care over the ensuing almost 5years between trial enrollments, including earlier diagnosis.

Currently, the only evidence-based, guideline-recommended, and FDA-approved therapy for ATTR cardiac amyloidosis is tafamidis,9 a TTR stabilizer, with promising clinical trial findings for acoramidis another stabilizer.8 Because TTR stabilizers inhibit the dissociation of the stable TTR tetramers into monomers, an essential step in fibril formation and subsequent tissue deposition, these agents do not reverse disease; once initiated, they only slow progression. Thus, early recognition and diagnosis of ATTR amyloidosis afford patients the greatest chance that treatment will favorably impact survival and prevent potentially irreversible loss of physical function and quality of life. In fact, only less symptomatic patients, those with New York Heart Association class 1 to 2symptoms at initiation, had better outcomes when treated with tafamidis in the ATT-ACT trial.9

If the key to better outcomes is early diagnosis, and early diagnosis requires increased awareness, then a crucial factor to prompt diagnosis of amyloidosis is recognition of the typical affected demographic. Observational studies unequivocally demonstrate that ATTR amyloidosis is most commonly diagnosed in those over age over 70years and more often in men than in women.3 However, this means that patients under 70years of age, as well as women, may experience delays in diagnosis. Given this, a better understanding of the age and sex differences in clinical manifestations may reduce demographic diagnostic bias and allow for increased awareness and earlier treatment in typically underrepresented groups. In the context, the study by Mora-Ayestaran etal11 in this issue of JACC: Advances used THAOS (Transthyretin Amyloidosis Outcomes Survey) examines the age- and sex-specific clinical manifestations of ATTR cardiac amyloidosis in the hopes that this information could increase clinicians’ awareness and recognition of cardiac amyloidosis.

THAOS is the largest global, longitudinal, observational registry of patients with ATTR amyloidosis, initiated in 2007 and comprising 53 centers from 15countries. The authors examined 1,251 patients with ATTRwt amyloidosis and made several important observations. First, while 17.1% of patients with ATTRwt amyloidosis were under 70years of age, 23.3% of them had New York Heart Association functional class 3 to 4 symptoms. This suggests that younger patients were not diagnosed until they developed more advanced disease, perhaps due to less awareness of amyloidosis as a potential diagnosis in younger patients.

A second important observation is that while most patients with ATTRwt amyloidosis were men, the proportion of women increased with age from 4.1% in patients under 70years of age to 14.3% in patients 90years of age or greater. In fact, the longest median time from symptom onset to diagnosis was in women 70years of age, with a delay in diagnosis of 5.2years.

A third important finding was that women with ATTRwt amyloidosis had lower left ventricular wall thickness than men, though not when wall thickness was indexed by height. This observation suggests that a sex-specific wall thickness threshold for diagnosis may be necessary to avoid underdiagnosis of cardiac amyloidosis in women.

While these findings are compelling, the limitations of the current analysis must be addressed. Ofthe 1,251 patients included in the analysis, only 7 were women under 70years of age and only 5 werewomen aged 90years or older. So while numerical trends may be observed, further studies are needed to confirm these findings, especially as other studies have not demonstrated sex-specific differences in disease presentation, progression, or prognosis.12

Nonetheless, there are important lessons for clinicians from this analysis. If woman under the age of 70presents with heart failure symptoms and increased left ventricular wall thickness on echocardiogram, particularly increased wall thickness indexed to height, clinicians should not discount a diagnosis of cardiac amyloidosis. Often, there are other helpful clinical clues suggesting the diagnosis, both cardiac (aortic stenosis, atrial fibrillation) and extra cardiac (sensory peripheral neuropathy, orthostatic hypotension, carpal tunnel syndrome, lumbar spinal stenosis).13

As with most areas of medicine, judgment and experience are key to providing the best care to patients with amyloidosis. Keeping an open mind to all diagnostic possibilities is essential; a patient’s presentation should be interpreted through the lens of their other medical history and in the case of amyloidosis, seemingly disparate neurologic or orthopedic manifestations may be part of a unifying diagnosis. As this study by Mora-Ayestaran etal demonstrates, these factors should not be discounted, even if the patient does not fit the typical demographic of age and sex.

Funding support and author disclosures

The author has reported that they have no relationships relevant to the contents of this paper to disclose.

