Transthyretin Amyloid Cardiomyopathy (ATTR-CM)
Description
Introduction:
The progressive infiltrative cardiomyopathy known as transthyretin amyloid cardiomyopathy (ATTR-CM) is brought on by the extracellular deposition of insoluble amyloid fibrils in the heart that are formed from misfolded transthyretin
(TTR) protein.
Characteristics:
- Thickening of the ventricle without dilation of the chamber.
- Restrictive cardiomyopathy resulting from diastolic dysfunction.
- Decreased or retained ejection fraction in heart failure.
- Anomalies of the conduction system and arrhythmias.
- Clinical significance: Misdiagnosed frequently, it resembles hypertrophic or hypertensive heart disease, but the
prognosis is different, and there are now treatments tailored to the illness.
Etiology
Transthyretin (TTR):
- Thyroxine (T4) and the retinol-binding protein–vitamin A complex are transported via transthyretin (TTR), a normal serum protein mostly generated by the liver.
- Usually exists as a stable tetramer; when tetramers split into misfolded monomers, or fibrils, amyloidosis occurs.
Types of ATTR-CM:
Wild-Type (ATTRwt):
- Formerly “senile systemic amyloidosis.”
- caused by the TTR tetramers' age-related instability.
- frequently seen in older males (>65–70 years).
- involvement mostly of the heart.
Hereditary (Variant) ATTR (ATTRv):
- Autosomal dominant mutations in TTR gene (>120 mutations described).
- Mutations determine the phenotype (cardiomyopathy vs. neuropathy).
- For instance, Thr60Ala, Val30Met, and Val122Ile (common in African descent, cardiac-predominant).
The study of epidemiology
Prevalence and Incidence:
ATTRwt: Underdiagnosed; according to autopsy reports, deposits may be seen in up to 25% of males over 80.
Geographically variable, ATTRv is endemic in Portugal, Japan, Sweden, and West Africa.
Gender: ATTRwt has a significant male preponderance.
Both sexes are affected by ATTRv, however females may have reduced penetration.
The study of epidemiology
Prevalence and Incidence:
ATTRwt: Underdiagnosed; according to autopsy reports, deposits may be seen in up to 25% of males over 80.
Geographically variable, ATTRv is endemic in Portugal, Japan, Sweden, and West Africa.
Gender: ATTRwt has a significant male preponderance.
Both sexes are affected by ATTRv, however females may have reduced penetration.
The study of epidemiology
Prevalence and Incidence:
- ATTRwt: Underdiagnosed; according to autopsy reports, deposits may be seen in up to 25% of males over 80.
Geographically variable, ATTRv is endemic in Portugal, Japan, Sweden, and West Africa.
- Gender: ATTRwt has a significant male preponderance.
Both sexes are affected by ATTRv, however females may have reduced penetration.
Risk groups:
- Elderly men with unexplained HFpEF.
- Val122Ile mutations in African Americans (3–4% frequency).
- Individuals with lumbar spinal stenosis, biceps tendon rupture, or bilateral carpal tunnel syndrome.
Clinical Characteristics
Symptoms of the Heart
- Tiredness, exercise intolerance, and progressive dyspnoea.
- Hepatomegaly, ascites, and oedema are examples of right-sided failure.
- Microvascular infiltration causes angina.
- Syncope or presyncope (caused by decreased cardiac output or arrhythmias).
Indications
- Elevated JVP with a noticeable downward slope.
- Ascites with peripheral oedema.
- S4 (stiff ventricles) is typically missing.
- Narrow pulse pressure and low blood pressure.
Extra-Cardiac Warning Signs
- Carpal tunnel syndrome on both sides (typically years before HF).
- Stenosis in the lumbar spine.
- Rupture of the biceps tendon ("Popeye sign").
- Autonomic and peripheral neuropathy (particularly prevalent with ATTRv).
Diagnostic Evaluation:
Laboratory:
Rule out AL amyloidosis:
- Serum/urine electrophoresis with immunofixation, serum free light chains.
- Cardiac biomarkers: NT-proBNP, troponin (often elevated).
ECG:
- Low QRS voltage despite LV wall thickening.
- Pseudoinfarct pattern (Q waves without CAD).
- Conduction abnormalities, AF common.
Echocardiography:
- Symmetric LV wall thickening.
- Bi-atrial enlargement.
- “Speckled” myocardium (not specific).
- Diastolic dysfunction → restrictive filling.
Strain imaging: apical sparing pattern ("cherry-on-top").
Cardiac MRI:
- Late gadolinium enhancement: Diffuse subendocardial or transmural.
- Abnormal T1 mapping, extracellular volume expansion.
Nuclear Imaging:
- 99mTc-pyrophosphate (PYP) scintigraphy:
- High uptake diagnostic for ATTR-CM in absence of monoclonal protein.
