**2.1 AL amyloidosis**

In AL amyloidosis, the deposits are formed by accumulation of kappa or lambda light chain proteins. These proteins in normal conditions are produced by plasma cells. However, when the cells overproduce light chains, they become amyloidogenic

#### **Figure 1.**

*Cardiac amyloidosis Pathophysiology. (A) Gross specimen inspection reveals a rubbery consistency of the myocardium. On some occasions, there can be evidence of intracardiac thrombi. The lighter-tan colored material is amyloid (green arrowhead) and the darker tissue represents normal myocardium (blue arrowhead). (B) Hematoxylin and eosin-stained (inset) microscopic sections with characteristic ring-like encircling of myofibers and the lack of the wavy fibrillar character of collagen. (C) 400× magnification and (D) is 400× magnification of the eosin-stained section with Congo Red staining microscopic sections, amyloid is red-orange, the protein is birefringent so that when Congo Red-stained tissue is viewed under polarized light it transmits an apple-green color.*

and deposit in the autonomic and peripheral sensory nervous system, spleen, lungs, and heart. This process can happen spontaneously or because of certain blood or immune system cancers. The major conditions associated with AL amyloidosis are multiple myeloma, Waldenström's macroglobulinemia, and B-cell lymphomas [6].

In addition to mechanical and architectural damage mediated by cardiac AL-fibril deposition, the soluble AL protein has been proven to have directly toxic effects on myocardial tissue. In experimental mouse models, it was shown that the rapid progression of heart failure and left ventricular dysfunction seen in AL amyloidosis is caused by toxic effect of circulating light chains on the already diseased myocardium by the amyloid protein deposition [7]. Later another group demonstrated that this toxic effect was mediated by p38α mitogen-activated protein kinases (MAPK) signaling which can upregulate pro-BNP. In fact, increased pro-BNP can be indicative of both amyloid disease activity and the degree of cardiac injury [8, 9].

#### **2.2 ATTR cardiomyopathy**

ATTR cardiomyopathy is caused by a transthyretin protein (TTP), previously known as prealbumin. It is a 55 kD protein whose main function is to transport both thyroxine (T4) and retinol-binding protein. About 85% of the TTP protein is produced in the liver, with the rest being synthesized in the choroid plexus, the retinal and ciliary pigment epithelia of the eye, and the pancreas [10–12]. TTP normally circulates as a homotetramer, with a small amount of transthyretin circulating in monomeric form. The monomeric form of transthyretin is prone to misfolding leading to a gradual formation of amyloid deposits. There are two types of transthyretin amyloidosis, hereditary or variant (ATTRv) and wild or senile (ATTRwt), both of which are caused by a misfolding of TTR protein.

#### *2.2.1 Hereditary ATTR (ATTRv)*

The hereditary type is caused by a TTR gene missense mutation the patient is born with, that causes a decrease in the stability of the tetramer conformation of the protein, promoting its dissociation into monomers and consequent leading to misfolding. Following the dissociation and misfolding events, the aggregation and deposition of insoluble TTR and nonbranching amyloid fibers, typically with a diameter of 10 nm, occur in the extracellular spaces of many tissues and organs [11]. Currently, there are over 130 identified point mutations in the gene that encodes TTR synthesis, which is located on the long arm of chromosome 18 [10, 11]. Most of these point mutations can cause amyloidosis disease. In the US, the most common mutation is the V122I, found in 3–3.5% of individuals of African descent. Despite the prevalence of the mutation within the African American population, cardiac amyloidosis still represents a severely underdiagnosed form of heart failure within this population [13]. ATTRv phenotypic expression will vary depending on the type of transthyretin protein mutation with symptoms ranging from severe peripheral neuropathy (familial amyloidotic polyneuropathy) to cardiac amyloid cardiomyopathy and conduction abnormalities (familial amyloid cardiomyopathy) [9–11].

#### *2.2.2 Wild-type or senile ATTR (ATTRwt)*

In ATTRwt, it is believed the phenomenon occurs as part of an unknown agingrelated mechanism, where TTR molecules misfold and deposit within the heart and other organs as amyloid fibrils. The most common clinical manifestations are motor and sensory neuropathy, gastrointestinal disturbances, and cardiomyopathy [14]. Both amyloid deposition and its effects on surrounding organs establish the phenotype of the disease [1]. Amyloid fibers can cause direct compression or obstruction in neighboring structures, which manifests as conditions such as carpal tunnel syndrome and vitreous opacities [14]. As amyloid fibers accumulate, patients experience progressive dysfunction with symptoms that may not start until years after the initial amyloid formation and deposition [11].
