Dr. Ahmad Masri, Director of the Cardiac Amyloidosis Program at Oregon Health & Science University (OHSU), reminds us about the traditional approach to diagnosis of cardiac amyloidosis. Unfortunately, this has not been enough. Thankfully, over the past decade that has all changed. He talks about OSHU’s approach to diagnosis today and what other data is used to arrive at a diagnosis of cardiac amyloidosis, offering four sample patient cases for insights.
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ATTRUBY (acoramidis) is now FDA-APPROVED for ATTR-CM in U.S.
Attruby (Acoramidis), was approved by the FDA on November 22, 2024 for ATTR-CM patients (both wild-type and hereditary) in the U.S.
Orally-administered, Attruby is a near complete TTR stabilizer (>= 90%), designed to reduce cardiovascular death and cardiovascular-related hospitalization. In addition, Attruby has been shown to preserve the native function of TTR as a transport protein of thyroxine and vitamin A.
To honor the courage of our U.S. clinical trial participants, BridgeBio will provide these patients Attruby free for life.
FDA CLEARS AI SCREENING TOOL FOR CARDIAC AMYLOIDOSIS
“Echocardiography is a powerful tool for evaluating cardiac structure and function and is central to the detection and monitoring of disease,” Ross Upton, PhD, CEO and founder of Ultromics, said in a statement. “However, there are some diseases that are very challenging for even the most expert clinician to detect on an echocardiogram. Requiring only a single apical four-chamber image, EchoGo Amyloidosis identifies cardiac amyloidosis and will help drive earlier access to appropriate treatment and care for patients with this underdiagnosed disease.”
Systemic Amyloidosis: You’ve Got to Think of IT to Diagnose IT
Dr. Mat Maurer, cardiologist at Columbia University Irving Medical Center, discusses the importance of developing a broad differential in order to diagnose this rare, potentially life-threatening, yet treatable disease. He shares a typical but unfortunate case of cardiac amyloidosis, along with statistics of misdiagnosis and delayed diagnosis. He shares his view on the appropriate process for diagnosis based on Dr. David Eddy’s 1982 New England Journal of Medicine piece “The Art of Diagnosis” and the need to create a broad enough differential in order to consider less common diseases such as systemic amyloidosis. Dr. Maurer lists common reasons for missing diagnosis of cardiac amyloidosis all clinicians should be aware of, punctuated by his concluding point … “The Key to Correct Treatment is Diagnosis, Diagnosis, and Diagnosis.” It’s simple … you cannot treat what has not been diagnosed.
This is a MUST VIEW video for clinicians who diagnose patients, regardless of sub-specialty.
Carpal Tunnel & Amyloidosis
Look to the Wrist for an Early Diagnostic Clue: Tissue samples from carpal tunnel surgery hold screening utility
According to the Cleveland Clinic, tenosynovial tissue biopsy at the time of carpal tunnel surgery can be a useful tool for detecting cardiac amyloidosis at an earlier stage, suggests a recent Cleveland Clinic study in the Journal of the American College of Cardiology (JACC) (2018;72:2040-2050).
“We found that 1 in 10 older patients who underwent carpal tunnel release surgery for idiopathic carpal tunnel syndrome had either ATTR [transthyretin] or AL [light chain] amyloidosis in a sample of patients who had tenosynovial tissue removed,” says Cleveland Clinic cardiologist Mazen Hanna, MD, the study’s primary investigator. “This may be an early marker or precursor of amyloid heart disease.”
An accompanying editorial in JACC (2018;72:2051-2053) calls the investigation “a well-conducted pilot study that should be seen as a justification for larger screening efforts.”
Better defining the amyloid/carpal tunnel connection
The study was prompted by recognition that, despite the classic association of amyloidosis with carpal tunnel syndrome, the frequency of cardiac involvement at the time of carpal tunnel release surgery had never been established.
“The index patient that got us thinking about this project was operated on by Cleveland Clinic orthopaedic surgeon William Seitz, MD, a key collaborator on the study, who noted thickened tenosynovial tissue and astutely asked for a Congo red stain,” Dr. Hanna explains. “In the wake of that, we decided to undertake this study to determine the prevalence and type of amyloid deposits in carpal tunnel surgery patients and assess for cardiac involvement.”
