Improved diagnosis and emerging treatments for cardiac amyloidosis

Until recent, cardiac transthyretin (ATTR) amyloidosis was considered a rare, progressive and fatal condition. With new diagnostic modalities, we have found that ATTR amyloid is present in up to 20% of patients with heart failure with preserved ejection fraction (HFpEF).  Several treatments are being developed, leading to a new approach and an improved outlook for patients with ATTR cardiac amyloid.

ATTR amyloidosis is caused by deposition of amyloid fibrils in the extracellular tissue of organs.  These fibrils are made of transthyretin, a transport protein made in the liver, which has destabilized and misfolded due to inherited mutations and/or an aging process (Fig 1).

Figure 1

Figure 1. Amyloidogenic ATTR cascade. Treatment points are highlighted at A, B and C.

Castano et al 2015

ATTR amyloidosis can affect multiple organs.  The heart, central and peripheral nervous system, kidneys and GI tract are often involved with varying degrees of organ dysfunction.  Of interest, patients with bilateral carpal tunnel syndrome are recommended to be screened for ATTR amyloid.  In cardiac involvement, there is progressive left ventricular hypertrophy with development of HFpEF due to restrictive cardiomyopathy (Fig 2).  Patients present with dyspnea, fatigue, peripheral oedema, pleural effusions and in late stages develop cardiac cachexia.

Figure 2

Figure 2. Echocardiogram showing severe left and right ventricular hypertrophy due to amyloid deposition (left); bull’s eye plot in ‘strain’ imaging showing contractility in a normal heart (middle); and classic ‘apical sparing’ pattern seen in cardiac amyloidosis (right).

Mocha A et al. 2017 and Gil J et al 2018

Echocardiographic findings are initially subtle with mild left ventricular hypertrophy (LVH) and diastolic impairment.  With use of newer echocardiographic strain imaging, we can better differentiate between LVH due to hypertension or cardiac amyloid (Fig 2 right).  The gold standard diagnosis of ATTR amyloid is a cardiac biopsy. Recently Gillmore et al showed a non-invasive diagnostic modality of nuclear medicine bone scans using technetium-labelled 99mTc-DPD, 99mTc-PYP or 99mTc-HMDP, to diagnosed ATTR amyloid with a high sensitivity and specificity (Fig 3). The diagnosis of ATTR amyloid must exclude AL amyloid or myeloma, which can be done by serum and urine EPG, IEPG, light chains and bence jones protein.

Figure 3

Figure 3. Bone scintigraphy demonstrating grades 0 (left) to 3 (right) of myocardial uptake in ATTR cardiac amyloid.

The findings of the ability of bone scintigraphy for accurate diagnosis has occurred in conjunction with the emergence of promising new treatment for ATTR amyloid.  These include ‘ATTR silencers’ such as injectable small interfering RNA (siRNA) and antisense oligonucleotides (ASO) that disrupt hepatic production of transthyretin (Fig1, A); ATTR stabilizes (eg. tafamidis, AG10) which bind and stabilize the transthyretin tetramer, preventing the formation of monomers that ultimately form fibrils (Fig 1, B); and lastly amyloid degraders, which remove amyloid fibrils or deposits in tissue (Fig 1, C).

Patients with LVH are now increasingly being screened for ATTR amyloid, and receiving treatment by access to clinical trials.  This is one of the new and exciting developments in the treatment of HFpEF, and we look forward to seeing improved symptoms, quality of life and survival in patients with ATTR amyloid.  

 References:

1. Castano A et al.  Eur Heart J 2015 Vol 36; Issue 38. 2595-97

2. Witteles R et al. JACC: Heart Failure 2019; Vol 7, Issue 8. 709-16

3. Mocha A et al. Arq Bras. Cardiol. 2017; Vol 108 Issue.1.

4. Gil J et al. Netherl Heart J. 2018; Vol 26, Issue 12: 635.

5. Gillmore J et al. Circulation. 2016;133:2404-2412.

 

KUMARASINGHE

Gayathri Kumarasinghe  MBBS BSc (Med) PhD FRACP

Consultant Cardiologist.

Dr. Kumarasinghe is a clinical and academic cardiologist. She subspecialises in heart failure, cardiac imaging and pulmonary hypertension.