Cardiac amyloidosis is a cardiomyopathy caused by the extracellular accumulation of misfolded light chain (AL) proteins in the myocardium. These misfolded proteins are unstable, leading to further misfolding, aggregation, and deposition as amyloid fibrils in the body. More than 30 proteins can form amyloid fibrils, with classification based on the precursor protein.1 The misfolded ALs derive from the anomalous clonal propagation of plasma cells or transthyretin (TTR) proteins (previously known as prealbumin), which are synthesized by the liver and typically involved in the transportation of thyroxine and retinol-binding protein.1
Cardiac amyloidosis is underrecognized in patients with heart failure; however, recent improvements in the understanding of this disease have led to developments in diagnosis and treatment. These include noninvasive imaging modalities that can be used without the need for confirmatory endomyocardial biopsy, as well as improved therapies. Early patient identification is important, as current treatments are most effective when initiated before the development of significant symptoms of cardiac dysfunction.
Etiology and Pathophysiology
Two main etiologies of cardiac amyloidosis have been identified: light chain cardiac amyloidosis (AL-CA) and TTR cardiomyopathy (ATTR-CM).
Continue Reading
AL-CA
AL-CA is the most common form of cardiac amyloidosis. It is caused by the production of misfolded AL proteins by clonal plasma cells and the deposition of these proteins in organs, leading to dysfunction. Approximately 90% of patients with AL-CA develop cardiac involvement, 50% develop diastolic heart failure, and 75% die from heart failure complications or fatal arrhythmias.2 Cardiac dysfunction results from the deposition of AL in the extracellular space and ensuing cytotoxic events, such as apoptosis, cellular dysfunction, and oxidative stress.2 Because the symptoms of cardiomyopathy can be vague, the disease may go unnoticed.
ATTR-CM
ATTR-CM arises from the extracellular deposition of insoluble TTR amyloid fibrils in the myocardium. TTR is composed of 4 beta sheets that circulate as tetramers and serve as carrier proteins. The misfolding of these proteins results in the extracellular deposition of amyloid fibrils and consequent tissue dysfunction. The 2 main types of ATTR-CM are the wild type (ATTRwt) and the mutated or variant type (ATTRm or ATTRv).
In ATTRwt, the TTR gene is not genetically altered; however, it is considered an unstable protein that deposits in tissue. Cardiac manifestations are seen at later stages, generally in patients aged 60 years or older. A recent review found that ATTRwt was present on autopsy in approximately 25% of patients older than 80 years.2 ATTRm is the autosomal-dominant inherited point mutation in the TTR gene that causes amyloid formation. The single amino acid substitution creates an unstable tetramer and the amyloidogenicity of the change determines the ability of the transition to destabilize the tetramer.2 Manifestations of ATTRm include both neurologic and cardiac deficits. The specific mutations that result in only cardiac manifestations include Thr60Ala, Ile68Leu, Leu111Met, and Val122Ile.2 Some of these mutations are geographically specific; Leu111Met occurs in only Danish families and Val30Met in individuals from Europe, specifically in areas including Portugal, Sweden, and Majorca .2,3
Clinical Presentation
AL-CA
AL-CA can affect all organ systems except the central nervous system. Because of the vague nature of the disease, it is rarely diagnosed before symptoms present. The most common early manifestation is dyspnea on exertion, followed by peripheral edema and ascites. Other presentations include exercise intolerance, fatigue, and lower-extremity edema.
Nephrologic manifestations of AL-CA include heavy proteinuria (>0.5 g/d), composed mainly of albumin, with detectable Als.2 Renal amyloidosis can occur; a renal biopsy is necessary to confirm the diagnosis but samples from other biopsy sources may be used. Approximately 20% of patients present with peripheral nerve involvement such as bilateral carpal tunnel syndrome, and 15% may exhibit macroglossia or other pathognomonic manifestations, which are highly suggestive of AL.2 Hepatic manifestations such as hepatomegaly, evidenced by increased serum alkaline phosphatase levels, may be evaluated and diagnosed. Respiratory manifestations such as interstitial lung disease result from amyloid deposits in the interstitium. Periorbital ecchymosis in patients with heart failure is considered pathognomonic of AL-CA.
