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Elsanhoury, A.; Tschöpe, C. Treatment of Transthyretin Amyloid Cardiomyopathy. Encyclopedia. Available online: (accessed on 21 June 2024).
Elsanhoury A, Tschöpe C. Treatment of Transthyretin Amyloid Cardiomyopathy. Encyclopedia. Available at: Accessed June 21, 2024.
Elsanhoury, Ahmed, Carsten Tschöpe. "Treatment of Transthyretin Amyloid Cardiomyopathy" Encyclopedia, (accessed June 21, 2024).
Elsanhoury, A., & Tschöpe, C. (2022, May 05). Treatment of Transthyretin Amyloid Cardiomyopathy. In Encyclopedia.
Elsanhoury, Ahmed and Carsten Tschöpe. "Treatment of Transthyretin Amyloid Cardiomyopathy." Encyclopedia. Web. 05 May, 2022.
Treatment of Transthyretin Amyloid Cardiomyopathy

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressively debilitating, rare disease associated with high mortality. ATTR-CM occurs when TTR amyloid protein builds up in the myocardium along with different organs, most commonly the peripheral and the autonomic nervous systems. Managing the cardiac complications with standard heart failure medications is difficult due to the challenge to maintain a balance between the high filling pressure associated with restricted ventricular volume and the low cardiac output. To date, tafamidis is the only agent approved for ATTR-CM treatment.

transthyretin amyloid cardiomyopathy tafamidis amyloidosis TTR

1. Introduction

Amyloidosis is a rare disease in which amyloid fibrils misfold and aggregate into toxic oligomers that build up extracellularly in the tissue [1]. It can affect different organs, most commonly the heart, kidneys, liver, spleen, peripheral nerves, and gastrointestinal tract [1][2]. There are different types of amyloidosis according to the nature of the misfolded protein. Immunoglobulin light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR) are the main two types of amyloidosis that affect the heart [2][3]. The first results from abnormal plasma cell production of monoclonal light chain fragments that misfold, causing myocardial toxicity [2][4]. The latter results from the dissociation and misfolding of the transthyretin (TTR), the protein that transports thyroxine (T4) and retinol-binding protein (RBP) in the serum and cerebrospinal fluid [2][5]. Both forms together account for nearly 95% of all cardiac amyloidosis cases [2][3][6]. TTR is mainly produced by the liver (90%) and circulates as a homotetramer. The choroid plexus and retinal epithelium produce the remaining 10% [7][8]. Destabilization of the tetramer results in the dissociation and aggregation of amyloid fibrils, which then accumulate in the interstitial space of various organs, causing progressive loss of function [9][10]. Transthyretin amyloid cardiomyopathy (ATTR-CM) is a rare, progressively debilitating disease that occurs when TTR builds up in the myocardium along with the peripheral and autonomic nervous systems [10]. ATTR-CM often presents with progressive heart failure with right- and left-sided symptoms, complicated by arrhythmias, most commonly atrial fibrillation, owing to conduction abnormalities [10][11]. However, cardiac symptoms are often proceeded by musculoskeletal manifestation (e.g., carpal tunnel syndrome) [12]. There are two forms of ATTR-CM, hereditary and wild type. Hereditary ATTR-CM (ATTRv) is characterized by a single amino acid substitution caused by a point mutation in the TTR gene, located on the long arm of chromosome 18 [13][14]. The most common mutation in ATTRv-CM is V122I, present in African Americans at a prevalence of 3.4% [15]. The prevalence of the V122I mutation in non-African American descents is low or possibly under-estimated. Wild-type ATTR-CM (ATTRwt), previously termed senile cardiac amyloidosis (SSA), is a non-familial form of the disease that predominantly presents in elderly male patients [16][17]. Both ATTR-CM forms are associated with impaired survival rates. The median survival of untreated ATTR-CM is 2.5 years for ATTRv V122I and 3.6 years for ATTRwt [18]. ATTR-CM is usually misdiagnosed, particularly early in its course owing to non-specific symptoms and multi-system involvement [19][20]. Lately, ATTR-CM is increasingly being recognized in clinical practice as a result of increased disease awareness and enhanced diagnostic techniques. Echocardiography-measured strain indices, advanced magnetic resonance imaging modalities, including T1 mapping and extracellular volume evaluation, as well as bone scintigraphy provide the necessary tools for the non-invasive diagnosis of ATTR-CM [20]. Moreover, genetic testing is instrumental to confirm the diagnosis of ATTRv. A definitive diagnosis could be reached with the aforementioned non-invasive tools, yet endomyocardial biopsy (EMB) evaluation is recommended in cases where AL amyloidosis cannot be ruled out via serum analysis [21]. However, histologic differentiation between ATTR and AL amyloidosis cannot be based solely on the Congo red staining. There is a compelling medical need to develop therapies for ATTR-CM, being an incapacitative illness that is eventually fatal if left untreated [22]. For many decades, the treatment of ATTRv-CM consisted of liver transplantation to remove the source of misfolded TTR or combined liver/heart transplantation, besides symptomatic treatments or solely heart transplantation in advanced ATTRwt-CM [23]. After the positive results of the ATTR-ACT study [24], the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have granted tafamidis 61 mg capsules marketing authorization for ATTRv and ATTRwt-CM. 

