Dr. Alexander is a cardiologist with advanced training in heart failure. He also works at Stanford University School of Medicine as an Assistant Professor of Cardiovascular Medicine. Dr. Alexander sees a wide range of patients and specializes in the care of severe heart failure and transplant situations. He also runs a research center that studies various types of heart failure. In this video Dr. Alexander discusses Using Bone Scintigraphy to Diagnose Cardiac Amyloidosis in Patients With a Monoclonal Gammopathy.
Link to Abstract-
When amyloid fibrils invade the myocardial interstitium, causing a stiffened myocardium and restrictive cardiomyopathy, cardiac amyloidosis (CA) develops. CA is caused by systemic light chain amyloidosis (AL) or transthyretin amyloidosis in more than 95% of cases (ATTR). A clonal plasma cell dyscrasia that produces amyloidogenic monoclonal immunoglobulins causes AL amyloidosis. These immunoglobulins then misfold and deposit in the heart, kidneys, liver, gastrointestinal tract, and peripheral nerves, among other organs (1). Transthyretin (2), a liver-derived thyroid hormone and retinol protein transporter, experiences tetramer dissociation, misfolds, and produces amyloid fibrils in various distant organs, resulting in ATTR amyloidosis (3).
It's critical to distinguish between AL and ATTR amyloidosis since their clinical outcomes and therapies are vastly different. Continued amyloid accumulation promotes greater organ damage, hence delays in diagnosis result in poorer results. Furthermore, diagnostic ambiguity may cause a delay in the start of amyloid-directed treatment.
As a result, a high index of clinical suspicion combined with adequate diagnostic sequencing can lead to an accurate and rapid diagnosis of CA. We provide a patient case that demonstrates the difficulties that can arise when 99mtechnetium pyrophosphate scintigraphy (99mTc-PYP) scanning is used inappropriately to identify ATTR-CA in a patient with suspected CA and a plasma cell dyscrasia.
Description of the Situation
A 63-year-old man with bilateral carpal tunnel syndrome reported with dyspnea on exertion, positional lightheadedness, and chest pain to an outpatient facility. He had a mildly increased troponin I level of 0.23 ng/mL during his first episode of chest pain (reference range: 0-0.09 ng/mL). He had 510 pg/mL of N-terminal pro–B-type natriuretic peptide (reference range: 100 pg/mL). In leads II, III, and aVF, an electrocardiogram indicated sinus rhythm, a right bundle branch block, and Q waves. A left ventricular ejection fraction of 55%, bi-atrial enlargement, concentric left ventricular hypertrophy, and grade II diastolic dysfunction were discovered on an echocardiography. Coronary angiography revealed that there was no evidence of obstructive coronary artery disease. The patient was prescribed furosemide, metoprolol, lisinopril, and spironolactone after being diagnosed with heart failure with preserved ejection fraction due to hypertension. However, due to hypotension, metoprolol was quickly withdrawn, and he was switched to midodrine. Despite medical treatment, the patient had many outpatient visits and was admitted to the hospital for dyspnea and chest pain on multiple occasions.
The patient was evaluated for ischemia again two years later. During exercise, an exercise treadmill test revealed no inducible ischemia but did reveal paroxysmal supraventricular tachycardia and infrequent premature ventricular contractions. In a second Zio Patch (iRhythm Technologies, Inc) investigation, nonsustained ventricular tachycardia was discovered, with the longest episode lasting 39 beats. A second coronary angiography revealed that there was no evidence of obstructive coronary artery disease. The patient's nonischemic cardiomyopathy was subsequently investigated further using cardiac magnetic resonance imaging (CMR). A left ventricular ejection fraction of 39%, modest concentric left ventricular hypertrophy, and diffuse late gadolinium enhancement with an inability to null the blood pool were all found on CMR imaging, all of which were problematic for CA.
Following these findings, the CMR report indicated that hematologic testing for monoclonal gammopathy and a 99mTc-PYP scan be conducted in parallel. An aberrant immunoglobulin G lambda monoclonal protein was discovered by serum electrophoresis with immunofixation. A serum free lambda of 152.03 mg/L (reference range: 5.71-26.30 mg/L), a serum free kappa of 8.91 mg/L (reference range: 3.30-19.40 mg/L), and a kappa:lambda ratio of 0.06 were found in serum free light chains (reference range: 0.26-1.65). When taken together, these findings point to a lambda monoclonal gammopathy. The patient also had a 99mTc-PYP scan during this time, which exhibited a heart/contralateral lung ratio of 1.47 and was read as grade 2 myocardial uptake (myocardial tracer uptake equals rib uptake) (Figure 1). However, single-photon emission computed tomography (SPECT) imaging with obvious myocardial uptake was inconclusive. His team identified him with wild-type ATTR amyloidosis based on the 99mTc-PYP scan and TTR genetic testing that came out negative for a variation.
