Continuing Education Activity

Transthyretin amyloid cardiomyopathy is a rare but severe cause of restrictive cardiomyopathy caused by the accumulation of transthyretin fibrils in the myocardium. It can present with new or worsening heart failure or new conduction system disease. Due to the lack of knowledge and efficient diagnostic modalities, this disease was often missed in clinical settings. However, with the advent of contemporary cardiac imaging techniques and effective therapeutic options, early diagnosis and treatment are possible. This activity reviews the pathophysiology, diagnosis, and treatment of Transthyretin amyloid cardiomyopathy and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Summarize the epidemiology of transthyretin amyloid cardiomyopathy. .
• Explain the common cardiac and non-cardiac findings associated with transthyretin amyloid cardiomyopathy.
• Describe the typical imaging findings associated with transthyretin amyloid cardiomyopathy.
• Outline the available treatment options for transthyretin amyloid cardiomyopathy.

Access free multiple choice questions on this topic.

Introduction

Transthyretin amyloid cardiomyopathy (ATTR-CM) is one of the types of systemic amyloidosis in which misfolded transthyretin (TTR) protein gets deposited in the myocardium. Another pertinent etiology of cardiac amyloidosis is due to the deposition of immunoglobulin light-chain (AL) aggregates. Several other amyloidogenic proteins may get deposited in various organs and tissues but rarely involve the myocardium.[1]

Transthyretin amyloidosis (ATTR) is a systemic disease. Due to amyloid deposition in extracardiac tissues, patients often have associated extracardiac signs and symptoms. However, isolated cardiac involvement has been reported as well.[2] Diagnosis of ATTR-CM was often missed or delayed due to previously lacking optimal diagnostic modalities. ATTR-CM often progresses to advanced stages with minimal clinical signs and symptoms initially and is therefore associated with poor prognosis.[3]

With improving bone avid radiotracer scintigraphy technology and the advent of new therapeutic options, diagnosis and treatment of ATTR-CM have become possible. As diagnostic capabilities are getting better, studies have shown a higher prevalence of ATTR-CM in patients with heart failure with preserved ejection fraction than previously perceived.[4]

Etiology

Transthyretin (previously known as prealbumin) is a normal circulating protein that functions as a carrier protein for retinol (vitamin A) and thyroxine. It is primarily synthesized by the liver (>95%). Additionally, in small amounts, it is also produced in the choroid plexus and retinal epithelium.[5][6] Usually, it circulates in a tetrameric form composed of 4 beta-sheet-rich monomers. However, structural changes in the TTR protein can cause it to misfold and lose the tetrameric form, causing it to aggregate and deposit in various tissues. The myocardium and peripheral nerves are the most common sites for the deposition of misfolded TTR protein.[7] The clinical phenotype of ATTR depends on the type and extent of tissue involvement.[8]

Chromosome 18 carries the gene for TTR protein. Therefore, a mutation in the gene coding for TTR can cause structural changes in TTR, causing it to misfold. This type of ATTR is referred to as hereditary transthyretin amyloid (hATTR). In addition, it has been observed that the normal aging process can render ATTR tetramer prone to misfolding, even when the genetic sequence of the TTR is expected.[3] This type of ATTR is referred to as wild-type transthyretin amyloid (wATTR).[9]

Myocardial deposition of misfolded TTR protein in both types of ATTR (hATTR and wATTR) causes a clinical phenotype of transthyretin amyloid cardiomyopathy (ATTR-CM). However, emerging clinical data have shown that wATTR-CM is more common than hATTR.[10][11]

Epidemiology

The prevalence data of ATTR-CM is limited and not well characterized.[12] Limited data is due to missed and delayed diagnosis in most patients, because of heterogenous clinical presentation, and majorly due to previously lacking sensitive diagnostic modality. With recent advancements in nuclear cardiac imaging with technetium pyrophosphate scan, the diagnosis of ATTR-CM is possible without cardiac biopsy. Therefore, more patients are being screened and diagnosed with ATTR-CM.[13] At the same time, survival has improved, increasing its prevalence. As a result, 5,000 to 7,000 new cases are identified annually in the United States. Recent studies suggest a prevalence rate of approximately 20% in a cohort with heart failure (HF) with increased myocardial wall thickening of more than 14 mm.[14][15] Thus, the prevalence is increasing as survival has improved dramatically.

wATTR-CM is the more common type of ATTR-CM. It is primarily seen in older patients and has a male predominance.[10][11] Several autopsy studies have shown that the incidence of wATTR deposits increases with advancing age.[16][17] It is often seen in conjunction with other cardiac diseases associated with aging, like aortic stenosis, atrial fibrillation, and heart failure with preserved ejection fraction (HFpEF).[17][18][19] A recent community-based cohort study reported a substantial prevalence of ATTR-CM in older male patients with HFpEF and left ventricular hypertrophy (LVH).[4]

The lower prevalence of wATTR in females may partly be understood by the hypothesized cardioprotective effect of estrogen and possible underdiagnosis due to smaller heart size in females not meeting the screening threshold for ATTR-CM. Compared to wATTR, hATTR is more equally distributed among males and females. However, clinical expression is still more common in males.[20] In a pooled analysis from 69 studies and 4669 patients with ATTR-CM, 17% were females, and 83% were men. Studies of wATTR had the lowest proportion of females (9%), whereas hATTR had the highest (29%).[21]

The TTR gene is present on chromosome 18. hATTR follows an autosomal dominant inheritance pattern. However, disease penetrance is more complicated and less understood. The age of onset of clinical disease in hATTR-CM varies widely and depends on the type of mutation. More than 100 different TTR mutations have been identified. These mutations have varied geographical distribution. The most common mutation in the USA is Val122lle. It is seen in approximately 3 to 4% of African Americans, with 1.5 million carriers. The most common mutation in the rest of the world is Val30Met.[22]

Pathophysiology

Misfolded TTR protein forms insoluble fibers. In the heart, they occupy interstitial spaces in the myocardium, making it stiff and rigid. TTR deposition causes further myocardial fibrosis and eventually affects its mechanical function. Due to TTR deposition, the myocardium appears thickened and hypertrophied on cardiac imaging. Compromise in ventricular compliance initially causes diastolic dysfunction. In advanced stages, myocardial dysfunction can result in globally reduced systolic dysfunction.[23]

Diastolic dysfunction causes an increase in left ventricular end-diastolic pressure and left atrial pressures. Persistently increased left atrial pressures and left atrial dilatation increased the likelihood of developing atrial arrhythmias in these patients. Myocardial infiltration often affects the electrical conduction system as well.[24] Ventricular arrhythmias have been reported in ATTR-CM but are significantly less common than AL cardiomyopathy.[25] The lower frequency of ventricular arrhythmias might be explained due to the direct cardiotoxic effect of light chain protein.[26]

The autonomic and peripheral nervous systems are common extra-cardiac sites for misfolded TTR protein deposition. It is seen that hATTR affects the nervous system more commonly, whereas cardiomyopathy is more commonly seen with wATTR-CM.[10][11]

Histopathology

Endomyocardial biopsy with congo red staining remains the gold standard to diagnose ATTR-CM.[27] The sensitivity and specificity reach up to 100% if a biopsy specimen is grabbed from greater than or equal to 4 intracardiac sites. However, the sensitivity of extracardiac tissue biopsy varies significantly and is usually not recommended, especially with the wATTR disease process.[28] In experimental labs, immunochemistry and tandem mass spectroscopy can be used to identify the type and nature of misfolded precursor protein.[29]

With the advent of cardiac technetium pyrophosphate scan and cardiac MRI, the need for tissue diagnosis has limited clinical significance.

