By Van Selby, MD

Assistant Professor of Medicine, University of California, San Francisco, Cardiology Division, Advanced Heart Failure Section

Dr. Selby reports no financial relationships relevant to this field of study.

SYNOPSIS: A testing strategy combining bone scintigraphy and laboratory testing allows accurate diagnosis of transthyretin amyloid cardiomyopathy without the need for a biopsy.

SOURCE: Gillmore JD, Maurer MS, Falk RH, et al. Non-biopsy diagnosis of cardiac transthyretin amyloidosis. Circulation 2016 Apr 22 [Epub ahead of print].

Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underrecognized cause of heart failure. Diagnosis can be challenging and traditionally requires tissue biopsy with Congo red staining demonstrating the presence of amyloid. Radionuclide bone scintigraphy using technetium-labeled bisphosphonates can identify myocardial amyloid deposits and may be useful for evaluating patients with suspected ATTR-CM. However, the diagnostic accuracy of this strategy has not been evaluated in a large, multicenter study.

Gillmore et al analyzed bone scintigraphy results from 1,217 patients referred to one of nine specialty centers for suspected cardiac amyloidosis. Researchers performed standard bone scintigraphy using one of three technetium-labeled radiotracers (99mTc-DPD in 877 patients, 99mTc-PYP in 99 patients, and 99mTc-HMDP in 141 patients), with the degree of myocardial uptake scored between 0-3 using a previously described scale. All patients underwent serum testing for free light chains as well as serum and urine immunofixation to evaluate for monoclonal light chain (AL) amyloid.

A total of 857 patients were found to have histologically proven amyloidosis, and 374 had endomyocardial biopsies. The presence of any myocardial radiotracer uptake on bone scintigraphy (grade 1 or greater) was more than 99% sensitive for ATTR-CM, but only 86% specific. Most of the false-positive results were due to low-level radiotracer uptake in patients with AL amyloidosis. The combined findings of grade 2-3 myocardial radiotracer uptake and negative serum and urine testing for AL amyloid demonstrated a positive predictive value of 100% and specificity of 100% for ATTR-CM. The authors concluded that bone scintigraphy can reliably diagnose ATTR-CM without tissue biopsy in patients who do not feature monoclonal light chains, and proposed an algorithm for the noninvasive evaluation of patients with suspected disease.

COMMENTARY

Cardiac amyloidosis causes progressive heart failure due to restrictive cardiomyopathy. The two major amyloid fibril types that affect the heart are AL (formerly called primary amyloidosis) and transthyretin (ATTR). The diagnosis of ATTR-CM is often delayed or missed all together, with autopsy studies reporting high rates of ATTR amyloid in the hearts of elderly patients with no pre-mortem diagnosis of ATTR-CM. Currently, there is no proven treatment for ATTR-CM, with the exception of heart and/or liver transplantation for a select few patients. However, new medical therapies for ATTR-CM are now in development, with multiple large-scale clinical trials underway. Therefore, the importance of identifying ATTR-CM is greater than ever.

Tissue confirmation of amyloidosis is often made by abdominal fat pad aspirate. However, in patients with ATTR amyloid, the fat pad aspirate is insensitive, and endomyocardial biopsy is required to confirm the diagnosis. Providers and patients may be reluctant to proceed with endomyocardial biopsy, particularly in elderly patients with wild type (or senile) form of ATTR-CM. Therefore, a non-invasive option for evaluating suspected ATTR-CM is an important advance for clinicians who evaluate and treat cardiac amyloidosis. The reported diagnostic accuracy in the Gillmore et al study is impressive and superior to what has been reported for any other noninvasive test for ATTR-CM, such as echocardiography or cardiac MRI.

One of the most important points to remember when using bone scintigraphy for the evaluation of suspected ATTR-CM is the need to test all patients for the presence of a monoclonal light chain. Nearly all false-positive results occurred in patients with AL amyloidosis, a rapidly progressive disease treated with chemotherapy. The diagnostic algorithm the authors proposed uses serum and urine immunofixation and serum free light chain measurement to rule out AL amyloid. If these tests are negative, then a bone scintigraphy score of 2 or 3 is considered diagnostic for ATTR-CM in patients with suspicion for cardiac amyloidosis. If either immunofixation or free light chains are abnormal, then referral for further evaluation is warranted.

All patients in this study were referred to amyloidosis specialty centers for suspected cardiac amyloid. The pretest probability for amyloidosis likely was much higher than what occurs in real-world settings, and it is unclear how the reported sensitivity and specificity will translate into routine clinical practice.

The authors demonstrated that a combination of laboratory testing and bone scintigraphy allows the diagnosis of ATTR-CM with high sensitivity and specificity. This option can be considered in patients with heart failure and other evidence of cardiac amyloidosis, such as cardiac MRI or echocardiography. Although this strategy should be validated in other, real-world patient cohorts, hopefully this non-invasive option will lead to increased testing and diagnosis in patients with suspected ATTR-CM.