Cardiac Amyloidosis Imaging, Part 1: Amyloidosis Etiology and Image Acquisition
Amyloidosis Etiology and Characteristics
Amyloidosis is a group of diseases involving protein-based infiltrates in body tissues.
Cardiac amyloidosis was once considered rare, but noninvasive diagnostic testing has increased diagnoses.
What is Amyloidosis?
Amyloidosis is a group of diseases where protein-based infiltrates deposit in extracellular tissue space.
Proteins have many functions, such as catalyzing reactions, providing support, regulating transport, protecting against diseases, and coordinating cell signaling.
The human body has approximately 100,000 different proteins.
Proteins fold into precise shapes based on amino acid sequences, determining their function.
Proteins must maintain their shape to function correctly.
Misfolded proteins are typically disassembled and removed by proteasomes.
If misfolded proteins aren't removed, they accumulate in organs within extracellular tissue.
In amyloid disease, misfolded proteins form long, unbranched strings called fibrils resist dismantling.
Accumulation of amyloid fibrils impairs organ function.
Amyloid fibrils can deposit in any tissue or organ, leading to different clinical manifestations based on the affected organ and deposited protein.
Over 30 different amyloid diseases have been identified.
All amyloid is morphologically similar, despite the heterogeneity of organ involvement and clinical syndromes
Types of Amyloidosis
Classification is based on the abnormal protein involved and whether it is localized or systemic.
Localized amyloidosis affects a single organ, such as the skin, bladder, eyes, lungs, or brain. Alzheimer's disease is a localized form.
Systemic amyloidosis includes:
Monoclonal immunoglobulin light-chain amyloidosis (AL)
Transthyretin amyloidosis (ATTR)
Serum amyloid A amyloidosis
AL is caused by an overabundance and misfolding of light-chain proteins (antibody components produced by plasma cells).
There are two types of light chains: k and \lambda.
Light-chain fibrils can accumulate in the heart, kidneys, peripheral nerves, liver, skin, and gastrointestinal system.
AL is acquired, typically diagnosed in individuals over 50 years old, and has rapid progression.
ATTR results from the misfolding of transthyretin protein, which transports thyroxine and retinol-binding protein.
ATTR can affect multiple organs, including the heart, peripheral nerves, and autonomic nervous system.
When deposited in the autonomic nervous system, it can affect bladder, digestive, and genital function.
Serum amyloid A amyloidosis is caused by misfolding of serum amyloid A protein, which is involved in inflammatory responses.
It commonly deposits in the kidney and liver and can affect individuals at any age.
It may be involved in long-term inflammatory conditions.
Amyloidosis can be challenging to diagnose because it can affect different organs, causing a wide range of symptoms.
What is Cardiac Amyloidosis?
Cardiac amyloidosis is a systemic form where protein-based infiltrates deposit in myocardial tissue.
The accumulation of amyloid fibrils causes the myocardium to thicken and stiffen, leading to diastolic dysfunction, restrictive cardiomyopathy, and heart failure.
Cardiac amyloidosis has been identified as a primary cause of heart failure, particularly unexplained heart failure with preserved ejection fraction (HFpEF) in the elderly.
Cardiac amyloidosis is often underdiagnosed, with a delay of 2 or more years from initial presentation to diagnosis.
AL and ATTR account for approximately 95% of cardiac amyloid diagnoses.
Other forms of systemic amyloidosis rarely affect the heart.
Differentiation between AL and ATTR is essential because the therapy and prognosis differ vastly.
Untreated, both types can lead to heart failure and reduced life expectancy.
Cardiac AL
AL results from plasma cell dyscrasia, the unregulated proliferation of a single plasma cell clone.
AL prognosis depends on the number and severity of organs involved, with cardiac involvement having the worst prognosis because of its rapid clinical progression and late diagnosis.
Untreated cardiac AL has a median survival of 6 months from the onset of heart failure.
Treatment focuses on symptom management and suppressing additional light-chain production, usually involving chemotherapy and immunotherapy.
Cardiac AL is relatively rare and typically diagnosed in patients between 40 and 80 years old.
Cardiac AL can be associated with other immunoglobulin-related diseases, such as multiple myeloma.
Cardiac ATTR
Compared with cardiac AL, there is less evidence of direct toxic effects associated with cardiac ATTR.
It is subdivided into wild-type ATTR and variant (hereditary) ATTR.
Wild-type ATTR is the most common type of cardiac amyloidosis and occurs with aging.
