Pathophysiology and Therapeutic Approaches to Cardiac Amyloidosis

Abstract

Often considered a rare disease, cardiac amyloidosis is increasingly recognized by practicing clinicians. The increased rate of diagnosis is in part due the aging of the population and increasing incidence and prevalence of cardiac amyloidosis with advancing age, as well as the advent of noninvasive methods using nuclear scintigraphy to diagnose transthyretin cardiac amyloidosis due to either variant or wild type transthyretin without a biopsy. Perhaps the most important driver of the increased awareness is the elucidation of the biologic mechanisms underlying the pathogenesis of cardiac amyloidosis which have led to the development of several effective therapies with differing mechanisms of actions. In this review, the mechanisms underlying the pathogenesis of cardiac amyloidosis due to light chain (AL) or transthyretin (ATTR) amyloidosis are delineated as well as the rapidly evolving therapeutic landscape that has emerged from a better pathophysiologic understanding of disease development.

Keywords: amyloidosis; biopsy; cardiomyopathy; incidence; light chain; prevalence; rare disease; transthyretin.

Figure 1:

Pathogenesis of Cardiac Amyloidosis and Therapies. Mechanisms underlying formation of cardiac amyloidosis in TTR and AL. Targets for therapy are enumerated in blue. Effective therapies approved for use are shown in black and experimental therapies in a particular class are shown in red. Those listed above specific mechanism are for TTR while those listed below a specific mechanism are for AL amyloidosis. (Illustration credit: Ben Smith).

Figure 2:

Mechanisms of myocardial dysfunction in TTR and AL amyloidosis. In both TTR and AL, extracellular deposition of amyloid fibrils causes mechanical disruption of normal tissue architecture, leading to impaired relaxation and increased ventricular stiffness. In AL amyloidosis, circulating free light chains cause cytotoxicity by increasing oxidative stress and activation of the p38 MAPK signaling pathway. Activation of the p38 MAPK pathway also leads to release of NT-proBNP. In TTR amyloidosis, circulating TTR monomers and oligomers have also been proposed to cause direct cytotoxicity. (Illustration credit: Ben Smith).

Figure 3:

Cardiac mechanics in TTR amyloidosis. Non-invasive pressure-volume loops (top) and isovolumetric pressure volume area (bottom). (Left) Progression of cardiac chamber dysfunction overtime marked by reduced ventricular capacitance and impaired contractility. Collectively, both abnormalities lead to reduced stroke volume and isovolumetric pressure volume area overtime. (Right) Compared to WT, patients with V122I associated ATTR-CA have more impaired cardiac function at baseline. Patients with both WT and V122I associated ATTR-CA have reduced ventricular capacitance. However, patients with V122I associated ATTR-CA also have impaired contractility, leading to lower stroke volume and isovolumetric pressure-volume area in V122I associated ATTR-CA compared to WT.

Figure 4:

Model of ATTR-CA progression over time. Myocardial amyloid infiltration occurs before clinically manifested changes in ejection fraction, cardiac biomarkers, and renal function. The ideal emerging therapeutic window for novel therapies is hypothesized to be before significant organ dysfunction has occurred and before rapid and potentially irreversible declines in functional capacity. The relative scale specific to each factor and time course are not proportional. (From Circulation. 2019 Jul 2;140(1):27–30).