ATTR Amyloidosis: Everything You Want to Know with Dr. Pankaj Arora • MyHeart

This article was created with Dr. Pankaj Arora, Director of the Cardiogenomics Clinic Program, Director of Clinical and Translational Research Program, University of Alabama at Birmingham.

Living with Amyloidosis: A Patient’s Perspective

An amyloidosis diagnosis is life-changing. From the moment symptoms start appearing—fatigue, swelling, nerve pain, or shortness of breath—everyday tasks can become overwhelming. The uncertainty of living with a rare and progressive disease brings both emotional and physical challenges.

Managing doctor visits, treatment regimens, and lifestyle adjustments can be daunting, but understanding the condition is the first step towards taking control. With advancing therapies and a supportive medical community, there is hope for a better quality of life, even in the face of this chronic illness.

What is Amyloid?

Amyloid refers to an abnormal protein that can accumulate in tissues and organs, disrupting their normal function. These misfolded proteins aggregate into insoluble fibrils that the body cannot easily break down, leading to amyloidosis. The condition can affect multiple organs, including the heart, kidneys, liver, and nervous system.

The Two Most Common Forms of Amyloidosis

AL Amyloidosis (Immunoglobulin Light Chain Amyloidosis)
- This form is caused by the overproduction of abnormal light chains, which are fragments of antibodies produced by bone marrow plasma cells. These light chains misfold and deposit as amyloid fibrils, often affecting the heart, kidneys, liver, and nervous system.
ATTR Amyloidosis (Transthyretin Amyloidosis)
- ATTR amyloidosis results from the misfolding of transthyretin (TTR), a protein responsible for transporting thyroid hormone and vitamin A. It can occur in a hereditary (mutant) form due to TTR gene mutations or in a wild-type (age-related) form. The primary targets of ATTR amyloidosis are the heart (leading to cardiomyopathy) and the nervous system (causing polyneuropathy, spinal stenosis, and carpel tunnel ).

Symptoms of Amyloidosis

The symptoms of amyloidosis depend on the organs affected but commonly include:

Cardiac Involvement: Heart failure symptoms like shortness of breath and lower extremity swelling, irregular heartbeat—in particular, atrial fibrillation, which is seen in over 70% of patients.
Renal Involvement: Protein in the urine, abnormal kidney function, edema.
Neurological Involvement: Numbness, tingling, carpal tunnel syndrome, spinal stenosis, dizziness, autonomic dysfunction (such as orthostatic hypotension), difficulty tolerating blood pressure medicine.
Gastrointestinal Symptoms: Diarrhea, constipation, weight loss.
General Symptoms: Fatigue, unexplained bruising, enlarged tongue (macroglossia in AL amyloidosis).

Diagnosis of Amyloidosis

The diagnosis of amyloidosis involves several steps to confirm the presence and type of amyloid deposits:

Serum and Urine Protein Electrophoresis (SPEP/UPEP) with Immunofixation: Helps identify abnormal light chains in AL amyloidosis.
Serum Free Light Chain Assay: Measures the levels of free light chains to detect AL amyloidosis.
Cardiac Imaging: Echocardiography demonstrating LVH or thickening of the walls of the left and right ventricles, and cardiac MRI can assess amyloid-related heart dysfunction.
Nuclear Scintigraphy: Used to differentiate ATTR amyloidosis from AL amyloidosis in suspected cardiac involvement.
Tissue Biopsy: The definitive diagnosis requires a biopsy of affected tissue (e.g., fat pad, bone marrow, kidney, heart) stained with Congo red to reveal apple-green birefringence under polarized light.
Genetic Testing: Essential for distinguishing hereditary from wild-type ATTR amyloidosis.

Treatment of AL Amyloidosis

The diagnosis of AL-amyloidosis requires the demonstration of amyloid in the tissue and evidence of abnormal plasma cells at bone marrow biopsy. Because the primary treatment requires chemotherapy or immunotherapy, the oncologist must be involved and is integral to the heart team.

The treatment targets the aberrant plasma cells, reduces the production of amyloid protein, and allows for the regression of amyloid tissue deposits. The treatment of AL amyloidosis is directed at control of the plasma cell clone with chemotherapy such as alkylating agents (Melphalan and Cyclophosphamide), steroids, protease inhibitors such as bortezomib (Velcade), immunotherapy with Daratumumab, and sometimes autologous stem cell transplant.

The treatment of amyloidosis depends on the type and severity of the disease. Standard guideline-directed medical therapies apply for treating patients with congestive heart failure with loop diuretics to alleviate the symptoms of fluid overload. Still, beta-blockers and vasodilator therapies (ACE inhibitors/ARBs, sacubitril/valsartan) are not well tolerated in patients with heart failure and normal LV ejection fraction and tend to develop hypotension.

Mineralocorticoids are usually recommended with or without the use of SGLT2 inhibitors, even if the experience with these medications is still somewhat limited. Patients with atrial fibrillation are at very high risk of forming a clot in their left atria and should be anticoagulated irrespective of their CHAD2DS2-VASC score.