History and Physical

ATTR-CM typically presents with clinical signs and symptoms of progressive congestive heart failure. In addition, they often have cardiac arrhythmia and conduction system disease, which may occur years before the development of heart failure.[30]

hATTR can have a variable presentation. It can present as primary cardiomyopathy or primary autonomic or peripheral neuropathy. Not uncommonly, it can present mixed clinical features of both cardiomyopathy and neuropathy.[31] The age of onset of clinical disease is also variable and depends on the type of mutation.[32] Comparatively, the clinical course of wATTR follows a more consistent pattern.[11][23][33] Comparatively, polyneuropathy is more familiar in hATTR than wATTR. Both conduction system disease and arrhythmias are more common with wATTR than hATTR.[34]

Congestive Heart Failure

ATTR-CM should be suspected in old patients with recurrent HF exacerbations, irrespective of their ejection fraction status. Often, they will have fatigue, poor exercise tolerance, and shortness of breath with the New York Heart Association (NYHA) functional class II to IV. In addition, it is seen that they have significant right ventricular involvement, causing peripheral congestive symptoms like elevated jugular venous pressure, lower extremity edema, hepatic congestion, and ascites. Often, at advanced stages, cardiorenal syndrome ensues. Interestingly, these patients often develop intolerance to beta-blockers and angiotensin convertase enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB), which they might have tolerated previously.[35]

Cardiac Arrhythmias

Atrial fibrillation is the most common cardiac arrhythmia seen in ATTR-CM. It is present in 40 to 60% of patients at the time of diagnosis. Eventually, all patients develop atrial fibrillation during the disease. When present, it is usually of persistent type.[36] Not uncommonly, non-sustained ventricular tachycardia is also seen.[37][24] Atrial fibrillation is poorly tolerated in this population due to the diastolic dysfunction and the restrictive nature of ATTR-CM. In atrial fibrillation, patients are often symptomatic and might experience significant shortness of breath, palpitation, and hypotension, even at a slower ventricular rate. In addition, they often present with frequent heart failure exacerbation.[24] Not uncommonly, patients may present with stroke or systemic embolization due to undiagnosed atrial fibrillation. In addition, all patients with ATTR-CM are at increased risk of forming intracardiac thrombus irrespective of their rhythm status.[38]

Conduction System Disease

Deposition of TTR amyloid in interstitial space disrupts the normal conduction system of the heart. Patients may present with varying degrees of heart block due to the involvement of atrioventricular (AV) nodal and infra AV nodal conduction. Due to associated conduction system disease, atrial fibrillation usually presents with a slow or controlled ventricular response. Patients will give a history of lightheadedness, presyncope, and unexplained falls. Elevated jugular venous distension with cannon A wave can be seen when the patient is in complete heart block due to AV dissociation. Eventually, one out of every three patients with wATTR-CM patients ends up requiring permanent pacemaker (PPM) implantation.[30][33]

Extracardiac Manifestations

Extracardiac TTR amyloid deposition can cause nerve entrapment in close spaces. Bilateral carpal tunnel syndrome (CTS) and lumbar spinal stenosis are commonly seen with the ATTR disease process.[16] More than half of wATTR-CM patients initially present with bilateral CTS.[11] When present, CTS usually occurs 5-10 years before the development of overt wATTR-CM.[39] Lumbar spinal stenosis occurs due to TTR deposition in ligamentum flavum causing spinal foraminal narrowing.[40] Tendinopathies and spontaneous tendon ruptures are not uncommon. A retrospective study showed that 33% of wATTR-CM patients had spontaneous rupture of the distal biceps tendon.[41] Autonomic neuropathy may manifest as orthostatic hypotension, erectile dysfunction, dyshidrosis, or gastrointestinal motility issues. "Natural cure of blood pressure" or intolerance of blood pressure-lowering medications, especially beta-blockers and ACEi/ARB, is in part related to autonomic dysregulation. Both autonomic and peripheral neuropathies are more common in hATTR than wATT.[3]

Clinical suspicion for ATTR-CM should be heightened, especially when cardiac and extracardiac findings are seen simultaneously.

Evaluation

Electrocardiogram (ECG)

Electrocardiogram (ECG) of ATTR-CM is described to have low voltage ECG patterns along with poor R wave progression across the precordial leads.[42] More commonly, the presence of Q waves unrelated to prior myocardial infarction (pseudo-infarct pattern) has also been reported.[31] Thus, the presence of low voltage ECG disproportionate to the LV wall thickness may help to differentiate ATTR-CM from other causes of left ventricular hypertrophy (LVH), like hypertensive heart disease and hypertrophic cardiomyopathies. 

However, these ECG findings are not acceptably sensitive.[35] They can aid with the diagnosis but should not be used as a screening tool.[43] Only 25 to 40% of patients with ATTR-CM may have low voltage ECG.[30] Moreover, the sensitivity of ECG is highly dependent on the definition used to describe the criteria for low voltage.[44] A high voltage QRS pattern ECG has been reported in the Val122Ile variant of hATTR.[45] Therefore, the presence of LVH on ECG does not exclude ATTR-CM.

Echocardiogram

Myocardial infiltration of ATTR causes concentric bi-ventricular hypertrophy. A septal wall thickness of >12 mm should heighten clinical suspicion but is not diagnostic.[46] Due to infiltration, the myocardium is more echogenic compared to that seen in ventricular hypertrophy. It is often referred to as a "granular sparkling appearance."[3] Small LV cavity size, biatrial enlargement, thickened interatrial septal, and thickened valves are other structural abnormalities that are commonly seen. Diastolic dysfunction with a restrictive flow pattern is frequently seen on the Doppler exams. Due to increased pressure in the left atrium, restrive flow pattern through the mitral valve, and the irregular atrial endocardial surface because of amyloid deposition, the left atrium is prone to form thrombus even in the absence of atrial arrhythmias.[47]

Strain echocardiography has emerged as a practical tool in the early detection of cardiac amyloidosis. "Apical sparing" with progressive worsening of longitudinal strain when moving to the midventricular and basal segment is characteristic of cardiac amyloidosis. It gives an appearance of a "bulls-eye pattern," sometimes referred to as "cherry on top" in the strain imaging. The apical to basal strain ratio and apical to mid-ventricular plus basal strain have shown good diagnostic accuracy.[47]

Echocardiographic parameters can help identify patients with cardiac amyloidosis but cannot be used to differentiate between hATTR, wATTR, or AL type.[48]