Severe hypotension precipitated by the use of angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEis) should raise suspicion of AL-CA. Physical examination is used to diagnose right-sided heart failure, including assessment for jugular venous distension with the absence of respiratory variation, displaced apical impulse due to extracellular deposition, auscultation of a loud fourth heart sound, discernable pedal edema, and hepatomegaly. Other clues warranting further evaluation include heart failure with preserved ejection fraction (HFpEF) without hypertension, recurrent embolic strokes, and an atrioventricular block.
The prevalence of AL-CA is similar across genders, with onset typically after 50 years of age. Early identification is essential, as median survival from the onset of heart failure is 6 months.2
ATTRm-CM
ATTRm-CM also presents with diverse symptoms, resulting in the potential for diagnostic delays of up to 8 years.2 Common initial symptoms include carpal tunnel syndrome, which occurs in approximately one-third of patients with ATTRm-CM, and peripheral and autonomic neuropathy.2 Autonomic dysfunction may manifest as nausea, vomiting, constipation, orthostatic hypotension, urinary retention, or sexual dysfunction. Due to the deposition of amyloid plaque in the subarachnoid space, ischemic stroke, intracerebral hemorrhage, or focal subarachnoid bleeding may occur, leading to ataxia, headache, seizures, or psychosis. Cardiovascular effects may result in slowly progressive heart failure with complications such as HFpEF, conduction block, or sudden cardiac death. Amyloid angiopathy and leptomeningeal amyloidosis may be present, but infrequently.
ATTRm-CM is more common in men than women and typically occurs in patients older than 40 years.
ATTRwt-CM
ATTRwt-CM presents with cardiac manifestations such as systolic dysfunction, atrial fibrillation, heart failure, and ventricular arrhythmias necessitating the use of an implantable cardioverter-defibrillator (ICD). Onset is insidious, with a slow gradual decrease in stamina, steady weight loss, and exercise intolerance. Other manifestations include carpal tunnel syndrome and renal insufficiency. A unique feature in 33% of patients (1 in 1000 individuals) with ATTRwt is rupture of the biceps tendon.2
ATTRwt-CM occurs more often in men than women, with onset after 70 years. The development of cardiomyopathy in older individuals should warrant suspicion of cardiac amyloidosis.4
Diagnosis and Differential Diagnosis
Cardiac amyloidosis should be considered in patients with a left ventricle wall thickness of more than 12 mm or criteria such as positive family history, peripheral neuropathy, autonomic dysfunction, proteinuria, macroglossia, ecchymosis, bilateral carpal tunnel syndrome, biceps tendon rupture, lumbar spinal stenosis, and plasma cell dyscrasia.5 Cardiac manifestations that necessitate further consideration of cardiac amyloidosis include persistently elevated biomarkers, heart failure in the presence of a nondilated left ventricle, unexplained right-sided heart failure, and aortic stenosis.5 Anomalies on electrocardiogram, echocardiogram, or cardiac magnetic resonance imaging (MRI) should warrant further workup for cardiac amyloidosis.
Specific assessment for cardiac amyloidosis may involve testing for monoclonal proteins via serum or urine and bone tracer cardiac scintigraphy scan. Follow-up with cardiac MRI and cardiac or other tissue biopsy may be indicated based on the results of the initial evaluation. For example:
- If monoclonal protein testing and scintigraphy scans are negative, then cardiac amyloidosis may be unlikely; otherwise, cardiac MRI and tissue biopsy may be warranted.
- A negative monoclonal protein testing and positive scintigraphy scan with grade 2 or 3 uptake are diagnostic for ATTR cardiac amyloidosis, eliminating the need for biopsy. If uptake is grade 1, then a biopsy may be necessary to confirm the diagnosis of ATTR.
