Increased Fibrosis Depresses Contractile Function in Myocardium from Patients with ATTR Cardiac Amyloidosis

Abstract

Background: ATTR cardiac amyloidosis is one of the most common forms of infiltrative cardiomyopathies and results in ventricular wall thickening and diastolic dysfunction.

Objectives: This study sought to measure the active and passive contractile properties of myocardium in patients with and without ATTR amyloidosis. Additional tests examined histological and biochemical changes in myocardium with amyloidosis.

Methods: Contractile function and stiffness measurements were performed on permeabilized muscle strips isolated from patients with and without ATTR amyloidosis. Biochemical assays were conducted on tissue homogenates to examine titin isoform ratios. Histology of tissue samples were used to quantify fibrosis, amyloid burden, and microcalcifications.

Results: Maximum force was reduced in amyloidosis myocardium with few changes in cross-bridge kinetics. Amyloidosis and non-failing myocardium had similar total stiffness but the proportion attributable to the extracellular matrix was larger with amyloidosis. Fibrosis was increased in amyloidosis myocardium but no changes in titin isoform were measured. Septal measurements of fibrosis and amyloid burden correlated with their respective measurements from the left ventricle. Microcalcifications were increased in the myocardium of patients with ATTR amyloidosis.

Conclusions: Decreased contractile force and increased extracellular matrix-based stiffness in amyloidosis myocardium reflects loss of myofibrillar volume secondary to amyloid and fibrosis. Fibrotic and amyloid burdens measured via septal biopsies are likely to reflect the characteristics of left ventricular myocardium. The mechanism by which technetium pyrophosphate scans diagnose patients with ATTR amyloidosis may be due to increased microcalcifications within the myocardium of these patients.

Note:
Funding Information: This study was supported by the National Institutes of Health (HL149164 to KSC) and (1F31HL170558 to AGWH) and the American Heart Association (24PRE1191551 to GNM).

Declaration of Interests: None.

Ethics Approval Statement: All procedures were approved by the University of Kentucky Institutional Review Board (IRB# 46103), and the subjects or their legally authorized representative gave written informed consent.

Keywords: Infiltrative Cardiomyopathy, Heart Failure, Myofilament Proteins, Muscle Mechanics, Fibrosis