Cardiac Magnetic Resonance Imaging (CMR) 

Cardiac magnetic resonance imaging (CMR) has considerable utility as both a screening tool and a tool to track treatment response.[35] CMR with late gadolinium enhancement (CMR-LGE) can detect extracellular deposits of amyloid. The presence of diffuse transmural or subendocardial deposits can diagnose amyloidosis with a sensitivity and specificity of 85 to 90%.[49] The inability to "null" or suppress the myocardial signal on phase-sensitive inversion recovery (PSIR) imaging of an LGE scan is also diagnostic.[50]

It is seen that T1 signals are amplified in cardiac amyloidosis, similar to post-contrast extracellular volume fraction (ECV). CMR with parametric imaging can identify native (non-contrast) myocardial T1 signal and ECV. Parametric imaging is believed to be a more sensitive and reliable measure of amyloid burden and, therefore, can be used for treatment tracking.[50][51]

CMR cannot reliably differentiate between hATTR, wATTR, or AL type.[52]

Nuclear Imaging 

Nuclear imaging using avid bone radiotracers is the sole imaging modality available that can accurately diagnose ATTR-CM without the need for a biopsy. There are majorly three types of bone avid radiotracers that are available. The most commonly used is technetium pyrophosphate (TC-PYP) (available in the USA). Other available radiotracers are Tc-DPD and Tc-HMDP (available in Europe).[3]

During the scan, TC-PYP is injected intravenously. Once in circulation, it selectively binds to osseous tissue and ATTR fibrils.[32] A possible mechanism of myocardial retention of TC-PYP could be due to the microcalcifications associated with ATTR cardiomyopathy.[53] Myocardial uptake of TC-PYP is visually graded compared to the bone update of the ribs to get a semiquantitative scheme.[54]

Table

TC-PYP scan offers few advantages over other imaging modalities. TC-PYP scan can detect ATTR deposition in the myocardium much earlier than the development of structural and conduction system changes. TC-PYP scan can diagnose ATTR-CM with 100% specificity without the need for biopsy when a grade 2 or 3 update is present, and there are no monoclonal proteins on urine and serum testing.[13] Quantitative comparison of radiotracer uptake of the heart and contralateral chest can help to differentiate ATTR from AL cardiac amyloid. A heart to the contralateral chest uptake ratio of 1.5 or greater suggests ATTR presence.[55] This ratio has also demonstrated a prognosticating value. ATTR-CM patients with a ratio of 1.6 or greater have the worst 5-year outcomes  

The specificity of the TC-PYP scan to differentiate ATTR from AL does reduce when monoclonal proteins are present. 40% to 50% of patients with ATTR were found to have coexisting unrelated monoclonal gammopathy.[56] In these cases, a myocardial biopsy might be necessary to diagnose ATTR-CM.[35]

Genetic Testing 

Genetic testing may be obtained once the diagnosis of ATTR-CM is confirmed (either with nuclear imaging or with cardiac biopsy). Genetic testing will help to differentiate hATTR-CM from wATTR-CM. In addition, differentiating between hATTR-CM from Wt-ATTR-CM might be needed to accommodate disease-specific treatment.[57]

Treatment / Management

Supportive Treatment of Cardiac Involvement

Management of Heart Failure

Dietary sodium restriction and diuretic use are essential to maintain euvolemia in ATTR-CM patients. Achieving and maintaining euvolemia is often challenging in these patients due to the small LV cavity and autonomic dysfunction. Loop diuretics with higher oral bioavailability (e.g., torsemide and bumetanide) are often preferred in combination with aldosterone receptor blockers. Beta-blockers and ACE, ARBs, or angiotensin receptor-neprilysin inhibitors (ARNi) therapies are usually not well tolerated because of ensuing hypotension due to the reasons mentioned above. With the progression of ATTR-CM and reduction of LV cavity size, stroke volume, and cardiac output reduce, resulting in a reduction in renal perfusion, causing cardio-renal syndrome.[58] In advanced cases, midodrine and compression stockings may be used. Verapamil (non-dihydropyridine calcium channel blockers) should be avoided due to reports of worsening hypotension and conduction system problems.[59]

Management of Arrhythmias

ATTR-CM patients have a narrow scope of heart rate variability. Extreme tachycardia and bradycardia are poorly tolerated due to the small LV cavity, high-grade diastolic dysfunction, and low stroke volume. Similarly, atrial contraction (often called "atrial kick") is crucial in ventricular filling. Therefore, rhythm control is the preferred strategy for managing atrial fibrillation. Rhythm control can be achieved by antiarrhythmics or by catheter ablation. Amiodarone is the preferred agent when using antiarrhythmics due to its better safety profile when dealing with cardiomyopathy and some clinical data demonstrating its safety in ATTR-CM.[36] However, these patients are at increased risk of developing intracardiac thrombus even when receiving anticoagulant therapy.[60] Therefore, all ATTR-CM patients with atrial fibrillation should be on life-long anticoagulation irrespective of their CHADs-VASc score.

A significant percentage of ATTR-CM patients develop conduction system disease, eventually requiring permanent pacemaker support.[30] When symptoms of palpitations, presyncope, or frank syncope are reported, Holter or event monitoring must be considered. When indicated, permanent pacing should be done per ACC/AHA/HRS guidelines.[61] In pacemaker-dependent patients with advanced disease who have recurrent heart failure exacerbation or have low systemic blood pressure, a lower rate limit for pacing can be increased to improve their cardiac output. Bi-ventricular pacing is often considered when significant ventricular dys-synchrony develops due to chronic right ventricular pacing. Implantable cardioverter-defibrillator (ICD) should only be used for secondary prevention and follow ACC/AHA/HRS guidelines. There is no clear data on ICD use for primary prevention in cardiac amyloidosis.[62][63]

Therapies Targeting Transthyretin

Currently, three major pharmacological strategies are being studied to specifically target ATTR-CM.[3] These are summarized in the table below. 

Table

Patisiran [64],  Inotersen [65]

The first two strategies described in the table above have a few pharmacological agents approved for clinical use by the US Food and Drug Administration (FDA). The third strategy of using doxycycline with tauroursodeoxycholic acid is still being evaluated in clinical trials.[3][57]

Table

Patisiran (Onpattro) &

Tafamidis

Tafamidis and tafamidis meglumine received FDA approval in May 2019 for treating ATTR-CM. Tafamidis selectively binds to the thyroxine-binding sites of TTR. It stabilizes the tetrameric form and slows dissociating into monomers, reducing amyloid formation.[68] It works by reducing further ATTR deposition; it can slow disease progression but may not reverse it. Also, treatment with tafamidis should be started early in the disease process to see the clinical benefits.

Tafamidis has demonstrated a reduction in all-cause mortality and cardiovascular hospitalization in both hATTR-CM and wATTR-CM patients with heart failure of NYHA functional Classes I and II. In addition, its treatment has been shown to reduce the decline in functional capacity (six-minute walk test) and quality of life (Kansas City cardiomyopathy questionnaire). In approximately six months, functional improvement was seen, and mortality reduction took nearly two years.[68][69] Based on these findings, the European Society of Cardiology has given a class 1B recommendation to use tafamidis in hATTR-CM and wATTR-CM patients with heart failure of NYHA functional classes I and II.[70]

The FDA-approved dose for tafamidis is 61 mg orally once daily, and for meglumine, it is 80 mg orally once daily. 

