INCIDENCE
The reported incidence for CA is 18-55 per 100,000 person-
years. In fact, its prevalence is difficult to determine
precisely, because the disease is often overlooked as it often
presents with non-specific symptoms[5]. A populationbased
autopsy study suggests that 25% of people aged 80-85 years have cardiac amyloid deposition[6]. The UK National
Amyloidosis Center database report, which includes data
on 11006 patients between 1997 and 2019, reports that the
number of patients suffering from amyloidosis increased
by 670% from 1987-1999 to 2010-2019[7]. Again, the same
report emphasizes that the incidence of CA, which was less
than 3% of all cases in the 1987-2009 period, increased to
14% in the 2010-2015 period and to 25% in the last 4 years.
It is conceivable that this increased incidence may be the
result of increased awareness of amyloidosis and diagnostic
cardiac imaging.
CLINICAL FEATURES
The disease usually first presents with shortness of breath
secondary to exertion, which is partly rapidly progressing
and results in peripheral edema and/or ascites. Left ventricular
diastolic dysfunction results in dyspnea. However,
significant hardening of the auricles likely contributes to
exertional dyspnea. The first signs of the disease include
cardiac arrhythmias (atrial/ventricular) and heart block
of varying degrees[8,9]. Deposits in the atrium cause dysfunction,
and thrombi can form even if the heart is operating
in sinus rhythm. This causes thromboembolism to be
seen as an early sign of the disease. If the clinician is not
aware of the phenomenon of left atrial systolic dysfunction
that is the source of neurological or systemic embolism, the disease can easily be overlooked[10]. Electrical conduction
disturbances in the heart due to amyloid deposition,
embolic events, and syncope are some of the reasons
for hospital admission for affected individuals. However,
patients often come to the health institution with cardiogenic
shock. In recent years, it can be said that awareness
of cardiac dysfunction caused by amyloidosis has increased[11]. In addition, it is reported that toxic infiltrative cardiomyopathy
from cardiac amyloidosis is much more common
than previously believed and is an underrecognized
cause of diastolic heart failure in particular[12].
PATHOGENESIS
Among the amyloidoses, CA has a special importance
because organ involvement significantly worsens the prognosis.
Cardiac amyloidoses are grouped under three headings:
AL amyloidosis due to amyloidogenic monoclonal
light chain production of a plasma cell clone; hereditary
TTR amyloidosis (ATTRv) caused by accumulation of
mutated Transthyretin (TTR); and wild-type (non-hereditary)
TTR amyloidosis (ATTRwt)[13]. Rarely, cardiac
involvement can be seen in secondary amyloidosis[14].
AL amyloidosis is a multi-organ disease, although involvement of one organ is usually predominant. The kidney is the first organ to be affected, and it manifests itself with nephrotic syndrome. The second most affected organ is the heart. There is a slight male dominance. Although the disease can be seen at any age from the fourth decade, it often occurs after the fifth decade[14]. AL amyloidosis is known to be the most severe of CAs. If the disease is not treated, the patient is expected to die within about 6 months after the onset of heart failure[15]. Although there is greater accumulation in the left ventricle in TTR amyloidosis, heart failure has been shown to be more severe in AL amyloidosis than in TTR amyloidosis[14,16]. Studies focusing on the pathogenesis of cardiac AL amyloidosis have shown that amyloidogenic light chains cause an increase in reactive oxygen products (ROP) and upregulation of heme oxygenase in rat cardiac muscle cells. Unfortunately, this process results in the deterioration of contraction and relaxation[14,17]. The initial response to amyloid deposition appears as lysosomal dysfunction. This leads to generation of highly ROP, functional loss in cells, impaired calcium homeostasis, and cell death, with disruption of autophagy[14,18]. The unbranched amyloid fibrils not only consist of precursor protein units, but also contain serum amyloid P and proteoglycans. Evidence has shown that amyloid can be reabsorbed, albeit slowly, after fibrillogenesis is stopped but generally the other proteins it contains are extremely resistant to degradation[14,19,20]. AL CA studies suggest that AL amyloidosis may have infiltrative as well as toxic effects[21]. In the light of the evidence, it would be more accurate to consider AL cardiac amyloidosis both as an infiltrative heart disease and as an infiltrative toxic cardiomyopathy.
