ATTR Amyloidosis
ATTR amyloidosis is a progressive, life-threatening, systemic disease caused by misfolding and deposition of transthyretin (TTR) in the organs. ATTR amyloidosis variably affects the heart, nerves, eyes, gastrointestinal tract, renal tract, and tenosynoviu.
See Amyloid fibril proteins and their clinical presentation
The most common type of systemic amyloidosis is transthyretin amyloidosis (ATTR).
There are two types of ATTR;
- The most common is wild-type (wild type=endogenous/physiologic) ATTR (ATTRwt)
- The rarer ATTR type is inherited ATTR (ATTRv where “v” stands for “variant” gene)
- Approximately 10% of those diagnosed with ATTR in Australia’s AAN clinics have an inherited TTR gene mutation/ATTRv
- There are more than 140 TTR gene mutations that can cause ATTRv
- ATTRwt primarily affects the heart and tenosynovium, the latter causing carpal tunnel syndrome, spinal canal stenosis and biceps tendon ruptures, for example
- ATTRv presents with cardiac, neuropathic or mixed disease, with variable involvement of the gastrointestinal, renal, ocular and tenosynovial tissues.
While the pattern of organ involvement can be helpful to distinguish between ATTRwt and ATTRv, genetic testing (link to genetic testing page) is essential to definitively confirm the subtype. Genetic testing has implications for an individuals’ ability to access treatments and to facilitate testing and early diagnosis within families.
AL amyloidosis can be indistinguishable from ATTR amyloidosis clinically, as a result all patients with a presumed diagnosis of ATTR amyloidosis must have a full plasma cell dyscrasia screen including serum free light chains, and serum and urine protein electrophoresis and immunofixation (SFLC, SPEP/sIFE and UPEP/uIFE) to exclude AL amyloidosis.
- If the SFLC, serum and urine EPG and IEPG are all normal or negative we can be 99% certain that a patient does not have AL Amyloidosis.
- If one or more of these tests are positive a diagnostic biopsy needs to be performed to confirm the amyloid subtype.
Cardiac ATTR can be diagnosed without the need for cardiac biopsy in the majority (but not all) cardiac ATTR cases. See Diagnosis for more details.
Neuropathic ATTR diagnosis still largely requires a biopsy, particularly in isolated nerve disease, however, can be supported by numerous other testing modalities. .
There have been recent significant advances in disease modifying therapies for ATTR which have dramatically improved outcomes for patients with ATTR Amyloidosis.
Targeted Treatments
Systemic Therapies target the clinical syndromes resulting from TTR deposition in the heart and its conduction system.
1. Heart Failure (HF)
HF is common in patients with ATTR-CA and is due to a progressive restrictive cardiomyopathy characterised by decreased myocardial compliance and elevated filling pressure, reduced stroke volume and cardiac output. LV ejection fraction remains relatively preserved until the most advanced stage of the disease (HFpEF). The evidence behind traditional HF therapy remains limited and treatment guidelines heavily rely on expert consensus.
- Excessive fluid and salt intake should be generally avoided.
- Loop (and thiazide) diuretics are recommended to manage oedema and patient symptoms.
- Spironolactone can be considered with limited data on its efficacy in patients with HFpEF but also due to its potassium sparring effect.
- SGLT2 inhibitors have been recently introduced to the therapy and recent data suggests that they provide patients with ATTR-CA with mortality and morbidity (reduction in heart failure hospitalisation) benefits.
- Beta blockers could be maintained in patients with reduced LV ejection fraction (LVEF<40%) and patients with AF to improve heart rate control but in general only low doses should be used. In advanced stage of the disease reduction in the dose or even cessation of beta blockade to allow maintenance of cardiac output (which relies on heart rate in view of progressive reduction in stroke volume) should be considered.
- Use of vasodilators (including ACE inhibitors, ARB and ARNI) increase the risk of systemic and postural hypotension and has not been associated with improved survival in patients with ATTR-CA.
- The use of prophylactic defibrillators and CRT is not supported. However in individual cases with clinical worsening after PPM implantation cardiac resynchronisation may be considered.