Tafamidis is well tolerated. In the ATTR-ACT trial, 441 patients with ATTR-CM were randomly assigned tafamidis 80 mg, 20 mg, and placebo in a 2:1:2 ratio. Patients were followed for 30 months. The rate of adverse events was similar in the treatment and placebo groups.[71] 

Organ Transplantation

A liver transplant can remove mutant TTR from circulation. It has previously been used to treat hATTR but cannot be used for wATTR.[72] Since the advent of TTR-specific therapies, the need for liver transplants has dramatically reduced. Although theoretically, combined liver and heart transplants can be done in selected patients with both wATTR-CM and hATTR-CM, it is rarely seen in clinical practice as these patients are often of advanced age with poor long-term survival.[73]

Differential Diagnosis

Light chain amyloid (AL) cardiomyopathy

Other causes of infiltrative cardiomyopathy

• Cardiac sarcoidosis
• Cardiac hemochromatosis
• Fabry disease
• Mucopolysaccharidoses

Hypertrophic cardiomyopathy

Pertinent Studies and Ongoing Trials

A gene-editing approach using CRISPR-associated protein 9 is under development to treat hATTR. This approach hypothesizes that target DNA can be permanently modified. Thus, permanently silencing mutated TTR may treat hATTR.

PRX-004 is being studied to treat ATTR amyloidosis. It is hypothesized to work by removing ATTR deposits from the myocardium.

Staging

Based on the threshold of troponin T ( >0.05 ng/ml) and Nt-proBNP (>3,000 pg/ml), Grogan et al. have described the Mayo Clinic wATTR-CM staging system.[33] The system classifies the disease into 3 stages, which are defined as:

Table

Prognosis

Data suggest that survival in hATTR-CM is worse when compared to wATTR-CM. Mean survival in hATTR-CM (Val122lle) is approximately 2.5 years. hATTR patients with isolated polyneuropathy with no heart involvement have a better prognosis with a mean survival of 8 to 10 years.[31]

The median survival in wATTR is approximately 3.5 years, and it can further be risk-stratified based on the Mayo Clinic wATTR-CM staging system. Stage I: 66 months; Stage II: 42 months; Stage III: 20 months.[33]

The U.K. National Amyloidosis Center studied both hATTR and wATTR cohorts and used Nt-proBNP (>3000 pg/dl) and estimated glomerular filtration rate (<45 ml/min/1.73 m²). They reported a mean survival in hATTR-CM (Val122lle) of 29 months and wATTR of 49 months. Interestingly, echocardiographic findings, including left ventricular mass, wall thickness, and degree of diastolic dysfunction, were not found to be an independent predictor of survival.[74]

Technitium pyrophosphate scan can be used for prognosticating ATTR-CM as well. A heart to the contralateral chest uptake ratio of 1.6 or greater has poorer 5-year outcomes.[54]

Complications

If untreated, ATTR-CM can cause progressive worsening heart failure, arrhythmias, and conduction system diseases, which can cause sudden cardiac death due to fatal arrhythmias or complete heart block. In addition, the functional capacity and the quality of life deteriorate exponentially with every heart failure exacerbation and subsequent hospitalization. 

Tafamidis, which is used for the treatment of ATTR-CM, is well tolerated. However, in clinical trials, the rate of adverse events was similar in tafamidis and placebo groups.[71]

Deterrence and Patient Education

What is Transthyretin Amyloid Cardiomyopathy (ATTR-CM)?

Transthyretin amyloid cardiomyopathy is caused by the deposition of an abnormally folded protein called transthyretin. Transthyretin is a naturally occurring protein in the human body that helps transport the thyroid hormone in the bloodstream.

This abnormally folded transthyretin protein can be deposited in various organs and tissues in the body, including nerves, the heart, the kidneys, and the gastrointestinal tract. An abnormal buildup of transthyretin amyloid protein in heart muscle stiffens it, eventually leading to congestive heart failure.

Are There Different Types of ATTR-CM?

There are two types of ATTR-CM: hereditary (hATTR-CM) and wild type (wATTR-CM). hATTR-CM is a genetic disease caused by a genetic mutation in the transthyretin gene. wATTR-CM is an aging disease in which normal transthyretin protein becomes structurally unstable and gets deposited in the heart. hATTR-CM can occur in younger people (50s to 60s), whereas wATTR usually occurs in older people (late 70s to 80s).  

What Are Some Common Clinical Symptoms of ATTR-CM?

Patients may develop heart failure, which can present as reduced exercise capacity, shortness of breath, and swelling in the legs. Patients may have a recurrent exacerbation of shortness of breath and difficulty breathing, requiring frequent emergency room and hospitalization. Atrial fibrillation is often seen. Patients often have lightheadedness, dizziness, and loss of consciousness due to slow heart rate and brief heartbeat pauses. This may be due to slow heart rate and transient pauses of the heartbeat. Patients often report intolerance (low blood pressure, postural hypotension) to traditional medications used for heart failure management, including beta-blockers and ACE inhibitors or angiotensin receptor blockers.  

Is There Any Treatment Available for ATTR-CM?

Few new drugs and treatment strategies have emerged in recent years, and many are still under clinical review. However, in  2019, the US FDA approved tafamidis for clinical use in ATTR-CM. Tafamidis is an oral medication that is used in once a day formulation. Tafamidis can prevent further disease progression but, unfortunately, cannot reverse the disease process. Therefore, early identification and treatment of ATTR-CM are advised.

Enhancing Healthcare Team Outcomes

ATTR-CM is emerging as an essential clinical entity in the realm of heart failure with preserved ejection fraction. Real-world clinical data have demonstrated an increased prevalence of ATTR-CM than previously perceived. Which improving novel non-invasive imaging techniques, clinicians can now facilitate early diagnosis of ATTR-CM. With the advent of effective therapeutic options for ATTR-CM, it is now possible to improve outcomes in these patients. However, as these therapies cannot reverse the disease process and can only prevent further progression, early identification is paramount for them to be most effective. 

Primary care physicians and general cardiologists should understand the disease process and pathophysiology of ATTR-CM. They should look for clinical cues of ATTR-CM and should screen patients who fit the clinical picture. Novel non-invasive cardiac imaging like cardiac MRI and bone avid scintigraphy may have an essential role in diagnosing ATTR-CM. Echocardiogram with strain imaging has also emerged as an efficient screening tool. Radiologists and cardiologists specializing in cardiac imaging should get more familiar with imaging patterns and findings of ATTR-CM.

Review Questions

• Access free multiple choice questions on this topic.
• Click here for a simplified version.
• Comment on this article.

References

1.

