Internalization of Systemic Amyloid Light Chains and Heparan Sulfate Proteoglycan Deposition

Trinkaus‐Randall, Vickery; Steeves, Shawn; Monis, Grace; Walsh, Mary T.; Chiu, Jenny D.; Eberhard, Jeremy; Connors, Lawreen H.; Skinner, M

doi:10.1201/9781420037494-50

Cited by 1 publication

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“…[3][4][5][6][7][8] Heart failure results from a multi-step process involving cellular dysfunction directly induced by AL LCs with an LC sequence derived from particular germline gene donors (amyloidogenic, cardiomyopathy-associated LC) as well as disruption of normal myocardial structure from extracellular amyloid fibril deposition. [9][10][11][12][13][14][15][16][17][18][19] Evidence suggests that exposure to amyloidogenic, cardiomyopathy-associated LCs may represent the initial event leading to cardiac dysfunction in AL amyloidosis. [9,10,17] Additionally, the unique phenomenon of LC-induced cardiac dysfunction may contribute to the disproportionately inferior prognosis of cardiac AL amyloidosis over other cardiac amyloidoses (such as transthyretin-related amyloid cardiomyopathy) despite similar levels of amyloid infiltration.…”

Section: Introductionmentioning

confidence: 99%

Abnormal global longitudinal strain and reduced serum inflammatory markers in cardiac AL amyloidosis patients without significant amyloid fibril deposition

Edwards,

Ferri,

Villegas-Galaviz

et al. 2024

Preprint

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Background: Cardiac dysfunction in AL amyloidosis is thought to be partly related to the direct impact of AL LCs on cardiomyocyte function, with the degree of dysfunction at diagnosis as a major determinant of clinical outcomes. Nonetheless, mechanisms underlying LC-induced myocardial toxicity are not well understood. We identified gene expression changes correlating with human cardiac cells exposed to a cardiomyopathy-associated κAL LC. We then sought to confirm these findings in a clinical dataset by focusing on clinical parameters associated with the pathways dysregulated at the gene expression level. Upon exposure to a cardiomyopathy-associated κAL LC, cardiac cells exhibited gene expression changes related to myocardial contractile function and inflammation, leading us to hypothesize that there could be clinically detectable changes in GLS on echocardiogram and serum inflammatory markers in patients. Thus, we identified 29 patients with normal IVSd but abnormal cardiac biomarkers suggestive of LC-induced cardiac dysfunction. These patients display early cardiac biomarker staging, abnormal GLS, and significantly reduced serum inflammatory markers compared to patients with clinically evident amyloid fibril deposition. Collectively, our findings highlight early molecular and functional signatures of cardiac AL amyloidosis, with potential impact for developing improved patient biomarkers and novel therapeutics.

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