2. Symptomatic Treatments

The distinctive pathophysiology of ATTR-CM, characterized by both restrictive ventricular filling and reduced stroke volume, renders the use of standard heart failure medications difficult [18], summarized in Table 1. Loop diuretics are vital to reduce cardiac and peripheral congestion, especially in patients with right ventricular (RV) congestion and pulmonary edema, which subsequently relieves dyspnea [18][25][26], preferably taken in combination with aldosterone antagonists to prevent hypokalemia. However, blood pressure must be monitored adequately, since reducing preload may adversely affect renal perfusion and cardiac output [18]. Drugs acting on the renin-angiotensin system are poorly tolerated since they exacerbate hypotension, especially in patients with amyloid-associated autonomic dysfunction [18][26]. Beta-blockers are also poorly tolerated due to their negative chronotropic effect, given the restricted ventricular volume and the reliance of the cardiac output on the heart rate [18][26]. Calcium channel blockers and digoxin are generally contraindicated due to their profound binding to amyloid, which intensifies their pharmacologic effects and can result in cardiac rhythm disturbances or sudden death [18][26][27]. However, digoxin can be an option for pulse control in uncontrollable tachyarrhythmia absoluta. Alpha-1-adrenoreceptor agonists such as midodrine can treat orthostatic hypotension allowing higher doses of diuretics [28]. Amiodarone is the anti-arrhythmic agent of choice for patients with atrial fibrillation/flutter [28]. Oral anticoagulants are particularly required for patients with atrial fibrillation since blood stasis is a major source of thromboembolic events [18][29][30]. Pacemaker implantation is necessary for up to 25–36% of ATTRv patients and as many as 43% of ATTRwt patients [26][31]. However, in ATTR-CM patients pacemaker implantation is associated with high risk and worse survival [32]. There is no clear indication for prophylactic implantable cardioverter-defibrillator (ICD) therapy in ATTR-CM, since arrhythmias are not the primary cause of cardiac death in this population, except for patients with a high burden of ventricular tachycardias [33]. In general, the symptomatic management of ATTR-CM follows the CHAD-STOP concept: conduction and rhythm disorders prevention, high heart rate maintenance, anticoagulation, diuretics, and STOP ß-receptor and calcium-channel blockers, digoxin, and renin-angiotensin-aldosterone inhibitors [34].
Table 1. The use of standard heart failure therapies in transthyretin amyloid cardiomyopathy. * except for pulse control in uncontrollable tachyarrhythmia absoluta.
  Yes Sometimes No
Diuretics ± aldosterone antagonists Jcm 11 02148 i001    
Renin-angiotensin system inhibitors   Jcm 11 02148 i002  
Beta-adrenoreceptor blockers   Jcm 11 02148 i002  
Alpha-1-adrenoreceptor agonists   Jcm 11 02148 i002  
Calcium channel blockers     Jcm 11 02148 i003
Digoxin *     Jcm 11 02148 i003

3. Supportive Therapy with Epigallocatechin-3-Gallate (Green Tea)

Epigallocatechin-3-gallate (EGCG) is a polyphenolic natural compound most abundant in green tea [35]. EGCG is well tolerated, without major safety concerns. It has been shown to disaggregate amyloid fibrils and prevent TTR formation [36]. An observational study reported that the treatment of ATTR-CM patients with green tea extract for nine months was able to reduce left ventricular (LV) wall mass and thickness [36]. However, in a single-center retrospective study, patients who received a 675 mg daily dose of EGCG for a minimum of nine months did not gain any survival benefit compared to patients on solely symptomatic treatment [37].


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