Wild-type ATTR accounts for about 80% of cardiac amyloidosis cases. On autopsy, nearly 30% of patients over 75 years old with HFpEF without an antemortem suspicion of amyloid disease were found to have wild-type ATTR.
Wild-type ATTR has been found in 13% of hospitalized patients with HFpEF and left ventricular wall thickness greater than 1.2 cm.
Wild-type ATTR occurs predominantly in people over 70 years old and affects men more often than women.
Wild-type ATTR is clinically associated with bilateral carpal tunnel syndrome, aortic stenosis, atrial fibrillation, and other conditions resulting in increased wall thickness.
The median survival from diagnosis is 57 months.
Variant ATTR is inherited from a genetic mutation in the transthyretin gene that affects the amino acid sequence.
Over 120 variant ATTR genotypic mutations have been identified.
Worldwide, the most common mutation is V30M, which is associated more with sensory or autonomic neuropathy than with cardiomyopathy.
In the United States, the V122I mutation, which is more likely to cause cardiomyopathy, is more common. It is estimated that 2 million people in the United States are carriers and that 3%–4% of African Americans carry the gene.
Like wild-type cardiac ATTR, variant cardiac ATTR is more common in men and is usually diagnosed between the ages of 55 and 75 years old.
It is also associated with bilateral carpal tunnel syndrome along with polyneuropathy.
The median survival from diagnosis is 31 months for the V122I form and 69 months for other forms of variant ATTR.
Signs and Symptoms of Cardiac Amyloidosis
Untreated, all forms of cardiac amyloidosis result in heart failure due to the restrictive nature of the disease and diastolic dysfunction.
Many patients experience the classic symptoms of heart failure:
Shortness of breath during exertion and when lying down
Swelling in the feet, ankles, and legs
Orthostatic hypotension
Irregular heart rhythms
Lightheadedness
Abdominal distension
Overall weakness and fatigue
If amyloid is deposited in the heart valves, it can lead to regurgitation or stenosis.
It is not uncommon to discover that patients being treated for severe aortic stenosis also have ATTR.
Treatment for both types of cardiac ATTR includes the management of heart failure symptoms and arrhythmias.
New pharmacotherapeutic drugs are available that can help silence, stabilize, or break down errant proteins.
Patients may experience red flags, such as numbness, tingling, or pain in the hands or feet.
Patients with cardiac amyloidosis may have skin changes, such as thickness or easy bruising.
Some patients with AL may demonstrate purple patches around the eyes (periorbital purpura), sometimes called panda or raccoon eyes.
Macroglossia, an enlarged tongue that looks rippled along the edge, is a symptom in patients with AL.
Patients may experience increased or decreased urination, diarrhea, or constipation because AL can affect the kidneys and gastrointestinal tract.
\text{99mTc}-Pyrophosphate Scan Acquisition
Because cardiac amyloidosis eventually results in cardiac dysfunction, a debilitating disease, and because the treatment options vastly differ between ATTR and AL, it is critical to diagnose and differentiate between them.
\text{99mTc}-pyrophosphate imaging can efficiently and effectively distinguish between ATTR and cardiac AL.
Although the exact mechanism underlying \text{99mTc}-pyrophosphate uptake in cardiac amyloidosis is unknown, ATTR amyloid plaque is thought to contain a higher concentration of microcalcifications that bind with the pyrophosphate, allowing for improved uptake on nuclear cardiac imaging.
\text{99mTc}-pyrophosphate imaging has a 97% sensitivity and nearly 100% specificity for identifying cardiac ATTR when the AL form of the disease is ruled out by the serum free light-chain ratio and serum and urine protein electrophoresis with immunofixation tests.
Several radiopharmaceuticals and imaging protocols have been used for cardiac amyloidosis imaging over the past 40 years.
The American Society of Nuclear Cardiology and other professional medical societies published consensus recommendations to standardize performance and interpretation to improve quality and patient outcomes.
The primary indication for \text{99mTc}-pyrophosphate imaging is the evaluation of patients with heart failure and increased left ventricular wall thickness not associated with other conditions or reasons.
\text{99mTc}-pyrophosphate imaging is also indicated for men over 60 years old who may be African Americans or patients with HFpEF.
Patients with signs of heart failure and a history of bilateral carpal tunnel syndrome, unexplained neuropathy, or atrial arrhythmias are also candidates for \text{99mTc}-pyrophosphate imaging.
In addition, \text{99mTc}-pyrophosphate imaging is indicated to differentiate variant from wild-type cardiac ATTR in patients with a suspected or known family history of amyloidosis.
Finally, patients who are believed to have cardiac ATTR but have contraindications to cardiac MRI are candidates for \text{99mTc}-pyrophosphate imaging.
