Consider cardiac amyloidosis to avoid ‘missed opportunity’ of early intervention
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Interest in transthyretin cardiac amyloidosis, or ATTR-CM, has grown in part due to three areas of recent advancement: imaging, recognition of the lesser-known disease and drug approvals.
Imaging techniques can now provide accurate, noninvasive diagnosis of ATTR-CM, and researchers have learned that the diagnosis of ATTR-CM may be underrecognized in a significant proportion of patients with heart failure. Additionally, there are now FDA-approved, disease-modifying agents for the treatment of ATTR-CM, offering individuals with the condition hope for improved outcomes.
Cardiac amyloidosis is a restrictive cardiomyopathy, most commonly due to either misfolded monoclonal immunoglobulin light chains (AL) from an abnormal clonal proliferation of plasma cells, or, transthyretin amyloidosis (ATTR), a liver-synthesized transport protein. ATTR-CM, a restrictive cardiomyopathy, is due to either a pathologic variant in transthyretin gene TTR (ATTRv) or wild-type transthyretin protein (ATTRwt).
Healio spoke with Michelle M. Kittleson, MD, PhD, director of post graduate medical education in heart failure and transplantation at Cedars-Sinai Heart Institute, about the latest advancements in understanding cardiac amyloidosis, new therapies that improve survival, and the importance of recognizing the disease as early as possible.
Clinical clues
The classic presenting symptoms and signs of ATTR myopathy are shortness of breath in the context of normal or near-normal ejection fraction, and increased left ventricular wall thickness on ECG, often — and mistakenly — attributed to aging, hypertension, or HF with preserved ejection fraction (HFpEF), according to Kittleson.
“Not considering a diagnosis of cardiac amyloidosis is a missed opportunity, as disease-modifying therapies work best if started early in the disease process and before severe symptoms manifest,” Kittleson said. “In addition to the classic symptoms and signs, consider cardiac amyloidosis in patients with intolerance to antihypertensive or HF medications due to hypotension, persistent low-level elevation in serum troponin, discordance between QRS voltage on ECG and wall thickness on ECG, unexplained atrioventricular block or pacemaker placement, and family history of cardiomyopathy.”
Cardiac amyloidosis has historically been considered rare, but researchers have learned it is, instead, frequently underrecognized. In a study published in the March 2017 issue of the Journal of the American College of Cardiology, Saberio Lo Presti, MD, of the Columbia Division of Cardiology at Mount Sinai Heart Institute in Miami Beach, Florida, and colleagues wrote that ATTR has been found in autopsy studies in up to 30% of patients with HFpEF. In a retrospective analysis, Lo Presti and colleagues assessed a cohort of 45 patients with HFpEF who underwent 99mtechnetium (99mTc) pyrophosphate (PYP) imaging, a noninvasive alternative to biopsy for diagnosing ATTR amyloidosis.
The researchers found the PYP scan was positive in 11 patients (24%), of which 6 (55%) had an H:Cl ratio of less than 1.5. Only two patients had histologic confirmation. In subgroup analyses, researchers found that patients with a positive scan showed that dyspnea was the most predominant symptom (55%) and low voltage electrocardiogram criteria was identified in two cases. Patients with amyloid deposition were older, had a lower systolic blood pressure, and lower left ventricular ejection fraction.
“These patients tend to be older and have worse systolic and diastolic left ventricular function,” the researchers wrote. “These findings create an opportunity for further investigation in the targeted therapy of patients with HFpEF.”
There are also non-cardiac clinical clues to the diagnosis, Kittleson said. Patients with ATTR-CM may have a history of autonomic dysfunction with orthostatic hypotension, carpal tunnel syndrome or lumbar spinal stenosis, as well as a family history of neuropathy.
Role of biopsy
Accurate, noninvasive diagnosis of ATTR-CM is possible due to the advent of 99mtechnetium (99mTc) pyrophosphate (PYP) scans. In a study published in October 2018 in Radiology Case Reports, Martin Krupa, MD, of the department of radiology at Eastern Virginia Medical School, and colleagues wrote that endomyocardial biopsy is the gold standard for diagnosis; however, scintigraphy with radiolabeled phosphate derivatives and cardiac magnetic resonance imaging have been shown to have high sensitivity and specificity in diagnosing cardiac amyloidosis.
“Furthermore, cardiac scintigraphy can reliably differentiate amyloid subtypes,” Krupa and colleagues wrote.
In order to diagnose ATTR-CM noninvasively, the 99mTc-PYP scans must be positive, and testing for clonal light chains must be negative, Kittleson said.
