Occult Transthyretin Cardiac Amyloid in Severe Calcific Aortic Stenosis

Abstract

Severe degenerative calcific aortic stenosis (cAS) is common, affecting 3% of individuals aged >75 years and leads to heart failure and death unless the valve is replaced.1,2 Its coexistence with cardiac amyloidosis has been reported, but this has not been studied systematically and the prognostic significance is unknown.3 Cardiac amyloidosis is a progressive infiltrative cardiomyopathy in which deposits of amyloid, almost always of either immunoglobulin light-chain (AL) or transthyretin amyloidosis (ATTR) type, 4-6 accumulate in the ventricular myocardium; ATTR amyloid is usually wildtype (wtATTR) and acquired, but it may also be hereditary and associated with mutant forms of transthyretin. Wild-type cardiac ATTR amyloid has a male preponderance and was formerly known as senile amyloid reflecting its first appearance beyond 60 to 70 years of age and prevalence at autopsy of up to 25% among octogenarians. 7,8 Its natural history and the prevalence of clinically significant ATTR amyloid deposition in the heart are unknown. In a recent small cohort of patients with AS who underwent transcatheter aortic valve Background-Calcific aortic stenosis (cAS) affects 3% of individuals aged >75 years, leading to heart failure and death unless the valve is replaced. Wild-type transthyretin cardiac amyloid is also a disorder of ageing individuals. Prevalence and clinical significance of dual pathology are unknown. This study explored the prevalence of wild-type transthyretin amyloid in cAS by myocardial biopsy, its imaging phenotype and prognostic significance. Methods and Results-A total of 146 patients with severe AS requiring surgical valve replacement underwent cardiovascular magnetic resonance and intraoperative biopsies; 112 had cAS (75±6 years; 57% men). Amyloid was sought histologically using Congo red staining and then typed using immunohistochemistry and mass spectrometry; patients with amyloid underwent clinical evaluation including genotyping and 99m TC-3,3-diphosphono-1,2-propanodicarboxylic-acid (DPD) bone scintigraphy. Amyloid was identified in 6 of 146 patients, all with cAS and >65 years (prevalence 5.6% in cAS >65). All 6 patients had wild-type transthyretin amyloid (mean age 75 years; range, 69-85; 4 men), not suspected on echocardiography. Cardiovascular magnetic resonance findings were of definite cardiac amyloidosis in 2, but could be explained solely by AS in the other 4. Postoperative DPD scans demonstrated cardiac localization in all 4 patients who had this investigation (2 died prior). At follow-up (median, 2.3 years), 50% with amyloid had died (versus 7.5% in cAS; 6.9% in age >65 years). In univariable analyses, the presence of transthyretin amyloidosis amyloid had the highest hazard ratio for death (9.5 [95% confidence interval, 2.5-35.8]; P=0.001). Conclusions-Occult wild-type transthyretin cardiac amyloid had a prevalence of 6% among patients with AS aged >65 years undergoing surgical aortic valve replacement and was associated with a poor outcome. (Circ Cardiovasc Imaging. 2016;9:e005066.

The quintessential form of diastolic heart failure in older adults: Wild type transthyretin cardiac amyloidosis

“…14 Notably, in both studies, patients with transthyretin amyloidosis were older than those without. Biceps tendon rupture represents another orthopedic condition that has been strongly associated with the pres- 23,24 The association between these conditions is therefore higher than previously recognized, likely due to the age-dependent pene- can lead to lower cardiac output that is already compromised by AS. 21 It will be important to study whether or not outcomes, including those after treatment with valve replacement, are affected by the presence of concomitant amyloidosis.…”

Coronary revascularisation in cardiac amyloidosis

“…In view of There is a growing body of evidence for the association between aortic stenosis and CA, with this subgroup of patients at increased risk following surgical valve replacement. 4 Although more limited, current evidence of mitral valve surgery in patients with concomitant CA report excellent outcomes. 5 Data on bypass surgery are far more limited but given reasonable reported outcomes in other cardiac surgical procedures, our initial view was that surgery, whilst high risk, was a reasonable approach.…”

Prognostic Significance of Occult Transthyretin Cardiac Amyloidosis in Patients With Severe Aortic Stenosis Undergoing Surgical Aortic Valve Replacement

“…To examine the prevalence and clinical significance of dual pathology (severe AS and wtATTR), Treibel et al, 5 in this issue of Circulation: Cardiovascular Imaging, examined a cohort of 146 patients with severe AS requiring surgical valve replacement (sAVR) as part of the RELIEF-AS study (Regression of Myocardial Fibrosis After Aortic Valve Replacement), in which intraoperative myocardial biopsy and comprehensive multimodarity imaging were performed in a single center. The echocardiography was performed as a clinical test and the cardiovascular magnetic resonance (CMR) as a research study preoperatively, whereas 3, 3-diphosphono-1, 2-propanodicarboxylic acid bone scintigraphy was conducted during subsequent specialist clinical evaluations of subjects found to have amyloid on the biopsy.…”

“…19 This phenomenon may be accounted for by the male dominancy of wtATTR (male:female=20-50:1), which may lead the poorer prognosis in male sex in these population. 20 In the study by Treibel et al, 5 patients with CMR-incompatible devices were excluded from the study. Because wtATTR patients may have advanced atrioventricular block requiring CMRincompatible devices, 20 some wtATTR patients with devices may have been possibly excluded from this study, may have resulted in an underestimation in the prevalence of wtATTR in patients with severe AS.…”