Targeted therapies for amyloidosis aim to reduce amyloid production, stabilize precursor proteins, and clear amyloid deposits.

RNA Interfering Therapy (Silencers or Suppressors of TTR Synthesis)

These therapies work by inhibiting the production of the transthyretin (TTR) protein in the liver:

Inotersen: An antisense oligonucleotide that reduces TTR production by interfering with its RNA translation and is used for patients with neuropathy.
Patisiran: A small interfering RNA (siRNA) therapy that decreases TTR protein synthesis in the liver and is used for patients with neuropathy. In the post-hoc analysis of the APOLLO clinical trial, the cardiac subpopulation with increased wall thickness showed some regression in the wall thickness with Patisiran and a 46% reduction in hospitalizations. In phase 3 Apollo B, Patisiran combined with Tafamidis appeared to improve symptoms and exercise capabilities (6-minute walk test) at 6 months. However, at 12 months, there was no difference in the secondary composite endpoint: win ratio for change in 6-min walk test, death, and CV hospitalization.
CARDIO-TTRansform is studying the effect of Eplontersen on death and cardiovascular hospitalizations, with expected completion in 2025.
HELIOS-B studied the effect of Vutrisiran on the cardiovascular outcomes of patients with amyloidosis cardiomyopathy. The study enrolled 655 patients to receive Vutrisiran 25 mg or placebo administered SC every 3 months for up to 36 months, followed by an open-label period. In the overall population, Vutrisiran reduced the risk of all-cause mortality by 36% and the cardiovascular mortality by 33%. Compared to placebo, Vutrisiran also lowered the hospitalization rate by 25% and urgent heart failure visits by 46%. The magnitude of the benefits was seen in patients with less severe heart failure symptoms, indicating that these medications could silence disease progression with early treatment of ATTR-CM.

Stabilizer Proteins

These medications stabilize TTR, preventing it from misfolding and forming amyloid fibrils:

Tafamidis: The first FDA-approved stabilizer for ATTR amyloidosis, particularly for cardiac involvement. The ATTR-ACT Study showed a 30% relative risk reduction in all-cause mortality starting at 18 months of treatment. This was particularly significant in the wild-type ATTR and if the patients had mild symptoms of heart failure. This was also true for hospitalizations. The benefit of Tafamidis was still evident at 5 years of treatment with 50% of the patients alive (vs 25% if they were to continue on placebo).
Acoramidis: ATTRIBUTE-CM demonstrated that Acoramidis was well tolerated and improved the primary end-point of all-cause mortality, cardiac-related hospitalizations, Nt-probnp, and the 6-minute walk test
Diflunisal: A nonsteroidal anti-inflammatory drug (NSAID) repurposed for ATTR amyloidosis due to its TTR-stabilizing properties. It is a non-selective agent.
AG10: A novel TTR stabilizer currently under investigation in clinical trials.

Amyloid Disruptors or Degradors

These therapies aim to break down existing amyloid deposits and prevent further tissue damage:

Doxycycline and TUDCA (Tauroursodeoxycholic acid): A combination that disrupts amyloid fibrils and reduces organ damage.
Monoclonal Antibody Therapy: Several antibodies are being investigated to target and clear amyloid deposits, with promising results in early clinical trials, with resolution of their findings on Technicium pyrophosphate or cardiac MRI.

The Future of CRISPR and Gene Editing

Gene-editing technologies like CRISPR-Cas9 offer exciting potential for treating hereditary amyloidosis at its root cause. By directly editing the TTR gene, scientists aim to permanently reduce or eliminate the production of misfolded proteins, potentially offering a one-time curative treatment. Early-phase trials of CRISPR-based therapies for ATTR amyloidosis have shown promise, paving the way for revolutionary advances in the field. In a phase 1 clinical trial, 12 patients received a single infusion and experienced a >90% TTR reduction at 28 days and sustained to 6 months. Potentially, a single treatment could produce permanent silencing with significant implications for adherence and cost.

Conclusion

Amyloidosis is a complex disease with diverse manifestations and multiple therapeutic strategies. Advances in RNA-based therapies, stabilizers, amyloid disruptors, and emerging gene-editing techniques offer hope for improved outcomes and potentially curative treatments in the future. Ongoing research and clinical trials continue to expand our understanding and approach to managing this challenging condition.

Several questions, however, remain:

Should we treat asymptomatic patients?
Will the TTR silencer work for amyloidosis cardiomyopathy, and will it provide additional benefits to the stabilizers like Tafemidis?
Will CRISPR-Cas 9 provide a durable solution?
Are amyloid degraders, particularly the antibodies, going to be effective at removing those amyloid deposits and improving outcomes in patients with cardiac amyloidosis?

For many reasons, physicians should proactively refer patients to amyloid specialists and encourage patients to enroll in clinical trials of newer agents that can potentially improve the quality of life and survival of patients with amyloidosis.

5/5 (8)