“This point cannot be overemphasized: the diagnosis of ATTR-CM requires a positive 99mTc-PYP scan along with negative testing for clonal plasma cell proliferation because 99mTc-PYP scans can also be positive in AL-CM,” Kittleson said. “If one assumes that a positive 99mTc-PYP scan alone without concomitant testing for clonal light chains means the patient has ATTR-CM, a diagnosis of AL-CM may be missed. This is a potentially life-threatening error, as life-saving therapies for AL-CM will not be instituted.”
Testing for clonal plasma cell proliferation requires assessing serum free light chain (FLC) concentration and serum and urine immunofixation electrophoresis (IFE), according to Kittleson.
“Another very important point to note: serum plasma electrophoresis (SPEP) and urine plasma electrophoresis (UPEP) testing are less sensitive and should not be used to assess for AL-CM,” Kittleson said. “Measurement of serum IFE, urine IFE, and serum FLC is over 99% sensitive for AL amyloidosis.”
Biopsy may be necessary to establish the diagnosis in patients with a positive 99mTc-PYP scan and evidence of a plasma cell dyscrasia by serum/urine IFE and/or serum free light chain analysis to exclude AL-CM, or for patients with a negative or equivocal 99mTc-PYP scan, despite a high clinical suspicion to confirm ATTR-CM.
“It is essential to note that a fat pad biopsy is sensitive for AL-CM but not for ATTR-CM and thus, if ATTR-CM is suspected and a biopsy needed, endomyocardial biopsy is preferred,” Kittleson said.
Treatment options
Median survival in untreated AL-CM is only 6 months, but with the administration of effective therapies, 4-year survival can be as high as 90% for patients successfully treated with stem cell transplantation. Therapy for AL-CM is directed by hematologist-oncologists and usually involves cyclophosphamide, bortezomib (Velcade, Millennium/Takeda) — a proteasome inhibitor targeting plasma cells which produce the light chains — and dexamethasone.
“Sometimes, daratumumab [Darzalex, Janssen], an antibody directed at plasma cells, may be used,” Kittleson said. “Ultimately, most patients undergo stem cell transplantation. In some patients, cardiac involvement may regress after treatment.”
Targets for disease-modifying therapies in ATTR-CM include TTR silencers and TTR stabilizers. TTR stabilizers bind to the TTR tetramer and prevent misfolding and thus deposition of amyloid fibrils. TTR silencers target TTR hepatic synthesis by interfering with RNA synthesis. The biggest recent advance in the treatment of ATTR-CM is the benefit of the TTR stabilizer tafamidis. Approved by the FDA in May 2019, tafamidis meglumine (Vyndaqel, FoldRx/Pfizer) and tafamidis (Vyndamax, FoldRx/Pfizer) are the first treatments for transthyretin-mediated amyloidosis. The recommended dose is 80 mg once per day of tafamidis meglumine, which is given as four 20-mg capsules, and 61 mg of tafamidis once per day, which is given as a single capsule. The single-capsule formulation was developed by Pfizer for patient convenience, according to the company.
The TTR silencers patisiran (Onpattro, Alnylam) and inotersen (Tegsedi, Akcea), which halt the production of transthyretin in the liver, slow progression of amyloid-related polyneuropathy in ATTRv but have not shown direct benefit in ATTR-CM, Kittleson said.
In both forms of cardiac amyloidosis, patients with advanced disease may be candidates for heart transplantation, Kittleson said. “In the case of AL-CM, ongoing chemotherapy with stem cell transplantation after heart transplantation is often necessary for disease control,” Kittleson said. “In ATTR-CM, patients with the ATTRv-CM and significant polyneuropathy may also undergo liver transplantation as debilitating neuropathy can progress despite heart transplantation as the liver continues to synthesize the mutant TTR.”
Roles for new agents
Despite advances in the management of cardiac amyloidosis, and ATTR-CM in particular, areas of active investigation remain. In particular, the role of the TTR silencers inotersen and patisiran in patients with ATTR-CM is not clear and studies are ongoing. In addition, timing of therapy initiation is not established. Early initiation of tafamadis appears to slow disease progression, but whether it should be prescribed in asymptomatic ATTRv gene carriers is not known. Finally, the role of combination therapy with TTR silencers plus TTR stabilizers in ATTR-CM is mechanistically appealing but remains unstudied, according to Kittleson. – by Regina Schaffer
References:
Krupa M, et al. Radiol Case Rep. 2018; doi:10.1016/j.radcr.2018.06.012.
Lo Presti S, et al. J Am Col Cardiol. 2017; doi:10.1016/S0735-1097(17)34272-9.
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