Footnotes

The author attests they are in compliance with human studies committees and animal welfare regulations of the author’s institution and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.

References

1. Grogan M., Scott C.G., Kyle R.A., et al. Natural history of wild-type transthyretin cardiac amyloidosis and risk stratification using a novel staging system. JAm Coll Cardiol. 2016;68:1014–1020. [PubMed] [Google Scholar]

2. Gillmore J.D., Damy T., Fontana M., et al. Anew staging system for cardiac transthyretin amyloidosis. Eur Heart J. 2018;39:2799–2806. [PubMed] [Google Scholar]

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. [PubMed] [Google Scholar]

4. Heidenreich P.A., Bozkurt B., Aguilar D., et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure. JAm Coll Cardiol. 2022;79:e263–e421. [PubMed] [Google Scholar]

5. Gillmore J.D., Maurer M.S., Falk R.H., et al. Non-biopsy diagnosis of cardiac transthyretin amyloidosis. Circulation. 2016;133(24):2404–2412. [PubMed] [Google Scholar]

6. Castano A., Narotsky D.L., Hamid N., et al. Unveiling transthyretin cardiac amyloidosis and its predictors among elderly patients with severe aortic stenosis undergoing transcatheter aortic valve replacement. Eur Heart J. 2017;38:2879–2887. [PMC free article] [PubMed] [Google Scholar]

7. Gonzalez-Lopez E., Gallego-Delgado M., Guzzo-Merello G., et al. Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J. 2015;36:2585–2594. [PubMed] [Google Scholar]

8. Gillmore J.D., Judge D.P., Cappelli F., et al. Efficacy and safety of acoramidis in transthyretin amyloid cardiomyopathy. NEngl J Med. 2024;390:132–142. [PubMed] [Google Scholar]

9. Maurer M.S., Schwartz J.H., Gundapaneni B., et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. NEngl J Med. 2018;379:1007–1016. [PubMed] [Google Scholar]

10. Ioannou A., Patel R.K., Razvi Y., et al. Impact of earlier diagnosis in cardiac ATTR amyloidosis over the course of 20 years. Circulation. 2022;146:1657–1670. [PMC free article] [PubMed] [Google Scholar]

11. Mora-Ayestaran N., et al. Age- and sex-related differences in patients with wild-type transthyretin amyloidosis: insights from THAOS. JACC: Adv. 2024;3 [Google Scholar]

12. Patel R.K., Ioannou A., Razvi Y., et al. Sex differences among patients with transthyretin amyloid cardiomyopathy - from diagnosis to prognosis. Eur J Heart Fail. 2022;24:2355–2363. [PMC free article] [PubMed] [Google Scholar]

13. Kittleson M.M., Ruberg F.L., Ambardekar A.V., et al. 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. JAm Coll Cardiol. 2023;81:1076–1126. [PubMed] [Google Scholar]

Cardiac Amyloidosis: Expanding Awareness to Optimize Diagnosis (2024)

FAQs

What is the life expectancy with cardiac amyloidosis? ›

The prognosis is variable and depends on the type of cardiac amyloidosis. The average survival time in untreated patients is as follows: AL (primary) 9 to 24 months, ATTR familial 7 to 10 years, senile amyloidosis 5 to 7 years, AA (secondary) amyloidosis more than ten years.

Is cardiac amyloidosis curable? ›

Most forms of cardiac amyloidosis are treatable, but curing this condition isn't always possible. The treatment also varies depending on the type of amyloidosis. In general, early detection is extremely important. Catching amyloidosis early can help long-term limit heart damage.

How fast does cardiac amyloidosis progress? ›

Though cardiac amyloidosis typically develops over several years, it can progress rapidly to a severe illness. Research has shown that there are many cardiac and non-cardiac signs that should be investigated as early as possible.

What are the red flags for cardiac amyloid? ›

Cardiac red flags are heart failure symptoms (often with preserved ejection fraction), abnormal electrocardiogram (ECG), elevated troponin and NT-proBNP, and specific findings in echocardiograms and cardiac magnetic resonance imaging (CMR).

What is the most common cause of death in amyloidosis patients? ›

Heart complications are the most common cause of death in patients with amyloidosis. The degree to which amyloidosis affects the heart is important in determining your prognosis. These amyloid deposits are in the kidneys.

