Cardiac amyloidosis is a form of disorder that is caused by deposits of amyloids (abnormal proteins) in the heart tissue, resulting in heart not being able to work properly. Light chain (AL) and transthyretin (TTR) are the two most common and clinically relevant amyloid that infiltrate the heart. TTR amyloid (ATTR) mainly deposits in heart muscles and nerves. There are two types of ATTR – hereditary or mutant (ATTRm) and wild type (ATTRwt).

By Asst Prof Tang Hak Chiaw, Senior Consultant, Department of Cardiology

Typically, in TTR cardiac amyloidosis, there will be left ventricular (LV) thickening that resembles hypertensive heart disease or hypertrophic cardiomyopathy (especially at its early stage). Hence, early accurate diagnosis can be elusive. Both ATTRm and ATTRwt cardiomyopathy can lead to heart failure. Any other cardiac manifestations include atrial fibrillation (AF) and conduction disorder. The risk of intracardiac thrombus increases in cardiac amyloidosis too.

ATTRwt are more commonly seen in men after 70 years old. Its extracardiac involvements include carpal tunnel syndrome (especially bilateral and can precede cardiomyopathy for several years), biceps tendon rupture and lumbar spinal stenosis.

ATTRm exhibit autosomal dominant inheritance, with variable penetrance. There are mutations mainly present with cardiomyopathy or neuropathy, and not uncommonly a mixture of both. Bilateral ascending motor-sensory neuropathy and/or autonomic neuropathy are the main manifestation of neurologic disease of ATTRm. 

ATTR cardiomyopathy had always been thought to be a rare disease. However, recent studies suggest otherwise; ATTRwt was detected in about 13% of heart failure with preserved ejection fraction (HFpEF) patients1, 5% of surgical severe aortic stenosis patients2 and 16% of transcatheter aortic valve implantation (TAVI) patients3.

Diagnosing ATTR

Heart failure patients who have neurologic features (carpal tunnel syndrome, peripheral paraesthesia, constipation/diarrhoea or significant postural hypotension) or family history of heart failure and/or neuropathy may be at risk of having ATTR. This also
includes elderly with long standing hypertension who becomes hypotensive and intolerant to antihypertensive medications.

Clinical Clues for ATTR Cardiomyopathy

  • Chronic hypertension patient becomes hypotensive, intolerant to ACE-inhibitor or beta blockers

  • Unexplained HFpEF in an elderly man

  • Heart failure patients with bilateral carpal tunnel syndrome or bicep tendon ruptures

  • Heart failure patients with peripheral neuropathy or profound autonomic neuropathy

Findings of Non-Invasive Test in Cardiac Amyloidosis

  • Biomarkers
    • Raised NT-proBNP out of proportion to the degree of heart failure
    • Persistent elevated troponin level in non-ACS (acute coronary syndrome) patient 

  • Electrocardiogram (ECG)
    • Pseudo Q waves with no prior history of myocardial infarction
    • Low ECG voltages with increased LV wall thickness (though low voltages is seen in less than half of TTR cardiomyopathy patients)

  • Echocardiography
    • Apical sparing in strain imaging
    • Impaired LV longitudinal function in the presence of normal or near normal LV ejection fraction

  • Cardiac Magnetic Resonance (CMR) Imaging
    • Difficulty in nulling myocardial signal in late gadolinium enhancement (LGE) imaging due to altered contrast agent gadolinium kinetics
    • Diffuse subendocardial or transmural LGE (not following coronary artery territory)
    • Increased myocardial native T1 (a type of CMR imaging technique) and extracellular volume (ECV) values 
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Bone bisphosphonate scintigraphy and endomyocardial biopsy (EMB):

The definitive diagnosis of amyloidosis is made based on the demonstration of amyloid tissue using Congo red stain, done through biopsy of a clinically affected organ (such as bone marrow, nerve, kidneys, heart, gut and others). As the yield of positive result of extracardiac biopsy for ATTR cardiomyopathy is poor, invasive EMB is usually necessary for histological diagnosis. This has resulted in delayed and under diagnosis of ATTR cardiomyopathy.

