Wild-Type Transthyretin Cardiac Amyloidosis: Novel Insights From Advanced Imaging

Abstract

Amyloidosis is caused by extracellular deposition of abnormal protein fibrils, resulting in destruction of tissue architecture and impairment of organ function. The most common forms of systemic amyloidosis are light-chain and transthyretin-related (ATTR). ATTR can result from an autosomal dominant hereditary transmission of mutated genes in the transthyretin or from a wild-type form of disease (ATTRwt), previously known as senile cardiac amyloidosis. With the aging of the worldwide population, ATTRwt will emerge as the most common type of cardiac amyloidosis that clinicians encounter. Diagnosis of systemic amyloidosis is often delayed, either because of the false assumption that it is a rare disease, or because of misdiagnosis as a result of mistaking it with other conditions. Clinicians must integrate clinical clues from history, physical examination, and common diagnostic tests to raise suspicion for ATTRwt. The historical gold standard for diagnosis of cardiac amyloid is endomyocardial biopsy analysis with pathological distinction of precursor protein type, but this method often results in delayed diagnosis because of the limited availability of expertise to perform and interpret the endomyocardial biopsy specimen. Emerging noninvasive imaging modalities provide easier, accurate screening for ATTRwt. These modalities include advanced echocardiography, using strain imaging and the myocardial contraction fraction; nuclear scintigraphy, which can differentiate between ATTR and light-chain cardiac amyloid; and cardiac magnetic resonance imaging, using extracellular volume measurement, late gadolinium enhancement, and distinct T1 mapping. These novel approaches reveal insights into the prevalence, clinical course, morphological effects, and prognosis of ATTRwt.

Figure 1. “Apical Sparing” Strain Pattern of ATTR Cardiac Amyloid on Echocardiogram

Patients with CA typically demonstrate marked decrease in longitudinal strain in basal and mid-wall areas with relative apical sparing, referred to as “cherry on top” or apical preservation.

Figure 2. Myocardial Contraction Fraction

The myocardial contraction fraction (MCF) is based on the principle that the myocardium is nearly incompressible and does not change volume significantly from end-diastole to end-systole. By indexing the stroke volume to the myocardial volume, the MCF is an index of the volumetric shortening of the myocardium that is independent of chamber size and geometry. The MCF, while analogous to EF in terms of being unitless and free of the need for indexation for body size, offers several theoretical advantages including expressing the strain relationship only in terms of that which shortens, namely the myocardium, thereby providing an ability to distinguish pathologic from physiologic hypertrophy.

Figure 3. Semiquantitative and Quantitative analysis of ^99mTc-PYP Myocardial Uptake

Semiquantitative visual cardiac score was assigned 0-3 according to the scale detailed (A). The representative image demonstrates a visual cardiac score of 3. Quantitative heart-to-contralateral (H/CL) ratio was calculated by drawing a region of interest (ROI) over the heart, copying and mirroring it to the contralateral chest, and calculating the ratio of heart ROI mean counts to contralateral ROI mean counts (B). The representative image demonstrates H/CL ratio 40/15=2.67.

Figure 4. Representative Examples of Cardiac Amyloid on CMR

Representative examples of CMR evidenced enhancement patterns among patients with cardiac amyloid. (A) Diffuse subendocardial enhancement (green arrow) on DE-CMR (inversion time [TI] 300msec). (B) Diffuse transmural enhancement on DE-CMR (left [equivalent TI]). (C) Corresponding T1 map enables quantification of extracellular volume fraction, which can be can be calculated via measurement of T1 in myocardium and blood pool (red circles) on matched pre- and post-contrast images.

Figure 5

Diagnosis Algorithm for ATTRwt Cardiac Amyloid using PYP scanning as an alternative to EMB