Transthyretin amyloidosis: The main function of Transthyretin (prealbumin) produced by the liver is to transport thyroxine and retinol. The gene encoding the protein is located on chromosome 18. Although it can acquire monomeric amyloidogenic properties in conditions such as genetic damage and aging, it is a homotetramer in its normal state. It has been shown that monomeric amyloidogenic intermediates can subsequently spontaneously revert to amyloid fibrils[22]. Point mutations that destabilize the tetramer are involved in hereditary amyloidogenesis[23]. More than 100 amyloidogenic mutations have been reported in TTR. However, the most common cause of familial amyloid cardiomyopathy is the isoleucine mutation at position 122, which is also seen in 3.9% of the Afro-Caribbean population (V122I)[24]. Caucasian variant mutations have also been identified: Leu111Met (Denmark), Ile68Leu (Italy), and Thr60Ala (Appalachian and Irish regions)[25].
The mechanism of heart failure in individuals carrying the V1221 allele has not been clearly elucidated. However, it is suggested that individuals carrying this allele have an increased risk of heart failure and death, particularly at the age of 60 to 65 years[26]. Connors et al.s study showed that ATTRv patients with the V122I mutation were older, had more pronounced ventricular hypertrophy, had lower left ventricular ejection fractions, and had more atrial dilatation on echocardiography (ECO) than Black Americans with AL amyloidosis. However, despite these findings, the patients' symptoms are less severe[27,28]. An isolated cardiomyopathy is often an expected finding in individuals with the V122I mutation. It is not surprising that cardiac involvement and familial amyloid polyneuropathy are more common in individuals with TTR gene mutations, which are endemic in Europe and Asia.[28]. Applications to healthcare institutions with non-cardiac symptoms such as purpura, easy bruising, carpal tunnel syndrome, and peripheral polyneuropathy are substantial[8]. When examining the mechanism of cardiac damage, as mentioned above, it is well known that light chains have direct toxicity to myocytes from those affected by AL amyloidosis[21]. However, it has been shown that mutant transthyretin fibrils can trigger different mechanisms that cause damage in cardiac muscle cells. These mechanisms include triggering the proinflammatory cascade mainly by NF-kB activation, disruption of calcium metabolism, and downregulation of proteosomal activity[28,29].
Transthyretin-associated nonhereditary amyloidosis (ATTRwt): The main reason ATTRwt is called senile systemic amyloidosis (SSA) is that the disease often begins after the age of 70. Similar to AL amyloidosis, it has a strong male predominance[6,20]. The prevalence of ATTRwt amyloidosis is not known precisely because the diagnosis cannot be made in many cases. Prolongation of life expectancy and the availability of modern diagnostic tools such as cardiovascular magnetic resonance imaging (CMR) and Technetium-99m-3,3-diphosphono-1,2-propanodicarboxylic acid (99m Tc-DPD) scintigraphy can be counted as the reason for the increasing prevalence today[7,10,20,30]. ATTRwt type CA is thought to result from misfolding in the TTR due to advancing age[12]. Oxidative modifications of proteins in aging-related proteogenesis and damage repair mechanisms are thought to contribute to the degradation and fibrillation of native TTR[31]. Cardiac symptoms in ATTRwt patients usually present as shortness of breath, fatigue, and malaise, and these symptoms are generally not considered to be related to old age and further investigation is not performed. This is one of the most important reasons for the delay in diagnosis[6,8,9]. Cardiac vascular amyloid deposition is a major cause of anginal chest pain, which can occur even in patients without obstructive coronary stenosis. Patients have heart failure but typically preserved ejection fraction[32]. Studies suggest that mean left ventricular wall thickness is greater in ATTRwt than in ATTRv[33]. Figure 1 shows the increase in ventricular thickness in the explant material of the patient who underwent cardiac transplantation due to ATTRv at Ege University (Figure 1). ATTRwt is expected to have a much better natural course than other amyloid cardiomyopathies[12,34]. In one of the first studies, the median survival from admission with symptoms of heart failure was 60 months, compared to 5.4 months in patients with cardiomyopathy from AL amyloidosis[33].
The distinction between ATTRwt and ATTRv needs to be made carefully as the families of patients diagnosed with ATTRv should be given genetic counseling and their family members should be screened for this disease. Also, if the individual has a V122I mutation, closer monitoring is required as aggressive progression may occur. In addition, a confirmed diagnosis of ATTRv is essential for the patient to receive only treatments approved for ATTRv[35]. Although some authors propose a diagnostic algorithm including NT pro-BNP level and age at diagnosis to distinguish senile ATTR cardiac amyloidosis from AL primary cardiac amyloidosis, it should not be forgotten that the definitive distinction can only be made with endomyocardial biopsy (EMB)[36,37].