What does cardiac amyloidosis feel like? ›

Cardiac amyloidosis can cause heart failure symptoms, such as shortness of breath, leg swelling, and irregular heart beat (arrhythmia), and it can lead to reduced life expectancy.

What drugs should be avoided in cardiac amyloidosis? ›

Conversely, nondihydropyridine calcium channel blockers (e.g., verapamil and diltiazem) should be avoided in patients with cardiac amyloidosis due to the negative chronotropic effects and risk of binding to amyloid fibrils that may lead to hyperphysiologic effects.

Is amyloidosis always terminal? ›

There's no cure for amyloidosis, but some types can be managed well through treatment to improve the symptoms. But for some people, amyloidosis eventually leads to organs such as your heart or kidneys no longer working properly. Your doctor will explain your treatment options and what to expect.

What is the earliest symptom in amyloidosis? ›

Signs and symptoms of amyloidosis include: Feeling very weak or tired. Losing weight without trying. Swelling in the belly, legs, ankles or feet.

Does exercise help with cardiac amyloidosis? ›

It is believed that exercise is beneficial for the general well-being of patients with amyloidosis. If there are amyloid deposits in the heart then exercise should usually be limited and light. It is important to be careful, and to exercise within limits, to avoid exhaustion.

What is the new drug for cardiac amyloidosis? ›

A new medication, tafamidis, was approved in 2018 as the first truly disease-modifying treatment for ATTR cardiac amyloidosis, and more medications have been approved for the neuropathy that often results from this disease. “All of these advancements,” Vaishnav says, “have led to a lot of excitement in the field.”

How do you stop amyloid build up? ›

However, generally, amyloid pathology can be improved through all of the lifestyle practices that we associate with good health, particularly regular exercise and a healthy diet low in sugar, alcohol and processed meats, while avoiding smoking.

What is the 5 5 5 rule for amyloidosis? ›

The TDI tracings shows the ''5-5-5'' sign (s' [systolic], e' [early diastolic], and a' [late (atrial) diastolic] tissue velocities are all <5 cm/s), which is seen in patients with more advanced cardiac amyloidosis. The dotted lines denote the 5 cm/s cut-off for systolic and diastolic tissue velocities.

What is the difference between amyloidosis and cardiac amyloidosis? ›

Amyloidosis is a collection of diseases caused when the protein amyloid abnormally deposits into one or more organs in the body. This can lead to disruption of normal organ functioning. Cardiac amyloidosis is the term used when amyloid protein deposits are found in the heart.

How rare is cardiac amyloidosis? ›

Cardiac amyloidosis is quite rare and produces symptoms very similar to other heart diseases. It is, therefore, often misdiagnosed. The disease is more common in men than in women and is rarely seen in people under age 40.

Is amyloidosis a terminal illness? ›

The condition is rare (affecting fewer than 4,000 people in the United States each year), but it can be fatal. Amyloidosis sometimes develops when a person has certain forms of cancer, such as multiple myeloma, Hodgkin's disease or familial Mediterranean fever (an intestinal disorder).

What are the symptoms of amyloidosis at the end of life? ›

Patients in advanced stages of AL amyloidosis often present with distressing symptoms of anorexia and cachexia [11]. Poor appetite, weight loss, muscle weakness, and decline in functional status are also common, most likely due to disease progression or toxicity from chemotherapy and other treatments [26].

Is amyloidosis a terminal of the heart? ›

Outlook (Prognosis)

Different types of amyloidosis can affect the heart in different ways. Some types are more severe than others. Many people can now expect to survive and experience a good quality of life for several years after diagnosis.

Top Articles
Latest Posts
Recommended Articles
Article information

Author: Foster Heidenreich CPA

Last Updated:

Views: 6174

Rating: 4.6 / 5 (56 voted)

Reviews: 95% of readers found this page helpful

Author information

Name: Foster Heidenreich CPA

Birthday: 1995-01-14

Address: 55021 Usha Garden, North Larisa, DE 19209

Phone: +6812240846623

Job: Corporate Healthcare Strategist

Hobby: Singing, Listening to music, Rafting, LARPing, Gardening, Quilting, Rappelling

Introduction: My name is Foster Heidenreich CPA, I am a delightful, quaint, glorious, quaint, faithful, enchanting, fine person who loves writing and wants to share my knowledge and understanding with you.