So Drs. Hanna and Seitz, together with colleagues from Cleveland Clinic’s Heart & Vascular and Orthopaedic & Rheumatologic Institutes, ended up prospectively studying consecutive men aged 50 or older and women aged 60 or older undergoing carpal tunnel release surgery at Cleveland Clinic over a one-year period. They stained samples of tenosynovial tissue from all patients; those with confirmed amyloid deposits were typed with mass spectrometry and the patients underwent cardiac evaluation consisting of electrocardiography, echocardiography with longitudinal strain, technetium pyrophosphate scintigraphy and blood tests for biomarkers.
Findings prompt therapy initiation in three patients
Of the 98 patients enrolled, 10 (10.2 percent) had a positive biopsy for amyloid — seven ATTR, two AL and one untyped. Two of these patients were diagnosed with hereditary ATTR, two were determined to have cardiac involvement (one AL, one ATTR wild-type) and three were started on pharmacologic therapy.
Notably, patients with ATTR demonstrated no difference in plasma transthyretin concentration or tetramer kinetic stability, which indicates that these measures likely cannot serve to detect cardiac amyloidosis on their own.
Low-cost method of early detection
“Amyloid cardiomyopathy is an underrecognized cause of heart failure with preserved ejection fraction,” Dr. Hanna observes. “We believe that screening patients for amyloidosis when they have carpal tunnel surgery can be an inexpensive way to diagnose cardiac involvement early and help avert progressive heart failure.”
This is particularly true, he notes, with the advent of the first effective therapies for cardiac amyloidosis, which recently have rendered the condition medically treatable for the first time.
“The early recognition made possible by tenosynovial tissue biopsy is critical, since current treatment strategies suppress the production of precursor protein or prevent protein misfolding but do not directly target current amyloid deposits,” Dr. Hanna explains. “This allows for implementation of disease-modifying therapy prior to development of cardiac symptoms.”
He adds that the detection of AL in two of the 10 patients with biopsy-diagnosed amyloidosis is especially notable since AL cardiac amyloidosis tends to progress more rapidly and has a poor prognosis once cardiac involvement advances.
Time for a screening algorithm
Dr. Hanna and his colleagues are continuing to follow up the study cohort to observe and report additional noteworthy findings. In the meantime, these initial results, together with emerging data related to soft tissue amyloidosis, have prompted implementation of a new screening algorithm at Cleveland Clinic.
The algorithm, available as a supplementary online figure to the JACC study report, guides hand surgeons on the appropriateness of tenosynovial biopsy at the time of carpal tunnel release surgery. If Congo red staining is positive, typing with mass spectrometry and referral to an amyloidosis specialist is indicated.
The authors of the accompanying JACC editorial note that while the best screening methodology remains to be determined, “a screening algorithm will likely be incorporated into everyday clinical practice in the near future.”
Cardiomyopathy & Amyloidosis
Cardiomyopathy is a broad term that is used to describe disease of the heart muscle, making it difficult for the heart to provide the body with an adequate blood supply. It can lead to heart failure and even death. In this article, we’ll discuss the types of cardiomyopathy and its connection to amyloidosis.
Risk Factors
It has no ideal target, as it can affect a person of any age, race, or gender. However, there are a number of risk factors that can put one at an increased chance of developing cardiomyopathy.
- Genetic History → Family history of cardiomyopathy, heart failure, or sudden cardiac arrest
- High Blood Pressure → Over a long period of time
- Heart Conditions → Past history of heart attack, coronary artery disease, or infection of the heart
- Obesity → Tends to make the heart work harder to perform its normal function
- Alcohol Use → Long period of alcohol use
- Drug Use → Use of illicit drugs, such as cocaine, amphetamines, and anabolic steroids
- Medications → Drugs used in the treatment of cancer, such as chemotherapy and radiation
Additionally, there are a number of diseases that increase the risk of developing cardiomyopathy, including:
- Amyloidosis
- Connective Tissue Disorders
- Diabetes
- Hemochromatosis (excess iron storage)
- Sarcoidosis
- Thyroid Disease
Types of Cardiomyopathy
- Dilated Cardiomyopathy → Dilation of the left ventricle prevents the heart from pumping effectively. It most commonly occurs in middle-aged men and is typically the result of coronary artery disease, heart attack, or genetic defects.
- Hypertrophic Cardiomyopathy → Abnormal thickening of heart muscle, most commonly affecting the muscles surrounding the left ventricle. This type of cardiomyopathy is strongly associated with a family history of the disease. There have been genetic mutations linked specifically with this type of cardiomyopathy.