DIAGNOSIS
The first steps on the way to the correct diagnosis of cardiac
amyloidosis is obtaining a detailed history, evaluating the
symptoms, and clinically suspecting the disorder as a result
of the examination. This suspicion is followed by laboratory
studies and cardiac imaging.
Scanning
International experts (ASNC/AHA/ASE/EANM/HFSA/
ISA/SCMR/SNMMI) recommend the appropriate use of
ECO, CMR, and radionuclide imaging in the diagnosis of
cardiac amyloidosis and/or in the evaluation of patients
with cardiac amyloidosis[38]. ECO has the ability to offer
clues to further testing, and CMR has the ability to show
an infiltrative process. However, 99m technetium pyrophosphate
scintigraphy allows for non-invasive diagnosis os
CA, although the mechanism of attachment of radioactive
material to amyloid deposits cannot be fully elucidated.
In this respect, it is considered as an important milestone
in the clinical diagnosis of cardiac amyloid[35,39]. It has
been reported that cardiac amyloidosis can be diagnosed
by evaluating the patient together with non-cardiac biopsy,
Tc-99m pyrophosphate scintigraphy and positron emission
tomography data using molecules targeting myocardial
amyloid uptake, as well as echocardiographic and
CMR findings in cases where the disease cannot be proven
with endomyocardial biopsy[38] (Table I). In addition, it
was suggested by the same authors that the need for invasive
endomyocardial or extracardiac biopsy is eliminated
if there are consistent echo or CMR findings in patients
without monoclonal plasma cell increase, as well as findings
consistent with ATTR cardiac amyloidosis on 99m Tc-
PYP/DPD/HMDP scintigraphy.
Table I: Diagnostic Criteria for Cardiac Amyloidosis (Dorbala, 2019)
Laboratory
Patients with suspected CA after evaluation should first be
evaluated for monoclonal gammopathy for AL-CA[40].
Laboratory tests should include serum-free kappa and
lambda light chains, as well as immune-fixed serum and
urine protein electrophoresis (SPEP/UPEP with IFE). The
sensitivity of serum plasma electrophoresis for AL amyloidosis
is lower than that of serum IFE (~70% and >90%,
respectively)[41]. Troponin, BNP (brain natriuretic peptide)
and NT-proBNP (N-terminal probrain natriuretic
peptide) are other markers whose usefulness in the diagnosis
and for predicting prognosis has been investigated. In
AL-CA, increased production of monoclonal AL also activates the MAP kinase signaling pathway, increasing natriuretic
peptide production. This results in elevated brain
natriuretic peptide (BNP) and N-terminal proBNP level[42]. However, the utility of these tests in the diagnosis of
TTR-CA is very limited. Patients with ATTR amyloidosis
often require EMB to confirm the diagnosis. When ATTR
amyloidosis is detected, genetic testing for the TTR gene
mutation should be performed. In addition, it has been
reported that circulating retinol-binding protein 4 may be
useful in identifying patients with ATTR-CA with V122I
mutant heart failure[43]. It should not be forgotten that
a high troponin level can be used to predict a worse prognosis
in both AL-CA and ATTR-CA, even if it is not in the
diagnosis[37].
Biopsy
In patients with suspected cardiac amyloidosis, scintigraphy
or biopsy should be performed after monoclonal protein
tests[44]. While biopsy is valid for all forms of cardiac
amyloidosis, noninvasive criteria are acceptable for ATTR
only[45]. In cases with monoclonal proteinemia, the accumulated
amyloid form can be detected in biopsy taken from
affected organ (such as endomyocardial, abdominal fat,
bone marrow)[46]. Because of its invasive nature, endomyocardial
biopsy carries a small risk of complications,
which can be serious. Its implementation requires technical
expertise. Fat pad biopsy is less invasive and carries
less risk, but its sensitivity in ATTR-CA is highly variable[47]. All types of cardiac amyloidosis cause extracellular
amyloid deposition and the accumulating form of amyloid is not expected to be distinguished by light microscopy.