There are no known contraindications specific to \text{99mTc}-pyrophosphate imaging other than the usual nuclear medicine procedure cautions related to pregnancy, breastfeeding, and other recent nuclear medicine scans.
There are no specific patient restrictions before \text{99mTc}-pyrophosphate imaging. Patients may eat, drink, and take their medications as usual.
However, patients should be warned about the 3-hour delay between injection and imaging.
A thorough patient medical history is crucial for accurate interpretation of \text{99mTc}-pyrophosphate cardiac amyloidosis scans.
Radiopharmaceutical
A variety of \text{99mTc}-diphosphonate and pyrophosphate bone-seeking agents, specifically \text{99mTc}-pyrophosphate, \text{99mTc}-3,3-diphosphono-1,2-propanodicarboxylic acid (\text{99mTc}-DPD), and \text{99mTc}-hydroxymethylene diphosphonate (\text{99mTc}-HMDP), can be used to diagnose ATTR cardiomyopathy.
In the absence of cardiac amyloidosis or subacute myocardial infarction, these bone tracers do not accumulate in the myocardium.
Thus, radionuclide imaging can differentiate cardiac amyloidosis from other conditions that mimic it, such as hypertrophic cardiomyopathy.
Although no studies to date have directly compared the 3 tracers, the published literature suggests they can be used interchangeably.
\text{99mTc}-DPD and \text{99mTc}-HMDP are predominantly used in Europe because \text{99mTc}-pyrophosphate is not available there.
\text{99mTc}-pyrophosphate is used in the United States because the Food and Drug Administration has not approved \text{99mTc}-DPD, and there is limited access to \text{99mTc}-HMDP.
\text{99mTc}-methylene diphosphonate has a significantly lower sensitivity and should not be used for cardiac amyloid imaging.
The recommended dose is 370–740 MBq (10–20 mCi) administered intravenously.
The total radiation exposure from a 555-MBq (15-mCi) dose is approximately 3 mSv.
\text{99mTc}-pyrophosphate clears from the blood pool, with rapid uptake in the bone and myocardium.
Accumulation of \text{99mTc}-pyrophosphate in the bone continues to increase over time.
However, myocardial uptake in amyloid disease peaks at about 1 hour and then slowly begins to decline.
The \text{99mTc}-pyrophosphate blood pool clearance rate depends on bone metabolism and renal function.
The higher the bone metabolism along with normal renal function, the faster the \text{99mTc}-pyrophosphate clears from the blood pool, improving the semiquantitative and quantitative interpretation of the study.
Acquisition
After intravenous injection of the \text{99mTc}-pyrophosphate, both planar and SPECT images of the patient’s chest are obtained 3 hours later.
Imaging is usually performed on a standard dual-head g-camera using a 90° detector configuration.
Patients are imaged supine with their arms above their head.
For cameras with a large field of view, the patient’s shoulders should be near the top of the field of view to visualize the entire ribcage.
The planar images include the anterior and left lateral projections.
The SPECT acquisition should include as much of the chest as will fit within the field of view.
SPECT imaging may be performed using a 180° or 360° acquisition.
If SPECT/CT is available, CT attenuation correction is recommended.
Whole-body imaging is optional and has been shown to be of benefit, especially when imaging with \text{99mTc}-DPD or \text{99mTc}-HMDP.
Whole-body imaging can demonstrate \text{99mTc}-DPD or \text{99mTc}-HMDP uptake in the shoulder and hip girdles, a specific indicator of systemic ATTR.
Summary
The recent discovery of the sizable prevalence of cardiac amyloidosis in the population has led to a dramatic increase in the number of laboratories performing cardiac amyloidosis imaging.
The lack of published guidelines delineating standardized imaging parameters and interpretation criteria for cardiac amyloidosis imaging led to considerable study variability and the potential for misdiagnoses.
The American Society of Nuclear Cardiology, the Society of Nuclear Medicine and Molecular Imaging, and several other professional societies published consensus recommendations for performing and interpreting \text{99mTc} -pyrophosphate cardiac amyloidosis imaging.
This article, part 1 of a 3-part series, explains the etiology and characteristics of cardiac amyloid disease so that technologists understand how the intricacies of the disease affect test performance.
This article further provides a technical foundation for study acquisition.
Part 2 details how to process and quantify the images and justifies some of the technical considerations of \text{99mTc}-pyrophosphate cardiac amyloidosis imaging.
Part 3 will put acquisition and data quantification together to describe study interpretation and the diagnosis and treatment of cardiac amyloidosis.