Martinez-Naharro A, Hawkins PN, Fontana M. Cardiac amyloidosis. Clin Med (Lond). 2018 Apr 01;18(Suppl 2):s30-s35. [PMC free article: PMC6334035] [PubMed: 29700090]

2.

Dubrey SW, Hawkins PN, Falk RH. Amyloid diseases of the heart: assessment, diagnosis, and referral. Heart. 2011 Jan;97(1):75-84. [PubMed: 21148582]

3.

Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin Amyloid Cardiomyopathy: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019 Jun 11;73(22):2872-2891. [PMC free article: PMC6724183] [PubMed: 31171094]

4.

AbouEzzeddine OF, Davies DR, Scott CG, Fayyaz AU, Askew JW, McKie PM, Noseworthy PA, Johnson GB, Dunlay SM, Borlaug BA, Chareonthaitawee P, Roger VL, Dispenzieri A, Grogan M, Redfield MM. Prevalence of Transthyretin Amyloid Cardiomyopathy in Heart Failure With Preserved Ejection Fraction. JAMA Cardiol. 2021 Nov 01;6(11):1267-1274. [PMC free article: PMC8387947] [PubMed: 34431962]

5.

Kelly JW, Colon W, Lai Z, Lashuel HA, McCulloch J, McCutchen SL, Miroy GJ, Peterson SA. Transthyretin quaternary and tertiary structural changes facilitate misassembly into amyloid. Adv Protein Chem. 1997;50:161-81. [PubMed: 9338081]

6.

Liz MA, Mar FM, Franquinho F, Sousa MM. Aboard transthyretin: From transport to cleavage. IUBMB Life. 2010 Jun;62(6):429-35. [PubMed: 20503435]

7.

Cornwell GG, Sletten K, Johansson B, Westermark P. Evidence that the amyloid fibril protein in senile systemic amyloidosis is derived from normal prealbumin. Biochem Biophys Res Commun. 1988 Jul 29;154(2):648-53. [PubMed: 3135807]

8.

Westermark P, Sletten K, Johansson B, Cornwell GG. Fibril in senile systemic amyloidosis is derived from normal transthyretin. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2843-5. [PMC free article: PMC53787] [PubMed: 2320592]

9.

Coelho T, Maurer MS, Suhr OB. THAOS - The Transthyretin Amyloidosis Outcomes Survey: initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis. Curr Med Res Opin. 2013 Jan;29(1):63-76. [PubMed: 23193944]

10.

Pomerance A. Senile cardiac amyloidosis. Br Heart J. 1965 Sep;27(5):711-8. [PMC free article: PMC469777] [PubMed: 5829755]

11.

Pinney JH, Whelan CJ, Petrie A, Dungu J, Banypersad SM, Sattianayagam P, Wechalekar A, Gibbs SD, Venner CP, Wassef N, McCarthy CA, Gilbertson JA, Rowczenio D, Hawkins PN, Gillmore JD, Lachmann HJ. Senile systemic amyloidosis: clinical features at presentation and outcome. J Am Heart Assoc. 2013 Apr 22;2(2):e000098. [PMC free article: PMC3647259] [PubMed: 23608605]

12.

Rozenbaum MH, Large S, Bhambri R, Stewart M, Whelan J, van Doornewaard A, Dasgupta N, Masri A, Nativi-Nicolau J. Impact of Delayed Diagnosis and Misdiagnosis for Patients with Transthyretin Amyloid Cardiomyopathy (ATTR-CM): A Targeted Literature Review. Cardiol Ther. 2021 Jun;10(1):141-159. [PMC free article: PMC8126532] [PubMed: 33877591]

13.

Gillmore JD, Maurer MS, Falk RH, Merlini G, Damy T, Dispenzieri A, Wechalekar AD, Berk JL, Quarta CC, Grogan M, Lachmann HJ, Bokhari S, Castano A, Dorbala S, Johnson GB, Glaudemans AW, Rezk T, Fontana M, Palladini G, Milani P, Guidalotti PL, Flatman K, Lane T, Vonberg FW, Whelan CJ, Moon JC, Ruberg FL, Miller EJ, Hutt DF, Hazenberg BP, Rapezzi C, Hawkins PN. Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis. Circulation. 2016 Jun 14;133(24):2404-12. [PubMed: 27143678]

14.

Lindmark K, Pilebro B, Sundström T, Lindqvist P. Prevalence of wild type transtyrethin cardiac amyloidosis in a heart failure clinic. ESC Heart Fail. 2021 Feb;8(1):745-749. [PMC free article: PMC7835553] [PubMed: 33205581]

15.

González-López E, Gallego-Delgado M, Guzzo-Merello G, de Haro-Del Moral FJ, Cobo-Marcos M, Robles C, Bornstein B, Salas C, Lara-Pezzi E, Alonso-Pulpon L, Garcia-Pavia P. Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J. 2015 Oct 07;36(38):2585-94. [PubMed: 26224076]

16.

Cornwell GG, Murdoch WL, Kyle RA, Westermark P, Pitkänen P. Frequency and distribution of senile cardiovascular amyloid. A clinicopathologic correlation. Am J Med. 1983 Oct;75(4):618-23. [PubMed: 6624768]

17.

Mohammed SF, Mirzoyev SA, Edwards WD, Dogan A, Grogan DR, Dunlay SM, Roger VL, Gertz MA, Dispenzieri A, Zeldenrust SR, Redfield MM. Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction. JACC Heart Fail. 2014 Apr;2(2):113-22. [PMC free article: PMC3984539] [PubMed: 24720917]

18.

Castaño A, Narotsky DL, Hamid N, Khalique OK, Morgenstern R, DeLuca A, Rubin J, Chiuzan C, Nazif T, Vahl T, George I, Kodali S, Leon MB, Hahn R, Bokhari S, Maurer MS. Unveiling transthyretin cardiac amyloidosis and its predictors among elderly patients with severe aortic stenosis undergoing transcatheter aortic valve replacement. Eur Heart J. 2017 Oct 07;38(38):2879-2887. [PMC free article: PMC5837725] [PubMed: 29019612]

19.

Witteles RM, Bokhari S, Damy T, Elliott PM, Falk RH, Fine NM, Gospodinova M, Obici L, Rapezzi C, Garcia-Pavia P. Screening for Transthyretin Amyloid Cardiomyopathy in Everyday Practice. JACC Heart Fail. 2019 Aug;7(8):709-716. [PubMed: 31302046]

20.

Lane T, Fontana M, Martinez-Naharro A, Quarta CC, Whelan CJ, Petrie A, Rowczenio DM, Gilbertson JA, Hutt DF, Rezk T, Strehina SG, Caringal-Galima J, Manwani R, Sharpley FA, Wechalekar AD, Lachmann HJ, Mahmood S, Sachchithanantham S, Drage EPS, Jenner HD, McDonald R, Bertolli O, Calleja A, Hawkins PN, Gillmore JD. Natural History, Quality of Life, and Outcome in Cardiac Transthyretin Amyloidosis. Circulation. 2019 Jul 02;140(1):16-26. [PubMed: 31109193]

21.