- Differentiates ATTR from AL amyloidosis.
Genetic Testing:
- For suspected hereditary ATTR (ATTRv).
Biopsy:
- Endomyocardial biopsy: Gold standard if diagnosis uncertain.
- Congo red positive, TTR-specific immunostaining or mass spectrometry.
Differential Diagnosis:
- Hypertrophic cardiomyopathy.
- Hypertensive heart disease.
- Aortic stenosis.
- AL amyloidosis.
- Sarcoidosis.
Protocol
Management
General Principles
There is no cure; the goal of treatment is to control heart failure, lower the amyloid load, and stabilise TTR.
Treatments that Modify Disease
- TTR Stabilisers:
Tafamidis: Prevents tetramer dissociation by binding TTR. enhances QoL and survival.
Off-label diflunisal is an NSAID that has a stabilising effect.
- Gene silencing therapy (mostly for ATTRv): Inotersen (antisense oligonucleotide) and Patisiran (siRNA). Reduce the formation of TTR in the liver.
Next-generation siRNA, or vutrisiran.
- Copying genes with CRISPR-Cas9: promising in clinical trials.
Symptomatic/Supportive:
- Diuretics for symptoms or support: For volume overload (take with caution, preload dependant).
- Steer clear of ACE drugs and beta-blockers (poorly tolerated).
- Anticoagulation: For atrial fibrillation, which increases the risk of stroke.
- ICD/pacemaker: For VT or conduction problems.
- Rare yet achievable in some ATTRv individuals without systemic disease is advanced heart transplantation.
Combined liver-heart transplant: less usual now with gene-silencers, but historically for ATTRv (since the liver generates mutant TTR).
- Issue: Symptoms of Heart Failure
Symptoms include exhaustion, dyspnoea, intolerance to physical activity, peripheral oedema, ascites, hepatic congestion, jugular vein distension, and cardiorenal syndrome.
- Administration:
Health: Use of loop diuretics (ideally torsemide or bumetanide because to their greater bioavailability) in conjunction with aldosterone receptor blockers and strict dietary salt restriction are advised; beta-blockers, ACE inhibitors, and ARBs should be avoided until absolutely required due to intolerance and the risk of hypotension.
Advanced interventions include compression stockings and midodrine (for hypotension).
- Interventions in Nursing:
To identify fluid overload early, keep a careful eye on your daily weight and fluid balance.
Promote a low-sodium diet and stress the value of following hydration guidelines.
Look for indications of electrolyte imbalance and dehydration due to forceful diuresis.
- The possibility of hypotension and autonomic dysfunction necessitates careful monitoring of vitel indicators, particularly orthostatic blood pressure.
Encourage increasing activities gradually as tolerated.
- Problem: Cardiac Arrhythmias (especially Atrial Fibrillation)
Symptoms include palpitations, syncope, stroke risk, and atrial fibrillation that is poorly tolerated because of restrictive physiology.
- Management:
Medication: Amiodarone is often used for rhythm management; in certain situations, catheter ablation may be considered.
Anticoagulation: Because of the significant risk of thrombus, lifelong anticoagulation is advised regardless of CHADS-VASc score.
- Interventions in Nursing:
Keep an eye on your heart's rhythm and pace, and report any new or worsening arrhythmias right once.
Check for signs of embolic events, such as limb ischaemia or stroke.
Inform patients on the symptoms of bleeding, adherence, and anticoagulant treatment.
If necessary, get ready for and help with any possible electrical cardioversion.
- Problem: Conduction System Disease
Symptoms include heart block, bradycardia, syncope, and dizziness; a pacemaker is frequently required.
- Management: Medical/Device: Pacemaker implantation according to ACC/AHA/HRS guidelines for symptomatic bradycardia or heart block.
- Nursing Interventions:
Keep an eye out for signs of bradyarrhythmias, such as dizziness or syncope.
Pacemaker implantation post-procedure care includes wound monitoring, infection control, and device education.
Teach people how to check their pulse and when to call for emergency assistance.
- Problem: Progressive Disease and Limited Pharmacotherapy Manifestation: Disease progression despite standard heart failure care due to amyloid deposition.
- Management:
FDA-approved Tafamidis (stabilises transthyretin tetramer), a disease-modifying medication that slows but does not halt the course of both hereditary and wild-type ATTR-CM.
Other treatments: Gene-silencing or gene-editing medicines are being researched, and liver transplants are being examined in a small number of hereditary cases.
- Nursing Interventions:
Monitor for adverse effects and make sure patients take their prescriptions as directed.
Encourage clinical trial participation if qualified.
Offer psychological assistance for managing chronic illnesses.
Notes
For more details visit https://www.ncbi.nlm.nih.gov/books/NBK574531/