Bone scintigraphy/ bone scan with technetium-labelled bisphosphonates has long been noted to show great affinity for cardiac amyloid tissue. Technetium-labelled diphosphonopropanodicarboxylic acid (DPD), pyrophosphate (PYP) and hydroxymethylene diphosphonate (HMDP) scintigraphy are both sensitive and specific for identifying TTR cardiac amyloidosis.

The seminal work by Gilmore et.al4 demonstrated a positive bone bisphosphonate scintigraphy that was 99% sensitive and 86% specific for cardiac TTR amyloid. The false positives were due to AL cardiac amyloidosis. After ruling out AL amyloidosis (negative blood and urine monoclonal protein studies), Gilmore was able to show strong positive bone scintigraphy that was 100% specific for TTR cardiac amyloid.

The use of bone scintigraphy has allowed ATTR cardiomyopathy to be diagnosed quickly and timely without the need for heart biopsy. Hence, there is great enthusiasm in developing and conducting clinical trials using pharmacological agents that block/suppress TTR production in the liver, stabilise the TTR tetramer to prevent unfolding, or remove the deposited amyloid fibril.

Treating ATTR

There are mainly two treatment approaches of ATTR cardiomyopathy – supportive and specific treatment.

Supportive treatment

Heart Failure
The aim is to maintain patient in fluid balance state. Due to stiff heart from amyloid infiltration, fluid overload is common, and therefore diuretics are commonly used. However, it must be used judiciously as over diuresis would lead to hypotension and poor
renal perfusion. ACE inhibitor and angiotensin receptor blocker (ARB) and beta blockers are usually poorly tolerated due to hypotension.

Atrial Fibrillation and Conduction Disorder
Rate control with calcium channel blocker is not advisable due to high risk of heart block. Digoxin is best avoided as it binds to amyloid fibers and increases risk of toxicity. Amiodarone is commonly used in rate and rhythm control. Long term anticoagulation should be initiated in atrial fibrillation patient regardless of CHA2VAS2-Vasc score. Pacemaker implantation is not uncommon due to high prevalence of conduction disorder.

Specific TTR treatment

TTR silencer (block protein synthesis)
Patisiran and Inotersen are two US FDA approved medications for treatment of ATTRm polyneuropathy, but not cardiomyopathy.

TTR tetramer stabiliser – Tafamidis and Diflunisal
Tafamidis binds to TTR and slows down the dissociation of TTR tetramers into monomers. A landmark trial5 in 2018 showed tafamidis was associated with reductions in all-cause mortality and cardiovascular-related hospitalisations and reduced the
decline in functional capacity and quality of life. Diflunisal is used in ATTRm polyneuropathy, with limited data on ATTR cardiomyopathy.

Amyloid fibril removal
Doxycycline and tauro-deoxychoilc acid (TUDCA) are currently being evaluated in clinical trial.

For selected patients with advanced ATTR cardiomyopathy, both hereditary and wild-type, heart transplantation (with combined liver transplantation in ATTRm) may be an option.

The availability of non-invasive diagnosis for ATTR cardiomyopathy using bone scintigraphy and blood test without biopsy of the heart have enabled the disease to be diagnosed in a more timely manner.

Together with established and investigational therapeutic agents targeting at different points of amyloid pathway, clinicians are going to be better equipped to diagnose and treat this condition. 

1Gonzalez-Lopez et al. Eur Heart J 2015;36:2585-94
2Treibel TA et al. Circ Cardiovasc Imag 2016
3Castaño A et al. Eur Heart J 2017;38:2879-89
4Gilmore et al. Circulation. 2016;133:2404-2412
5Mathew S. Maurer et al. N Engl J Med 2018; 379:1007-1016

This article is from Murmurs Issue 35 (September – December 2019). Click here to read the full issue.