Bruno M, Castaño A, Burton A, Grodin JL. Transthyretin amyloid cardiomyopathy in women: frequency, characteristics, and diagnostic challenges. Heart Fail Rev. 2021 Jan;26(1):35-45. [PMC free article: PMC7769788] [PubMed: 32794090]

22.

Buxbaum JN, Ruberg FL. Transthyretin V122I (pV142I)* cardiac amyloidosis: an age-dependent autosomal dominant cardiomyopathy too common to be overlooked as a cause of significant heart disease in elderly African Americans. Genet Med. 2017 Jul;19(7):733-742. [PMC free article: PMC5509498] [PubMed: 28102864]

23.

Connors LH, Sam F, Skinner M, Salinaro F, Sun F, Ruberg FL, Berk JL, Seldin DC. Heart Failure Resulting From Age-Related Cardiac Amyloid Disease Associated With Wild-Type Transthyretin: A Prospective, Observational Cohort Study. Circulation. 2016 Jan 19;133(3):282-90. [PMC free article: PMC4718760] [PubMed: 26660282]

24.

Donnellan E, Wazni OM, Hanna M, Elshazly MB, Puri R, Saliba W, Kanj M, Vakamudi S, Patel DR, Baranowski B, Cantillon D, Dresing T, Jaber WA. Atrial Fibrillation in Transthyretin Cardiac Amyloidosis: Predictors, Prevalence, and Efficacy of Rhythm Control Strategies. JACC Clin Electrophysiol. 2020 Sep;6(9):1118-1127. [PubMed: 32972546]

25.

Khanna S, Lo P, Cho K, Subbiah R. Ventricular Arrhythmias in Cardiac Amyloidosis: A Review of Current Literature. Clin Med Insights Cardiol. 2020;14:1179546820963055. [PMC free article: PMC7545745] [PubMed: 33088185]

26.

Falk RH, Alexander KM, Liao R, Dorbala S. AL (Light-Chain) Cardiac Amyloidosis: A Review of Diagnosis and Therapy. J Am Coll Cardiol. 2016 Sep 20;68(12):1323-41. [PubMed: 27634125]

27.

Pellikka PA, Holmes DR, Edwards WD, Nishimura RA, Tajik AJ, Kyle RA. Endomyocardial biopsy in 30 patients with primary amyloidosis and suspected cardiac involvement. Arch Intern Med. 1988 Mar;148(3):662-6. [PubMed: 3341867]

28.

Quarta CC, Gonzalez-Lopez E, Gilbertson JA, Botcher N, Rowczenio D, Petrie A, Rezk T, Youngstein T, Mahmood S, Sachchithanantham S, Lachmann HJ, Fontana M, Whelan CJ, Wechalekar AD, Hawkins PN, Gillmore JD. Diagnostic sensitivity of abdominal fat aspiration in cardiac amyloidosis. Eur Heart J. 2017 Jun 21;38(24):1905-1908. [PMC free article: PMC5837229] [PubMed: 28605421]

29.

Vrana JA, Gamez JD, Madden BJ, Theis JD, Bergen HR, Dogan A. Classification of amyloidosis by laser microdissection and mass spectrometry-based proteomic analysis in clinical biopsy specimens. Blood. 2009 Dec 03;114(24):4957-9. [PubMed: 19797517]

30.

Rapezzi C, Merlini G, Quarta CC, Riva L, Longhi S, Leone O, Salvi F, Ciliberti P, Pastorelli F, Biagini E, Coccolo F, Cooke RM, Bacchi-Reggiani L, Sangiorgi D, Ferlini A, Cavo M, Zamagni E, Fonte ML, Palladini G, Salinaro F, Musca F, Obici L, Branzi A, Perlini S. Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types. Circulation. 2009 Sep 29;120(13):1203-12. [PubMed: 19752327]

31.

Ruberg FL, Berk JL. Transthyretin (TTR) cardiac amyloidosis. Circulation. 2012 Sep 04;126(10):1286-300. [PMC free article: PMC3501197] [PubMed: 22949539]

32.

Pilebro B, Suhr OB, Näslund U, Westermark P, Lindqvist P, Sundström T. (99m)Tc-DPD uptake reflects amyloid fibril composition in hereditary transthyretin amyloidosis. Ups J Med Sci. 2016;121(1):17-24. [PMC free article: PMC4812053] [PubMed: 26849806]

33.

Grogan M, Scott CG, Kyle RA, Zeldenrust SR, Gertz MA, Lin G, Klarich KW, Miller WL, Maleszewski JJ, Dispenzieri A. Natural History of Wild-Type Transthyretin Cardiac Amyloidosis and Risk Stratification Using a Novel Staging System. J Am Coll Cardiol. 2016 Sep 06;68(10):1014-20. [PubMed: 27585505]

34.

Rosenbaum AN, AbouEzzeddine OF, Grogan M, Dispenzieri A, Kushwaha S, Clavell A, Daly RC, Edwards BS. Outcomes After Cardiac Transplant for Wild Type Transthyretin Amyloidosis. Transplantation. 2018 Nov;102(11):1909-1913. [PubMed: 29677073]

35.

Maurer MS, Bokhari S, Damy T, Dorbala S, Drachman BM, Fontana M, Grogan M, Kristen AV, Lousada I, Nativi-Nicolau J, Cristina Quarta C, Rapezzi C, Ruberg FL, Witteles R, Merlini G. Expert Consensus Recommendations for the Suspicion and Diagnosis of Transthyretin Cardiac Amyloidosis. Circ Heart Fail. 2019 Sep;12(9):e006075. [PMC free article: PMC6736650] [PubMed: 31480867]

36.

Mints YY, Doros G, Berk JL, Connors LH, Ruberg FL. Features of atrial fibrillation in wild-type transthyretin cardiac amyloidosis: a systematic review and clinical experience. ESC Heart Fail. 2018 Oct;5(5):772-779. [PMC free article: PMC6165925] [PubMed: 29916559]

37.

John RM. Arrhythmias in Cardiac Amyloidosis. J Innov Card Rhythm Manag. 2018 Mar;9(3):3051-3057. [PMC free article: PMC7252761] [PubMed: 32477799]

38.

Feng D, Syed IS, Martinez M, Oh JK, Jaffe AS, Grogan M, Edwards WD, Gertz MA, Klarich KW. Intracardiac thrombosis and anticoagulation therapy in cardiac amyloidosis. Circulation. 2009 May 12;119(18):2490-7. [PubMed: 19414641]

39.

Nakagawa M, Sekijima Y, Yazaki M, Tojo K, Yoshinaga T, Doden T, Koyama J, Yanagisawa S, Ikeda S. Carpal tunnel syndrome: a common initial symptom of systemic wild-type ATTR (ATTRwt) amyloidosis. Amyloid. 2016;23(1):58-63. [PubMed: 26852880]

40.

Westermark P, Westermark GT, Suhr OB, Berg S. Transthyretin-derived amyloidosis: probably a common cause of lumbar spinal stenosis. Ups J Med Sci. 2014 Aug;119(3):223-8. [PMC free article: PMC4116761] [PubMed: 24620715]

41.