- Referral for Cardiac Transplantation could be considered in younger patients with ATTR-CA (below the age of 70 years), who have no evidence of significant extracardiac amyloid deposition or important comorbidities (lungs, liver, kidneys) often found in this group of patients. Mechanical circulatory support (LVAD) for those patients is in general not recommended.
- Liver transplantation – As most of TTR is produced by the liver, liver transplantation was historically used in patient with hereditary disease. Liver transplantation is no longer recommended.
2. Arrhythmias and Conduction Disease
- Atrial Fibrillation (AF) is the commonest arrhythmia in patients with ATTR-CA. Its prevalence increases with stage of the disease (stage 1 – 61%, stage 3 – 76%). The presence of AF is associated with worse outcomes. Adequate anticoagulation is imperative in all patients with ATTR-CA and AF due to the highest risk of thromboembolism. Bridging with Heparin should be considered in all patients undergoing non cardiac surgery irrespective of the type.
Rhythm control. As the freedom from recurrent AF varies between the stages (~90% at 30 days in stage 1, <50% at 30 days for stage 3) in general the attempt at restoring sinus rhythm (with Direct Current CardioVersion DCCV + oral amiodarone) is not recommended in advanced ATTR -CA. TOE should guide any attempt at DCCV with adequate provision of therapeutic anticoagulation in view of high risk of atrial thrombi formation and stroke. AF ablation is generally not recommended due to its low efficacy.
Rate control. In majority of patients with ATTR–CA adequate control should be achieved by low dose beta blockers or Amiodarone. Calcium channels blockers are contraindicated. Judicious use of low dose Digoxin could be tried in those with low blood pressure and no alternative. - Ventricular arrhythmias (VT). Asymptomatic non-sustained VT are commonly detected in patients with ATTR-CA and may not require specific treatments. Sudden cardiac death (SCD) from sustained VT appears to be less common and a survival benefit from ICD therapy has not been proven. In general, there is limited benefit from primary prevention ICD but use of device in survivors of SCD is generally accepted.
- Conduction disease is commonly encountered in patients with ATTR-CA and standard indications for pacing are recommended.
3. Aortic Stenosis (AS)
ATTR-CA is found in as many as 16% of patients with severe AS and recent data suggests that such patients derive benefit from percutaneous valve replacement TAVI. Frailty assessment remains important and recommended component of evaluation patients referred for TAVI.
Disease-Modifying Therapies (DMT)
DMTs slow the progression of the disease and can be divided into 2 groups:
- TTR synthesis suppressing.
- TTR stabilisers.
TTR synthesis suppressing.
Patisiran and Vutrisiran (small interfering RNA) and Inotersen (ASO) inhibit the TTR production by mRNA degradation.
Patisiran (PBS approved in Australia for hereditary ATTRv with nerve involvement) is administered by intravenous infusion every 3 weeks. Vutrisiran (not yet registered) is used by subcutaneous (sc) injection every 3 months. Inotersen is given sc on weekly basis.
The drugs reduce the TTR blood levels by ~80% and as a result stabilise neuropathy, improve 6MWT and QOL in patients with ATTRv.
Vutrisiran in recently published HELIOS B trial reduced the mortality and HF hospitalisation in patients with ATTR-CA.
TTR stabilisers
Tafamidis (Vyndamax) is currently the only selective TTR stabiliser available in Australia. It has shown efficacy in reducing all cause mortality and CV related hospitalisation in patients with ATTR-CA and NYHA class 1 and 2 dyspnoea. The drug is well tolerated and should not be used in patients with severe renal dysfunction (eGFR<25mls/min).
Acoramidis (AG10) another selective TTR stabiliser is not yet available in Australia.
Diflunisal (an “old” NSAID) is a non-selective TTR stabiliser with limited evidence of efficacy in patient with ATTR-CA. It appears that the drug could slow the progression of polyneuropathy and improves QOL due to its analgesic effect. Diflunisal should be used with caution in patients with kidney dysfunction and GI problems with regular review of renal function and prophylactic use of PPI.
Other therapies
EGCG (green tea extract), Doxycycline and biliary acid (TUDCA) have anecdotal evidence for slowing the deposition of the amyloid fibrils. While these agents are well tolerated the evidence of their efficacy is very limited.
