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 (AL) and transthyretin-related (ATTR). ATTR can result from an autosomal dominant hereditary transmission of mutated genes in the TTR (ATTRm) or from a wild-type form of disease (ATTRwt), previously known as senile cardiac amyloidosis (SCA). 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 due to the false assumption that it is a rare disease, or due to misdiagnosis as a result of mistaking it with other conditions. Clinicians must integrate clinical clues from history, physical exam, and common diagnostic tests to raise suspicion for ATTRwt. The historical gold standard for diagnosis of cardiac amyloid is endomyocardial biopsy (EMB) with pathological distinction of precursor protein type, but this method often results in delayed diagnosis given the limited availability of expertise to perform and interpret the EMB. 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 AL cardiac amyloid; and cardiac magnetic resonance, 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.

Transthyretin Cardiac Amyloidosis in Older Adults: Optimizing Cardiac Imaging to the Corresponding Diagnostic and Management Goal

“…Typical echocardiographic features of CA include left ventricular (LV) and right ventricular (RV) wall thickening without an explanatory stimulus (i.e. hypertension or valvular disease, specifically aortic stenosis) [10], bi-atrial enlargement, thickening of the interatrial septum, and the presence of a pericardial effusion [11–14]. Diastolic dysfunction is common [13, 15] and often advanced, typically with a restrictive filling pattern with high early (E) and relatively low atrial (A) wave with an E/A ratio >2, and a short deceleration time [10, 13, 15].…”

“…CMR can assess morphological and functional characteristics of myocardial tissue using specialized post-contrast techniques, including inversion recovery imaging for late gadolinium enhancement (LGE) and T1 mapping for fractionation of extracellular volume (ECV) [10, 31]. A shortened post-contrast T1 signal is seen in CA due to interstitial expansion by amyloid infiltration and subsequent gadolinium deposition.…”

“…Until recently, the gold standard for a definitive diagnosis of CA required endomyocardial biopsy and tissue typing with histological staining, immunohistochemistry, and mass spectrometry [10]. However, procedural risk in a frail elderly population and the need for pathologic expertise at experienced centers limits this approach and may delay the diagnosis.…”

<i>In vivo</i> quantification of amyloid burden in TTR-related cardiac amyloidosis

“…Gillmore and colleagues reported recently that 99m Technetium-3,3-diphosphono-1,2-propanodicarboxylic acid ( 99m Tc-DPD) could be used to diagnose cardiac ATTR amyloidosis with excellent sensitivity (> 99%) and high specificity (~86%) (4). Although the exact mechanism is not completely understood, 99m Tc-DPD shows highly preferential, potentially calcium-dependent, uptake in myocardial amyloid infiltrations caused by extracellular deposits of destabilized and dissociated TTR-tetramers which form fibrils consisting of misfolded TTR-subunits in a cross β-sheet structure (1,5).…”

“…Quantification of myocardial disease severity is important to determine clinical relevance of disease and treatment success of emerging therapeutic strategies for cardiac ATTR amyloidosis. However, quantification and 3D-mapping of cardiac ATTR amyloidosis using 99m Tc-DPD apart from visual assessment of planar images or heart-to-contralateral ratio is unknown (5).…”