Geller HI, Singh A, Alexander KM, Mirto TM, Falk RH. Association Between Ruptured Distal Biceps Tendon and Wild-Type Transthyretin Cardiac Amyloidosis. JAMA. 2017 Sep 12;318(10):962-963. [PMC free article: PMC5818850] [PubMed: 28898370]

42.

Hassan W, Al-Sergani H, Mourad W, Tabbaa R. Amyloid heart disease. New frontiers and insights in pathophysiology, diagnosis, and management. Tex Heart Inst J. 2005;32(2):178-84. [PMC free article: PMC1163465] [PubMed: 16107109]

43.

Gertz M, Adams D, Ando Y, Beirão JM, Bokhari S, Coelho T, Comenzo RL, Damy T, Dorbala S, Drachman BM, Fontana M, Gillmore JD, Grogan M, Hawkins PN, Lousada I, Kristen AV, Ruberg FL, Suhr OB, Maurer MS, Nativi-Nicolau J, Quarta CC, Rapezzi C, Witteles R, Merlini G. Avoiding misdiagnosis: expert consensus recommendations for the suspicion and diagnosis of transthyretin amyloidosis for the general practitioner. BMC Fam Pract. 2020 Sep 23;21(1):198. [PMC free article: PMC7513485] [PubMed: 32967612]

44.

Mussinelli R, Salinaro F, Alogna A, Boldrini M, Raimondi A, Musca F, Palladini G, Merlini G, Perlini S. Diagnostic and prognostic value of low QRS voltages in cardiac AL amyloidosis. Ann Noninvasive Electrocardiol. 2013 May;18(3):271-80. [PMC free article: PMC6932192] [PubMed: 23714086]

45.

Dungu J, Sattianayagam PT, Whelan CJ, Gibbs SD, Pinney JH, Banypersad SM, Rowczenio D, Gilbertson JA, Lachmann HJ, Wechalekar A, Gillmore JD, Hawkins PN, Anderson LJ. The electrocardiographic features associated with cardiac amyloidosis of variant transthyretin isoleucine 122 type in Afro-Caribbean patients. Am Heart J. 2012 Jul;164(1):72-9. [PubMed: 22795285]

46.

Syed IS, Glockner JF, Feng D, Araoz PA, Martinez MW, Edwards WD, Gertz MA, Dispenzieri A, Oh JK, Bellavia D, Tajik AJ, Grogan M. Role of cardiac magnetic resonance imaging in the detection of cardiac amyloidosis. JACC Cardiovasc Imaging. 2010 Feb;3(2):155-64. [PubMed: 20159642]

47.

Pagourelias ED, Mirea O, Duchenne J, Van Cleemput J, Delforge M, Bogaert J, Kuznetsova T, Voigt JU. Echo Parameters for Differential Diagnosis in Cardiac Amyloidosis: A Head-to-Head Comparison of Deformation and Nondeformation Parameters. Circ Cardiovasc Imaging. 2017 Mar;10(3):e005588. [PubMed: 28298286]

48.

Quarta CC, Solomon SD, Uraizee I, Kruger J, Longhi S, Ferlito M, Gagliardi C, Milandri A, Rapezzi C, Falk RH. Left ventricular structure and function in transthyretin-related versus light-chain cardiac amyloidosis. Circulation. 2014 May 06;129(18):1840-9. [PubMed: 24563469]

49.

Zhao L, Tian Z, Fang Q. Diagnostic accuracy of cardiovascular magnetic resonance for patients with suspected cardiac amyloidosis: a systematic review and meta-analysis. BMC Cardiovasc Disord. 2016 Jun 07;16:129. [PMC free article: PMC4897958] [PubMed: 27267362]

50.

Martinez-Naharro A, Treibel TA, Abdel-Gadir A, Bulluck H, Zumbo G, Knight DS, Kotecha T, Francis R, Hutt DF, Rezk T, Rosmini S, Quarta CC, Whelan CJ, Kellman P, Gillmore JD, Moon JC, Hawkins PN, Fontana M. Magnetic Resonance in Transthyretin Cardiac Amyloidosis. J Am Coll Cardiol. 2017 Jul 25;70(4):466-477. [PubMed: 28728692]

51.

Carvalho FP, Erthal F, Azevedo CF. The Role of Cardiac MR Imaging in the Assessment of Patients with Cardiac Amyloidosis. Magn Reson Imaging Clin N Am. 2019 Aug;27(3):453-463. [PubMed: 31279449]

52.

Dungu JN, Valencia O, Pinney JH, Gibbs SD, Rowczenio D, Gilbertson JA, Lachmann HJ, Wechalekar A, Gillmore JD, Whelan CJ, Hawkins PN, Anderson LJ. CMR-based differentiation of AL and ATTR cardiac amyloidosis. JACC Cardiovasc Imaging. 2014 Feb;7(2):133-42. [PubMed: 24412186]

53.

Stats MA, Stone JR. Varying levels of small microcalcifications and macrophages in ATTR and AL cardiac amyloidosis: implications for utilizing nuclear medicine studies to subtype amyloidosis. Cardiovasc Pathol. 2016 Sep-Oct;25(5):413-7. [PubMed: 27469499]

54.

Castano A, Haq M, Narotsky DL, Goldsmith J, Weinberg RL, Morgenstern R, Pozniakoff T, Ruberg FL, Miller EJ, Berk JL, Dispenzieri A, Grogan M, Johnson G, Bokhari S, Maurer MS. Multicenter Study of Planar Technetium 99m Pyrophosphate Cardiac Imaging: Predicting Survival for Patients With ATTR Cardiac Amyloidosis. JAMA Cardiol. 2016 Nov 01;1(8):880-889. [PubMed: 27557400]

55.

Bokhari S, Castaño A, Pozniakoff T, Deslisle S, Latif F, Maurer MS. (99m)Tc-pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretin-related familial and senile cardiac amyloidoses. Circ Cardiovasc Imaging. 2013 Mar 01;6(2):195-201. [PMC free article: PMC3727049] [PubMed: 23400849]

56.

Phull P, Sanchorawala V, Connors LH, Doros G, Ruberg FL, Berk JL, Sarosiek S. Monoclonal gammopathy of undetermined significance in systemic transthyretin amyloidosis (ATTR). Amyloid. 2018 Mar;25(1):62-67. [PMC free article: PMC6157907] [PubMed: 29424556]

57.

Ash S, Shorer E, Ramgobin D, Vo M, Gibbons J, Golamari R, Jain R, Jain R. Cardiac amyloidosis-A review of current literature for the practicing physician. Clin Cardiol. 2021 Mar;44(3):322-331. [PMC free article: PMC7943900] [PubMed: 33595871]

58.

Bhuiyan T, Helmke S, Patel AR, Ruberg FL, Packman J, Cheung K, Grogan D, Maurer MS. Pressure-volume relationships in patients with transthyretin (ATTR) cardiac amyloidosis secondary to V122I mutations and wild-type transthyretin: Transthyretin Cardiac Amyloid Study (TRACS). Circ Heart Fail. 2011 Mar;4(2):121-8. [PMC free article: PMC4939845] [PubMed: 21191093]

59.

