Wild-type Transthyretin Amyloid Deposition in an Ascending Aortic Aneurysm

Amyloid deposition in aortic tissue is associated with increased stiffness. We report a patient with ascending aortic aneurysm and chronic abdominal aortic dissection who had significant wild-type transthyretin amyloid deposition on surgical pathology. The patient did not have cardiac involvement on further workup.

A n active, asymptomatic, 64-year-old man with a medical history of hyperlipidemia, pre-diabetes, and spinal stenosis presented for a routine cardiac risk evaluation.He had no significant history of alcohol or tobacco use.His history, physical examination, and electrocardiogram were unremarkable with a normal arm span and joint laxity.Because the patient had an intermediate atherosclerotic cardiovascular disease score of 8.8% and was hesitant about initiating statin therapy, he underwent a coronary calcium scoring computed tomography scan for further evaluation and shared decision-making, which showed, a 4.6-cm ascending aortic aneurysm.
A follow-up echocardiogram showed a tricuspid aortic valve, no evidence of aortic stenosis or regurgitation, a body surface area of 2.2 m 2 , a 4.3 cm aortic root and a 4.4 cm ascending aorta, normal left ventricular cavity size and wall thickness (Supplemental Figure 1).Six-month follow-up imaging with a magnetic resonance angiography of the chest showed an ascending aortic diameter of 4.6 cm (Supplemental Figure 2).In addition, a computed tomography angiogram of the abdomen showed a normal-sized aorta with a chronic dissection originating at the superior mesenteric artery and extending to the left common iliac artery (Supplemental Figure 3).
He had no history of hypertension, family history of thoracic aortic aneurysm, bicuspid aortic valve, or syndromic connective tissue disorders.The most likely etiology of his aortopathy was presumed to be idiopathic congenital medial degeneration.Given the ascending aortic diameter and the fact that he had already dissected a normal caliber abdominal aorta, his ascending aortic aneurysm was considered to be at significantly  increased risk for dissection.Consequently, the surgical threshold for his ascending aortic diameter was considered to be 4.5 cm rather than 5.5 cm.He, therefore, underwent open ascending aortic replacement, and the resected ascending aorta was sent for pathological evaluation.Surgical pathology (Figure 1) showed intimal thickening, medial degeneration (characterized by subintimal smooth muscle cell loss, as highlighted by the trichrome and elastic stains), and amyloid deposits in multiple adventitial vessels of the aorta (as seen on Congo Red staining).No evidence of active aortitis or significant atherosclerosis was seen on pathology.Mass spectrometry on a paraffin block yielded a peptide pattern consistent with transthyretin (TTR) amyloidosis (also known as ATTR).Laboratory evaluation including serum and urine plasma electrophoresis with reflex immunofixation, and serum free light chains was unremarkable (Supplemental Table 1).TTR genetic testing was negative for known pathological mutations. 99mTc-pyrophosphate scintigraphy and cardiac magnetic resonance imaging were not suggestive of cardiac amyloidosis (normal biventricular systolic function without late gadolinium enhancements, normal parametric mapping values, normal end-diastolic left ventricular myocardial wall thickness with a normal extracellular volume of 25%).Noninvasive cardiac pulmonary exercise testing with imaging showed preserved exercise capacity with a largely normal central cardiac response to exercise.
Because the workup for TTR amyloid cardiomyopathy was negative, he did not meet the current criteria for treatment with tafamidis, a TTR stabilizer. 1 After weighing the potential risks and benefits, off-label treatment with diflunisal to slow down the progression of TTR amyloidosis was considered, but ultimately deferred.
Although he will be monitored closely for meeting indications for approved disease-modifying therapy for TTR amyloidosis, there are no clear data on how and how often to monitor patients with TTR amyloidosis outside of the heart and the nervous system or how to treat it.As the awareness of TTR amyloidosis grows, we are more likely to find TTR amyloid deposition outside of the heart and the nervous system and the need to address this gap in literature will escalate.

FUNDING SUPPORT AND AUTHOR DISCLOSURES
r e a t i v e c o m m o n s .o r g / l i c e n s e s / b y / 4 .0 / ) .

FIGURE 1
FIGURE 1 Histopathological Features of the Ascending Aortic Aneurysm with Amyloid Deposition Dr Gaggin has received research grant support from Roche Diagnostics, Pfizer, Alnylam, Akcea (IONIS), and Eidos/BridgeBio; consulting income from Amgen, AstraZeneca, Bayer, Eidos/BridgeBio, Merck, Novo Nordisk, Pfizer, and ExpertConnect; stock option for Eko; research payments for clinical endpoint committees from Baim Institute for Clinical Research for Abbott, Siemens, Innolife, and Beckman Coulter, and from ACI Clinical for Abbott Laboratories; in kind support from the HeartShare fellowship.Dr Hoteit is in part funded by Pfizer's Transthyretin Cardiac Amyloidosis Fellowship.Dr Stone has received consulting fees from Cook Medical.All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.Kittleson MM, Ruberg RL, Ambardekar AV, et al. 2023 ACC expert consensus decision pathway on comprehensive multidisciplinary care for the patient with cardiac amyloidosis: a report of the American College of Cardiology Solution Set Oversight Committee.J Am Coll Cardiol.2023;81: 1076-1126.https://doi.org/10.1016/j.jacc.2022.11.022 KEY WORDS ascending aortic aneurysm, transthyretin amyloidosis APPENDIX For supplemental figures and supplemental tables, please see the online version of this paper.