Although the type of amyloid deposition cannot be clearly
differentiated from the deposition pattern, AL amyloidosis
predominantly presents with pericellular, endocardial,
and arterial and/or arteriolar deposits; nodular deposits are
usually seen in ATTR (Figure 2A)[48]. Regardless of left
ventricular wall thickness, the diagnosis of CA is confirmed
when amyloid deposition is demonstrated on endomyocardial
biopsy with Congo red (Figure 2B,C). Once amyloid
deposition is detected, the next step should be the classification
of the amyloid fibril protein. The gold standard in
classification is mass spectrometry, immunohistochemistry,
or immunoelectron microscopy, which are routinely
used in specialized centers (Figure 2D)[49]. In a study of
117 patients with amyloid, immunohistochemical analysis was reported to have 96% sensitivity and 100% specificity in
identifying hereditary amyloidoses[50]. In Ege University,
where the first cardiac transplantation was performed in
1998, myocardial biopsy has been used for the diagnosis of
cardiac diseases for approximately 25 years. In cases where
clinical, laboratory data or histopathology arouses suspicion,
amyloid accumulation in the tissue is investigated
with histochemical congo red. When cardiac amyloidosis
accumulation is detected, immunohistochemical subtyping
is performed with Amyloid A, C4d, Fibrinogen, Pre Albumin/
Transthyretin (TTR), Lambda, Lysozyme, and Kappa.
Evaluation using these antibodies provides sensitivity and
specificity rates similar to the study of Schönland et al. in
detecting hereditary amyloidosis in our center.
TREATMENT
Medical Treatments
In patients with cardiac amyloid, the two ventricles are usually
affected together; moreover, the left ventricle is greatly
shrunk secondary to muscle hypertrophy. Therefore,
durable left ventricular assist devices are often not a good
option[51]. Amyloid deposition, which causes damage to
organs, is seen in both ATTR and AL amyloidosis, but the
treatment regimens of these diseases are different[52]. The
main agent used in the treatment of ATTR is TTR silencing,
which is involved in the synthesis of TTR in the liver,
TTR stabilization that prevent misfolding by binding to the
tetramer, and TTR disruption that ensures the clearance of
amyloid from the organism[35]. The TTR stabilizer tafamidis,
which was approved in 2019, has taken its place in
the treatment of amyloid cardiomyopathy[7,53]. In addition,
new treatments such as patisiran and inotersen, which
reduce hepatic TTR production in hereditary ATTR amyloidosis,
are also promising[7,54,55].
Since light chain toxicity causes cardiac damage in AL amyloidosis, correction of the relevant light chain should be the main goal[52]. Autologous stem cell transplantation (ASCT) is among the emerging treatments for AL amyloidosis patients and has been shown to have very good longterm results. However, it has been reported that it may be an appropriate treatment option in a small proportion of patients with CA[56]. The advent of effective anti-plasma cell therapies has changed the definition of hematological response from a complete response to a modified, strict, and absolutely relevant free light chain response. The agents used in anti-plasma cell therapy are mainly alkylating agents, immunomodulators, corticosteroids, and proteasome inhibitors[52].
Orthotopic Cardiac Transplantation
Cardiac transplantation (CTx) may be considered in cardiac
AL amyloidosis responding to light chain suppressive
therapies and in cases with end-stage heart failure secondary
to ATTR. In the past, cardiac amyloidosis, especially the
AL type, was a contraindication for heart transplantation
(HTx) because the disease is systemic and carries a high risk
of death. However, effective therapies used today, including
proteasome inhibitors, have made heart transplantation an
option for AL-CA patients as well[57-59]. Cardiac amyloidosis
patients have a higher heart transplant waiting list
mortality than cardiomyopathy from other causes[51,60].
The 2018 UNOS heart allocation scheme gives priority
clearance for CTx to patients with CA as they are at high
risk of mortality[51,61]. For patients with ATTRwt-CA
or ATTRv-CA with the V122I mutation, heart transplantation
alone is usually sufficient, but may need to be considered
for dual heart/liver transplantation in the presence
of other variants such as Thr60Ala[52]. However, followup
studies unfortunately show that disease recurrence and
improvement in extracardiac manifestations may occur
after Tx[62]. Cardiac transplantation was performed on a
patient with ATTRwt-CA mutation in our Ege University
heart transplant program. However, the patient died from
Candida sepsis at 6 weeks postoperatively.
Conflict of Interest
The authors declare no potential conflicts of interest regarding the
research, authorship and/or publication of this article. Only the
authors are responsible for the content and writing of the article.
Authorship Contributions
Concept: AA, DN, FYB, Design: AA, DN, FYB, Data collection or
processing: AA, DN, FYB, Analysis or Interpretation: AA, DN, FYB,
Literature search: AA, DN, FYB, Writing: AA, DN, FYB, Approval:
AA, DN, FYB
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