Infusion of light chains from patients with cardiac amyloidosis causes diastolic dysfunction in isolated mouse hearts.
BACKGROUND
Primary (AL) amyloidosis is a plasma cell dyscrasia characterized by clonal production of immunoglobulin light chains (LC) resulting in the subsequent systemic deposition of extracellular amyloid fibrils. Cardiac involvement is marked by the hemodynamic pattern of impaired diastolic filling and restrictive cardiomyopathy. Although cardiac death in patients with AL amyloidosis is usually associated with extensive myocardial infiltration, the infiltration alone does not correlated with the degree of heart failure or survival. We hypothesized that circulating monoclonal LC may directly impair cardiac function, in addition to any mechanical effects of amyloid fibril deposition. Therefore, we examined the effects of amyloid LC proteins on diastolic and systolic cardiac function, as measured in an isolated mouse heart model.


RESULTS
LC were obtained from patients with nonamyloid disease or from those with noncardiac, mild cardiac, and severe cardiac involved AL amyloidosis. Saline or LC (100 microgram/mL) was infused into a Langendorff-perfused, isovolumically contracting mouse heart. Saline and control, noncardiac, and mild-cardiac LC infusions did not alter ex vivo cardiac function. In contrast, infusion of sever cardiac LC resulted in marked impairment of ventricular relaxation with preservation of contractile function.


CONCLUSIONS
These results demonstrate that infusion of LC from patients with AL amyloidosis result in diastolic dysfunction similar to that observed in patients with cardiac involved AL amyloidosis, and they suggest that amyloid LC proteins may contribute directly to the pathogenesis and the rapid progression of amyloid cardiomyopathy, independent of extracellular fibril deposition.
Liao
R
R
Cardiac Muscle Research Laboratory, Amyloid Treatment and Research Program, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA. rliao@bu.edu
Jain
M
M
Teller
P
P
Connors
L H
LH
Ngoy
S
S
Skinner
M
M
Falk
R H
RH
Apstein
C S
CS
D000686:Amyloidosis / Q000209:etiology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000302:isolation & purification / Q000494:pharmacology; D003971:Diastole; D006321:Heart / Q000503:physiopathology; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000302:isolation & purification / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D051379:Mice; D018754:Ventricular Dysfunction / Q000209:etiology* / Q000503:physiopathology
D000911:Antibodies, Monoclonal; D007147:Immunoglobulin Light Chains