Pollak A, Falk RH. Left ventricular systolic dysfunction precipitated by verapamil in cardiac amyloidosis. Chest. 1993 Aug;104(2):618-20. [PubMed: 8339658]

60.

El-Am EA, Dispenzieri A, Melduni RM, Ammash NM, White RD, Hodge DO, Noseworthy PA, Lin G, Pislaru SV, Egbe AC, Grogan M, Nkomo VT. Direct Current Cardioversion of Atrial Arrhythmias in Adults With Cardiac Amyloidosis. J Am Coll Cardiol. 2019 Feb 12;73(5):589-597. [PMC free article: PMC6378685] [PubMed: 30732713]

61.

Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA, Freedman RA, Gettes LS, Gillinov AM, Gregoratos G, Hammill SC, Hayes DL, Hlatky MA, Newby LK, Page RL, Schoenfeld MH, Silka MJ, Stevenson LW, Sweeney MO, Smith SC, Jacobs AK, Adams CD, Anderson JL, Buller CE, Creager MA, Ettinger SM, Faxon DP, Halperin JL, Hiratzka LF, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura RA, Ornato JP, Page RL, Riegel B, Tarkington LG, Yancy CW., American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices). American Association for Thoracic Surgery. Society of Thoracic Surgeons. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices) developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. J Am Coll Cardiol. 2008 May 27;51(21):e1-62. [PubMed: 18498951]

62.

Kristen AV, Dengler TJ, Hegenbart U, Schonland SO, Goldschmidt H, Sack FU, Voss F, Becker R, Katus HA, Bauer A. Prophylactic implantation of cardioverter-defibrillator in patients with severe cardiac amyloidosis and high risk for sudden cardiac death. Heart Rhythm. 2008 Feb;5(2):235-40. [PubMed: 18242546]

63.

Varr BC, Zarafshar S, Coakley T, Liedtke M, Lafayette RA, Arai S, Schrier SL, Witteles RM. Implantable cardioverter-defibrillator placement in patients with cardiac amyloidosis. Heart Rhythm. 2014 Jan;11(1):158-62. [PubMed: 24121001]

64.

Suhr OB, Coelho T, Buades J, Pouget J, Conceicao I, Berk J, Schmidt H, Waddington-Cruz M, Campistol JM, Bettencourt BR, Vaishnaw A, Gollob J, Adams D. Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study. Orphanet J Rare Dis. 2015 Sep 04;10:109. [PMC free article: PMC4559363] [PubMed: 26338094]

65.

Yarlas A, Lovley A, McCausland K, Brown D, Vera-Llonch M, Conceição I, Karam C, Khella S, Obici L, Waddington-Cruz M. Early Data on Long-term Impact of Inotersen on Quality-of-Life in Patients with Hereditary Transthyretin Amyloidosis Polyneuropathy: Open-Label Extension of NEURO-TTR. Neurol Ther. 2021 Dec;10(2):865-886. [PMC free article: PMC8571454] [PubMed: 34355354]

66.

Maurer MS, Elliott P, Merlini G, Shah SJ, Cruz MW, Flynn A, Gundapaneni B, Hahn C, Riley S, Schwartz J, Sultan MB, Rapezzi C., ATTR-ACT Study Investigators. Design and Rationale of the Phase 3 ATTR-ACT Clinical Trial (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial). Circ Heart Fail. 2017 Jun;10(6) [PubMed: 28611125]

67.

Berk JL, Suhr OB, Obici L, Sekijima Y, Zeldenrust SR, Yamashita T, Heneghan MA, Gorevic PD, Litchy WJ, Wiesman JF, Nordh E, Corato M, Lozza A, Cortese A, Robinson-Papp J, Colton T, Rybin DV, Bisbee AB, Ando Y, Ikeda S, Seldin DC, Merlini G, Skinner M, Kelly JW, Dyck PJ., Diflunisal Trial Consortium. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA. 2013 Dec 25;310(24):2658-67. [PMC free article: PMC4139164] [PubMed: 24368466]

68.

Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M, Kristen AV, Grogan M, Witteles R, Damy T, Drachman BM, Shah SJ, Hanna M, Judge DP, Barsdorf AI, Huber P, Patterson TA, Riley S, Schumacher J, Stewart M, Sultan MB, Rapezzi C., ATTR-ACT Study Investigators. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med. 2018 Sep 13;379(11):1007-1016. [PubMed: 30145929]

69.

Damy T, Garcia-Pavia P, Hanna M, Judge DP, Merlini G, Gundapaneni B, Patterson TA, Riley S, Schwartz JH, Sultan MB, Witteles R. Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and long-term extension study. Eur J Heart Fail. 2021 Feb;23(2):277-285. [PMC free article: PMC8048553] [PubMed: 33070419]

70.

McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, Burri H, Butler J, Čelutkienė J, Chioncel O, Cleland JGF, Coats AJS, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam CSP, Lyon AR, McMurray JJV, Mebazaa A, Mindham R, Muneretto C, Francesco Piepoli M, Price S, Rosano GMC, Ruschitzka F, Kathrine Skibelund A., ESC Scientific Document Group. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021 Sep 21;42(36):3599-3726. [PubMed: 34447992]

71.

Rozenbaum MH, Garcia A, Grima D, Tran D, Bhambri R, Stewart M, Li B, Heeg B, Postma M, Masri A. Health impact of tafamidis in transthyretin amyloid cardiomyopathy patients: an analysis from the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and the open-label long-term extension studies. Eur Heart J Qual Care Clin Outcomes. 2022 Aug 17;8(5):529-538. [PMC free article: PMC9382662] [PubMed: 33895806]

72.

Vollmar J, Schmid JC, Hoppe-Lotichius M, Barreiros AP, Azizi M, Emrich T, Geber C, Schad A, Weyer V, Otto G, Heise M, Mittler J, Birklein F, Lang H, Galle PR, Zimmermann T. Progression of transthyretin (TTR) amyloidosis in donors and recipients after domino liver transplantation-a prospective single-center cohort study. Transpl Int. 2018 Nov;31(11):1207-1215. [PubMed: 30091268]

73.

Sousa M, Monohan G, Rajagopalan N, Grigorian A, Guglin M. Heart transplantation in cardiac amyloidosis. Heart Fail Rev. 2017 May;22(3):317-327. [PubMed: 28281017]

74.

Gillmore JD, Damy T, Fontana M, Hutchinson M, Lachmann HJ, Martinez-Naharro A, Quarta CC, Rezk T, Whelan CJ, Gonzalez-Lopez E, Lane T, Gilbertson JA, Rowczenio D, Petrie A, Hawkins PN. A new staging system for cardiac transthyretin amyloidosis. Eur Heart J. 2018 Aug 07;39(30):2799-2806. [PubMed: 29048471]

Disclosure: Anubhav Jain declares no relevant financial relationships with ineligible companies.

Disclosure: Farah Zahra declares no relevant financial relationships with ineligible companies.