- A positive monoclonal protein testing and negative scintigraphy scan indicate the potential for AL amyloidosis and necessitate further testing with cardiac MRI.
- Negative cardiac MRI indicates that cardiac amyloidosis is unlikely, whereas positive cardiac MRI necessitates tissue biopsy for confirmation.5
Potential for AL or ATTR or combined cardiac amyloidosis can be inferred with positive monoclonal protein testing and scintigraphy; however, it necessitates cardiac tissue biopsy for diagnostic confirmation.5 All ATTR-CM diagnoses warrant a referral to a geneticist with further testing necessary to determine prognosis, treatment choice, and screening of family members.
Treatment and Follow-Up
The prevention and management of complications associated with cardiac amyloidosis are essential. Complications include heart failure, atrial fibrillation, thromboembolism, conduction disorders, ventricular arrhythmias, and aortic stenosis. Because of the risk for significant hypotension, ACEis and ARBs should be used with caution. Discretion should also be used with digoxin because of the risk for toxicity.
Treatment for ATTRwt-CM or hereditary acquired ATTR includes tafamidis, which stabilizes TTR and prevents proteins from misfolding.5 In addition, patients with polyneuropathy may receive patisiran, which silences TTR genes and prevents the production of variant and wt TTR.5 Because of cardiac amyloidosis is a progressive disease, organ transplant may also be considered.5
An ideal approach to follow-up and serial testing of cardiac amyloidosis has not been determined. Referral to a specialist is essential.
Evidence for Diagnostic and Treatment Recommendations
Testing for monoclonal ALs and bone scintigraphy is considered a grade B recommendation for patients with cardiac amyloidosis.6 The initiation of a TTR tetramer stabilizer to reduce cardiovascular morbidity and mortality in cases of ATTRwt-CM or ATTRm-CM with New York Heart Association Class I to III heart failure symptoms is considered a grade B recommendation.6 Tafamidis provides low economic value in ATTRwt-CM and ATTRm-CM with heart failure, as its cost is more than $180,000 per quality-adjusted life year.6
Kristie Branham, BSN, RN, is an emergency department nurse interested in endocrinology, cardiology, psychiatric/mental health, and emergency medicine. She is currently enrolled in a Doctoral Family Nurse Practitioner program.
References
1. Kittleson MM, Maurer MS, Ambardekar AV, et al. Cardiac amyloidosis: Evolving diagnosis and management: A scientific statement from the American Heart Association. Circulation. Published online June 1, 2020. doi: 10.1161/CIR.0000000000000792. Errata in: Circulation. 2021;144(1):e10 and Circulation. 2021;144(1):e11.
2. Pour-Ghaz I, Bath A, Kayali S, et al. Review of cardiac amyloidosis: Presentation, diagnosis, and treatment. Curr Probl Cardiol. Published online August 20, 2022. doi:10.1016/j.cpcardiol.2022.101366
3. Damy T, Kristen AV, Suhr OB, et al. Transthyretin cardiac amyloidosis in continental Western Europe: an insight through the transthyretin amyloidosis outcomes survey (THAOS). Eur Heart J. 2019;43(5):391-400. doi:10.1093/eurheartj/ehz173
4. Motwani M, Arumugam P, Rocci A, Venetucci L. Evaluating suspected cardiac amyloidosis. JACC Case Rep. 2019;1(2):141-145. doi:10.1016/j.jaccas.2019.06.027
5. Garcia-Pavia P, Rapezzi C, Adler Y, et al. Diagnosis and treatment of cardiac amyloidosis: A position statement of the ESC working group on myocardial and pericardial diseases. Eur J Heart Fail. Published online April 7, 2021. doi:10.1002/ejhf.2140
6. Heidenreich PA, Boxkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: Executive summary: A report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. J Am Coll Cardiol. Published online April 1, 2022. doi:10.1016/j.jacc.2021.12.011
