Overview
Cardiac Amyloidosis, once thought of as a rare disease, is increasingly being diagnosed as new methods allow for non-invasive diagnosis. Therefore, it is important that we are aware of the symptoms and treatments available for this irreversible disease, as many patients suffer from delayed diagnosis resulting in advanced disease progression, severely affecting their quality of life. It is now thought that cardiac amyloidosis may be present in up to 14% of patients with Heart Failure with Preserved Ejection Fraction (HFpEF), meaning an updated treatment plan to address CA is required[1]. The underdiagnosis of cardiac amyloidosis may negatively impact clinical trial outcomes of HFpEF medications and is thought to be a contributing factor for many phase III trial failures.
What are the causes of Cardiac Amyloidosis?
The two most common forms of cardiac amyloidosis, AL and ATTR, occur due to different reasons; however, they can broadly be grouped into acquired and hereditary
AL Amyloidosis is caused by light chain monoclonal immunoglobulins produced in the bone marrow misfolding to form amyloid fibrils. AL Amyloidosis is caused by the proliferation of an abnormal clone of plasma cells that overproduce light chain immunoglobulins. However, individuals undergoing prolonged treatment with dialysis may be more likely to develop AL Amyloidosis
Caused by mutations to the TTR gene, which occur on chromosome 18. This mutation results in the repeated misfolding of the prealbumin, a thyroxine and retinol transport protein produced in the liver, resulting in the accumulation of amyloid deposits.
Risk Factors
There are also several risk factors associated with cardiac amyloidosis, including those that mean these populations have a higher probability of suffering from amyloidosis:
Age
Depending on the form of the disease present, the age of onset varies. In most cases, this occurs over the age of 60, especially in individuals with wild-type ATTR cardiac amyloidosis. Cardiac amyloidosis can occur in individuals in their 20s, although this is rare.
Sex
Wild-type ATTR cardiac amyloidosis is more prevalent in men compared to women, with there being 25 to 50 cases in men for every case in women. In AL and ATTRv, there is no difference in occurrence between men and women.
Country of Origin
A genetic mutation responsible for familial ATTR amyloidosis is notably more prevalent in specific countries, such as Donegal (Ireland), Portugal, Japan, Sweden, and Finland, along with several other European nations.
Race
Another mutation leading to familial ATTR amyloidosis occurs in around 4% of Black individuals of West African heritage, encompassing African Americans as well as Black populations from Latin America and the Caribbean.
Symptoms
Part of the challenge in diagnosing cardiac amyloidosis is due to the broad range of symptoms, which vary based on the causes of the disease. Due to the broad spectrum of symptoms, cardiac amyloidosis is often incorrectly diagnosed as other cardiac diseases, including HFpEF.
Non-cardiac symptoms include:
- Carpal tunnel syndrome (especially bilateral carpal tunnel syndrome)
- Lumbar spinal stenosis
- Peripheral and autonomic neuropathy (numbness and tingling in hands or feet, light-headedness, or dizziness)
- Orthostatic hypotension (low blood pressure upon standing)
- Poor appetite, diarrhoea, or constipation
- Purple discoloration around eyelids (specific to AL amyloidosis)
- Easy bruising/bleeding (specific to AL amyloidosis)
- Enlarged tongue (specific to AL amyloidosis)
Cardiac Symptoms include:
- Fatigue
- Heart failure symptoms (breathlessness, edema, light-headedness, and fainting)
- Family history of heart failure
- Conduction system disease
- Atrial fibrillation
- Pseudoinfarct pattern
- Increased LV wall thickness
- Discordant GRS voltage for the level of increased LV wall thickness
- Diastolic dysfunction
- Abnormal longitudinal strain with apical sparing
Treatment
The type of treatment used will depend on the cause of the amyloidosis. It is extremely important to detect which genetic mutation is present in the case of ATTR amyloidosis, as this will establish the most appropriate therapy. As with most diseases, the earlier the diagnosis is made and treatment commenced, the greater the impact on disease progression and the patient's quality of life. In the case of cardiac amyloidosis, early detection is extremely important as it can enable the use of effective therapies and prevent irreversible damage, potentially avoiding the need for heart transplantation.
AL Cardiac Amyloidosis
Stem cell transplant and Chemotherapy
Autologous stem cell transplant and high-dose melphalan are the gold standard of treatment; however, there are no standardized eligibility criteria, and therefore suitability is determined by the treatment center. Cardiac involvement is one of the strongest predictors of mortality and morbidity, and as few as 25% of newly diagnosed patients are eligible due to delayed diagnosis, resulting in avoidable disease progression ruling them out of this effective treatment[2].
Daratumumab-CyBorD is currently the standard of care for newly diagnosed patients with AL amyloidosis and offers a lifeline for patients who are ineligible for stem cell transplant. The groundbreaking ANDOMRA trial found that over 50% of patients had a complete hematologic response, which was defined as an involved free light-chain level less than the upper limit of the normal range with negative serum and urine immunofixation[3].
While this trial did not report on mortality rates, a complete hematologic response is associated with prolonged life, and the safety profile of Daratumumab-CyBorD was comparable to CyBorD.
Immunotherapy
Your immune system typically identifies malfunctioning cells as threats and eliminates them. However, in diseases like cancer or AL amyloidosis, the immune system fails to recognize these faulty cells as harmful. Immunotherapy works by training the immune system to recognize and attack these malfunctioning cells.
ATTR Cardiac Amyloidosis
Liver Transplant
In years past, the sole method to prevent your liver from producing faulty proteins was through a liver transplant. While this option is no longer the exclusive choice, it remains a valuable and effective one.
TTR Stabilization
These therapies aim to stabilize the TTR protein and hinder further progression of amyloidosis by impeding the formation of amyloid deposits.
Currently, two treatments are available for this purpose:
Tafamidis – operates by binding to the TTR protein to stabilize it and reduce the rate of misfolding. Clinical trial evidence has demonstrated a statistically significant reduction in all-cause mortality and hospitalization, as well as significantly improved quality of life and exercise capacity.
Diflunisal – also a TTR stabilizer, offering a more cost-effective option for individuals unable to use Tafamidis. However, they lack the same level of evidence and are generally less well tolerated.
Future Therapies
Currently, several therapies that work by inhibiting the production of the TTR protein are in stage III clinical trials, having already received FDA approval for ATTR amyloidosis with polyneuropathy, including Acromidis, which had positive results and is now awaiting FDA approval, and Patisiran, which failed to meet its endpoints for cardiac amyloidosis. However, there are still several therapies in late-stage clinical trials with the same purpose. These therapies aim to halt the production of the TTR protein and prevent disease progression.
In the future, it is possible that monoclonal antibodies may be able to reverse the deposition of amyloid deposits; however, these are still undergoing clinical trials.
Reference List
- Porcari A et al. Incidence and Characterization of Concealed Cardiac Amyloidosis Among Unselected Elderly Patients Undergoing Post-mortem Examination. Frontiers in cardiovascular medicine 2022;8.749523
- Kittleson MM et al. 2023 ACC Expert Consensus Decision Pathway on Comprehensive Multidisciplinary Care for the Patient With Cardiac Amyloidosis. Journal of the American College of Cardiology. 2023;81(11):1076–126.
- Kastritis E et al. Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis. New England Journal of Medicine. 2021;385(1):46–58.