Our center was referred to the patient for further treatment. The patient underwent an endomyocardial biopsy two months following the 99mTc-PYP scan due to the existence of a monoclonal gammopathy, which proved CA. When mass spectrometry was used to subtype amyloid, it discovered a peptide profile that was compatible with AL (lambda)-type amyloid deposition rather than ATTR amyloidosis. A later bone marrow biopsy indicated a lambda-restricted plasma cell population of 10% to 20%. As a result, the patient was diagnosed with AL-CA. The initial misdiagnosis of ATTR-CA was due to the incorrect use and interpretation of 99mTc-PYP imaging. As a result, there was a three-month gap between the initial identification of a monoclonal gammopathy and the start of AL-CA treatment.
Bortezomib, cyclophosphamide, and dexamethasone were given to the patient as an anti-plasma cell therapy. Daratumumab was later added to the mix. Hematologic remission was achieved for the patient. Despite his hematologic remission, he nevertheless had considerable limitations as a result of his cardiac condition (New York Heart Association functional class III heart failure symptoms and orthostasis, requiring midodrine).
This instance illustrates the dangers of using and interpreting 99mTc-PYP scans incorrectly during a CA examination. It also underlines the significance of early detection and therapy in AL-CA in order to reverse the myocardium's consequences of light chain toxicity and fibril deposition. For detecting ATTR amyloidosis, bone scintigraphy has emerged as a viable noninvasive alternative to endomyocardial biopsy. Endomyocardial biopsy has long been the gold standard for confirming ATTR amyloidosis histologically. This treatment, however, can result in problems like as tamponade and valvular injury, and should only be performed by experienced clinicians. Bone scintigraphy, on the other hand, is simpler to perform and more widely available in most clinical settings. As a result, bone scintigraphy may make it easier to diagnose ATTR amyloidosis, a previously underdiagnosed but curable cause of heart failure (2).
Expert guidelines and consensus recommendations underline the need of excluding AL amyloidosis when scheduling a bone scintigraphy scan because >20 percent of patients with AL-CA will have grade 2 or 3 radiotracer uptake (4,5). If a monoclonal gammopathy is ruled out via serum and urine testing, grade 2 or 3 myocardial radiotracer uptake on bone scintigraphy provides a 100 percent specificity and positive predictive value for ATTR-CA (6). It's crucial to get SPECT pictures for bone scintigraphy scans in addition to ruling out AL amyloidosis. Planar scintigraphy can result in false-positive scan results if radiotracer blood pooling occurs and is mistaken for myocardial uptake (7). According to follow-up SPECT imaging, the false-positive rate in individuals with grade 2 uptake on planar images is 64 percent due to blood pooling or a lack of myocardial uptake (8).
In situations of monoclonal gammopathy, a biopsy (e.g., endomyocardial) should be used instead of a 99mTc-PYP scan to confirm the presence of CA and correctly characterize the amyloid subtype. Because many older individuals with ATTR-CA can also have an unrelated monoclonal gammopathy, biopsy is still required in many cases in lieu of a 99mTc-PYP scan to confirm an ATTR-CA diagnosis (9).
It's critical to follow diagnostic standards to guarantee a thorough and accurate assessment of CA (10). Understanding the appropriate usage and caveats of interpreting bone scintigraphy will be critical to avoid misdiagnosis as ATTR-CA becomes more widely recognized and 99mTc-PYP scans become more extensively used. When there is a clinical suspicion of CA based on history, electrocardiography, echocardiography, CMR imaging, or biomarkers, consensus recommendations call for CA screening. Many clinical indicators were present in our patient, including intolerance to heart failure medicines and orthostatic hypotension needing midodrine. He also experienced bilateral carpal tunnel syndrome and a low-level positive troponin reading for a long time. Although ATTR was suspected, the initial step was to rule out the presence of a monoclonal gammopathy, as finding a monoclonal protein would necessitate an endomyocardial biopsy to rule for AL amyloidosis. A positive 99mTc-PYP scan must be evaluated in the context of ruling out AL amyloid while screening for a monoclonal gammopathy and undergoing 99mTc-PYP. Furthermore, whereas 99mTc-PYP planar pictures demonstrated grade 2 tracer uptake in our patient, SPECT imaging revealed no obvious myocardial uptake, increasing the possibility of a false-positive finding due to blood pool uptake. Despite the existence of a gammopathy, the patient was wrongly diagnosed with ATTR-CA because the 99mTc-PYP scan indicated radiotracer uptake. After a later endomyocardial biopsy and amyloid subtyping using mass spectrometry, the actual diagnosis of AL amyloidosis was made.
In patients with signs of monoclonal gammopathy, an endomyocardial biopsy is required for a proper diagnosis of CA. Bone scintigraphy imaging is a potentially noninvasive technology that has the potential to improve ATTR-CA diagnosis, a previously unknown but now curable cause of heart failure. A clear framework for CA evaluations, on the other hand, is critical for avoiding diagnostic delays and increasing outcomes. This is especially important for AL-CA, which has a median survival time of 6 months if left untreated (11). Our example highlights the dangers of using and interpreting bone scintigraphy imaging for CA incorrectly, as well as the significance of checking for an underlying plasma cell dyscrasia. Providers will need to follow a systematic diagnostic strategy as knowledge of CA and novel therapeutics rises, in order to minimize undue financial hardship and diagnostic delay.