Advanced Cardiac Amyloidosis Associated with Normal Interventricular Septal Thickness: An Uncommon Presentation of Infiltrative Cardiomyopathy

Abstract

Background Increased interventricular septum (IVS) thickness by echocardiography is a diagnostic criterion for cardiac amyloidosis and classically precedes decrement in left ventricular ejection fraction (LVEF). Here, we describe patients with histologically confirmed cardiac amyloidosis who have significant myocardial dysfunction (LVEF≤40%) despite having normal IVS thickness. Methods All patients with systemic amyloidosis and LVEF ≤ 40% were analyzed to identify the prevalence of normal IVS thickness. Patients with a known history of cardiomyopathy or coronary artery disease were excluded. Histological evaluation of tissue included assessment of amyloid burden and average myocyte diameter. Results There were 255 amyloidosis patients with LVEF ≤ 40% of whom 7 (3%) had normal IVS thickness and histological confirmation of cardiac involvement. Of these, 6 had immunoglobulin light chain amyloidosis and one had senile amyloidosis. A majority of patients (86%) presented with new-onset cardiac dysfunction associated with edema and/or dyspnea. Electrocardiographic findings included low-voltage (43%) and a pseudoinfarct pattern (29%). The 1-year survival from initial tissue diagnosis in the normal IVS thickness cohort was similar to matched amyloid patients with increased IVS thickness and LVEF ≤ 40% (21% vs. 18%, respectively; p=0.32). Myocardial tissue amyloid burden and average myocyte diameter were significantly reduced in cases compared to controls. Conclusion Cardiac amyloidosis can uncommonly present with normal IVS thickness despite significant myocardial dysfunction. The prognosis of these patients is as poor as those with increased IVS thickness. Amyloidosis should be considered in the differential diagnosis of patients with cardiomyopathy and reduced LVEF despite normal IVS thickness.

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“…Although cardiac AL amyloidosis is generally considered a condition in which LVEF is preserved, a subset of patients may present with reduced LVEF and minimal or no ventricular wall thickening, again perhaps because of direct LC toxicity or predominant vascular involvement. 26 Last, some patients with AL amyloidosis present with primarily endocardial involvement, leading to atypical imaging findings with thickened valves and endocardial surfaces but normal or only mildly increased wall thickness. 27 …”

Immunoglobulin Light-Chain Amyloidosis: From Basics to New Developments in Diagnosis, Prognosis and Therapy

“…However, the wall measure may remain normal, despite significant cardiac dysfunction. The reported incidence of this ‘nontraditional' presentation ranges from 3% [60] to a third of cardiac involvement [61], although in the former study only patients with an ejection fraction ≤40% were included.…”

Epigenomic profiles of African American Transthyretin Val122Ile carriers reveals putatively dysregulated amyloid mechanisms

“…Amyloid-beta-treated neurons show elevated glutaminase expression, which increases glutamate levels and disrupts calcium neural regulation 45 . Additionally, neurofibrillary tangles have been shown to coexist with higher glutaminase activity 46 One of the clinical findings associated with cardiac amyloidosis is increased left ventricular wall thickness, which can lead to heart failure 54 . Electrical perturbations resulting from lower potassium repolarizing current leads to a prolonged action potential in heart failure 55 .…”