Unfolding Cardiac Amyloidosis –From Pathophysiology to Cure

Abstract

Deposition of amyloidogenic proteins leading to the formation of amyloid fibrils in the myocardium cause cardiac amyloidosis. Although any form of systemic amyloidosis can affect the heart, light-chain (AL) or transthyretin amyloidosis (ATTR) account for the majority of diagnosed cardiac amyloid deposition. The extent of cardiac disease independently predicts mortality. The reversal or arrest of adverse cardiac remodeling is the target of current therapies, as cardiac-related mortality worsens prognosis in patients where the underlying systemic amyloidosis was successfully treated. Here, we provide a condensed overview on the pathophysiology of AL and ATTR cardiac amyloidoses and describe treatments that are currently used or investigated in clinical or preclinical trials. We also briefly touch on acquired amyloid deposition in cardiovascular disease other than AL or ATTR.

Daily Fasting Improves Health and Survival in Male Mice Independent of Diet Composition and Calories

“…With aging, there is a progressive loss of the complex proteostasis network, characterized by an increased vulnerability of the proteome to misfolding and aggregation leading to cellular dysfunction (Kaushik and Cuervo, 2015). A number of disorders in human tissues result from amyloid deposition and other types of aggregrates, underscoring that failure to maintain protein homeostasis gives rise to disease (Chiti and Dobson, 2017) along with common age-associated disorders such as the systemic amyloidosis that worsens cardiac-related mortality in patients (Ablasser et al, 2018). Our survival analysis combined with histopathological data on tissues and organs from old B6 mice that spontaneously died has provided insights into their extent of systemic amyloidosis, with incidence consistent with previous studies (Solleveld et al, 1982).…”

Desmin Phosphorylation Triggers Preamyloid Oligomers Formation and Myocyte Dysfunction in Acquired Heart Failure

“…Light-chain and transthyretin (TTR) amyloidosis (AL and ATTR, respectively) are two notorious examples of genetic cardiac amyloidosis where the mutation of a protein sequence or its overproduction trigger the massive accumulation of cardiac amyloid 31 . Although both are systemic amyloidosis, one of the organs that is most affected and usually determines prognosis is the heart 31 . Wild type TTR also generates amyloid in the aging heart, in what was formerly known as cardiac senile amyloidosis and is now referred to as wild type TTR amyloidosis (ATTRwt).…”

Cardiac Amyloidosis

“…From a pathophysiological standpoint there is interstitial deposition of immunoglobulin light chains, as well as direct toxicity on the myocytes caused by the free light chains. These chains can induce lysosomal dysfunction, oxidative stress, apoptosis, and dysregulation of MAP kinase signaling transduction pathways as well as autophagy [4]. The amount of cardiac involvement independently predicts mortality [4].…”

“…These chains can induce lysosomal dysfunction, oxidative stress, apoptosis, and dysregulation of MAP kinase signaling transduction pathways as well as autophagy [4]. The amount of cardiac involvement independently predicts mortality [4].…”