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.
Transthyretin is a normal circulating protein that functions as a carrier protein for retinol (vitamin A) and thyroxine.
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.
It is primarily synthesized by the liver (>95%).
Additionally, in small amounts, it is also produced in the choroid plexus and retinal epithelium.
Usually, it circulates in a tetrameric form composed of 4 beta-sheet-rich monomers.
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.
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.
The clinical phenotype of ATTR depends on the type and extent of tissue involvement.
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.
This type of ATTR is referred to as wild-type transthyretin amyloid (wATTR).
Myocardial deposition of misfolded TTR protein in both types of ATTR causes a clinical phenotype of transthyretin amyloid cardiomyopathy (ATTR-CM).
wATTR-CM is more common than hATTR.
With recent nuclear cardiac imaging with technetium pyrophosphate scan, the diagnosis of ATTR-CM is possible without cardiac biopsy, so that more patients are being screened and diagnosed with ATTR-CM.
Survival has improved, increasing its prevalence.
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.
Thus, the prevalence is increasing as survival has improved dramatically.
It is primarily seen in older patients and has a male predominance.
Several autopsy studies have shown that the incidence of wATTR deposits increases with advancing age.
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).
A recent community-based cohort study reported a substantial prevalence of ATTR-CM in older male patients with HFpEF and left ventricular hypertrophy (LVH).
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.
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%).
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 and depends on the type of mutation.
More than 100 different TTR mutations have been identified.
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.
Misfolded TTR protein forms insoluble fibers, occupying 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.
Diastolic dysfunction causes an increase in left ventricular end-diastolic pressure and left atrial pressures.
Persistently increased left atrial pressures and left atrial dilatation increases the likelihood of developing atrial arrhythmias.
Myocardial infiltration often affects the electrical conduction system as well.
Ventricular arrhythmias have been reported in ATTR-CM but are significantly less common than AL cardiomyopathy.
The lower frequency of ventricular arrhythmias might be explained due to the direct cardiotoxic effect of light chain protein.
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.
Endomyocardial biopsy with congo red staining remains the gold standard to diagnose ATTR-CM.
The sensitivity of extracardiac tissue biopsy varies significantly and is usually not recommended, especially with the wATTR disease process.
Immunochemistry and tandem mass spectroscopy can be used to identify the type and nature of misfolded precursor protein.
With the advent of cardiac technetium pyrophosphate scan and cardiac MRI, the need for tissue diagnosis has limited clinical significance.
ATTR-CM typically presents with clinical signs and symptoms of progressive congestive heart failure, and often have cardiac arrhythmia and conduction system disease, which may occur years before the development of heart failure.
hATTR can present as primary cardiomyopathy or primary autonomic or peripheral neuropathy.
Not uncommonly, it can present mixed clinical features of both cardiomyopathy and neuropathy.
The age of onset of clinical disease is also variable and depends on the type of mutation.
Comparatively, the clinical course of wATTR follows a more consistent pattern.
Comparatively, polyneuropathy is more familiar in hATTR than wATTR.
Both conduction system disease and arrhythmias are more common with wATTR than hATTR.
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.
They may 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.
Patients often develop intolerance to beta-blockers and angiotensin convertase enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB), which they might have tolerated previously.
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.
Not uncommonly, non-sustained ventricular tachycardia is also seen.
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.
Patients often present with frequent heart failure exacerbations.
Patients may present with stroke or systemic embolization due to undiagnosed atrial fibrillation.
All patients with ATTR-CM are at increased risk of forming intracardiac thrombus irrespective of their rhythm status.
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.
One out of every three patients with wATTR-CM patients ends up requiring permanent pacemaker (PPM) implantation.
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.
More than half of wATTR-CM patients initially present with bilateral CTS.
When present, CTS usually occurs 5-10 years before the development of overt wATTR-CM.
Lumbar spinal stenosis occurs due to TTR deposition in ligamentum flavum causing spinal foraminal narrowing.
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.
Autonomic neuropathy may manifest as orthostatic hypotension, erectile dysfunction, dyshidrosis, or gastrointestinal motility issues.
Natural resolution of hypertension 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.
Clinical suspicion for ATTR-CM should be heightened, especially when cardiac and extracardiac findings are seen simultaneously.
Evaluation
Electrocardiogram (ECG) of ATTR-CM is described to have low voltage ECG patterns along with poor R wave progression across the precordial leads.
More commonly, the presence of Q waves unrelated to prior myocardial infarction (pseudo-infarct pattern) has also been reported.
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.
ECG findings are not acceptably sensitive, but can aid with the diagnosis but should not be used as a screening tool.
Only 25 to 40% of patients with ATTR-CM may have low voltage ECG.
Moreover, the sensitivity of ECG is highly dependent on the definition used to describe the criteria for low voltage.
A high voltage QRS pattern ECG has been reported in the Val122Ile variant of hATTR.
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.
hATTR-CM can occur in younger people (50s to 60s), whereas wATTR usually occurs in older people (late 70s to 80s).
Due to infiltration, the myocardium is more echogenic compared to that seen in ventricular hypertrophy, and is often referred to as a granular sparkling appearance.
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.
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.
The apical to basal strain ratio and apical to mid-ventricular plus basal strain have shown good diagnostic accuracy.
Echocardiographic parameters can help identify patients with cardiac amyloidosis but cannot be used to differentiate between hATTR, wATTR, or AL type.
Cardiac magnetic resonance imaging (CMR) has considerable utility as both a screening tool and a tool to track treatment response.
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%.
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.
CMR cannot reliably differentiate between hATTR, wATTR, or AL type.
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).
During the scan, TC-PYP is injected intravenously.
Once in circulation, it selectively binds to osseous tissue and ATTR fibrils.
A possible mechanism of myocardial retention of TC-PYP could be due to the microcalcifications associated with ATTR cardiomyopathy.[
Myocardial uptake of TC-PYP is visually graded compared to the bone update of the ribs to get a semiquantitative scheme.
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.
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.
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.
In these cases, a myocardial biopsy might be necessary to diagnose ATTR-CM.
Genetic testing may be obtained once the diagnosis of ATTR-CM is confirmed.
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.
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.
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.
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.
However, these patients are at increased risk of developing intracardiac thrombus even when receiving anticoagulant therapy.
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.
When symptoms of palpitations, presyncope, or frank syncope are reported, Holter or event monitoring must be considered.
When indicated, permanent pacing should be done.
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.
Therapies Targeting Transthyretin
Three major pharmacological strategies are being studied to specifically target ATTR-CM.
These are summarized in the table below.
Patisiran, Inotersen
The third strategy of using doxycycline with tauroursodeoxycholic acid is still being evaluated in clinical trials.
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.
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.
In approximately six months, functional improvement was seen, and mortality reduction took nearly two years.
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.
A liver transplant can remove mutant TTR from circulation.
It has previously been used to treat hATTR but cannot be used for wATTR.
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.
Differential Diagnosis
Light chain amyloid (AL) cardiomyopathy
Other causes of infiltrative cardiomyopathy
Cardiac sarcoidosis Cardiac hemochromatosis Fabry disease Mucopolysaccharidoses Hypertrophic cardiomyopathy
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.
The system classifies the disease into 3 stages.
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.
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.
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.
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.
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.
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.
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.