- Restrictive Cardiomyopathy → Stiffening of the heart muscle results in an inelasticity, making it difficult for the heart to expand and fill. It is most commonly seen in the elder population. The disease can be of idiopathic origin or of disease such as amyloidosis. This is the least common type of cardiomyopathy.
- Arrhythmogenic Right Ventricular Dysplasia → Scar tissue replaces healthy tissue of the right ventricle. This form of cardiomyopathy is rare and often the result of genetic mutations.
- Unclassified Cardiomyopathy → All other forms of cardiomyopathy fall within this category.
Amyloidosis
Cardiomyopathy is one of the hallmarks of amyloidosis, often seen in the transthyretin form of amyloidosis (ATTR). ATTR-CM, or transthyretin amyloid cardiomyopathy, is a disease where the transthyretin protein becomes unstable and misfolds. This unstable protein (“amyloid”) then deposits in the heart muscle, resulting in thickening and stiffening of the heart.
The two types of ATTR-CM are wild-type ATTR-CM (wtATTR) or hereditary ATTR-CM (hATTR). wtATTR-CM is the most common form of ATTR-CM, affecting predominantly white males 60+ years old. hATTR-CM is genetic affecting both men and women, and presents as early as 50+ years old. Interestingly, one of the mutations causing hATTR, V122I, is seen almost exclusively in individuals of African ancestry. It is believed that approximately 3-4% of African Americans carry this mutation, regardless of whether or not they develop symptoms.
Most importantly, these are the most common and important signs and symptoms to be aware of, in order to diagnose ATTR amyloidosis.
Expert Insights – Cardiac Clues and Clinical Signs
In part 1 of a 2-part series, Dr. Keyur Shah, cardiologist from VCU Health’s cardiac amyloidosis care team, discusses the two most common types of transthyretin (TTR) amyloidosis: hereditary and wild-type. He details how ATTR cardiomyopathy amyloidosis presents and manifests itself to impair the heart. Dr. Shah lists clinical clues, “red flags,” and biomarkers which can raise suspicion of the presence of amyloidosis. Next he discusses insights that can be gained from echocardiograms, electrocardiograms, and cardiac MRIs and how they offer possible indicators of the disease presence. Once amyloidosis is suspected, definitive diagnosis testing is next.
In part 2 of a 2-part series, Sarah Paciulli, Heart Failure Nurse Practitioner, from VCU Health’s cardiac amyloidosis care team, continues from where Dr. Keyur Shah ended in Part I and discusses here in Part II the non-cardiac clues of transthyretin (TTR) amyloidosis. She expands the list of clinical clues and “red flags” that clinicians should be alert to, including orthopedic manifestations, erectile dysfunction, and polyneuropathy.
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References:
https://www.mayoclinic.org/diseases-conditions/cardiomyopathy/symptoms-causes/syc-20370709
https://www.yourheartsmessage.com
https://healthjade.net/familial-amyloidosis/
Cardiac Amyloidosis – AL and ATTR: Two Different Conditions
Dr. Mazen Hanna, cardiologist at the Cleveland Clinic and co-director of the Amyloid Program, explains how cardiac amyloidosis can originate from two very different types of amyloidosis: AL or ATTR. Dr. Hanna illustrates how physicians can identify cardiac amyloidosis and look to different diagnostic work-ups to understand whether the issues are due to AL or ATTR amyloidosis. These two conditions are treated differently and have different prognoses, emphasizing the importance of understanding the type of amyloidosis involved.
Cardiac Clues that Suggest Transthyretin Amyloidosis – Part I
In part 1 of a 2-part series, Dr. Keyur Shah, cardiologist from VCU Health’s cardiac amyloidosis care team, discusses the two most common types of transthyretin (TTR) amyloidosis: hereditary and wild-type. He details how ATTR cardiomyopathy amyloidosis presents and manifests itself to impair the heart. Dr. Shah lists clinical clues, “red flags,” and biomarkers which can raise suspicion of the presence of amyloidosis. Next he discusses insights that can be gained from echocardiograms, electrocardiograms, and cardiac MRIs and how they offer possible indicators of the disease presence. Once amyloidosis is suspected, definitive diagnosis testing is next. See Part II: “Clinical Signs that Suggest Transthyretin Amyloidosis: Non-cardiac Clues” for more information.
Clinical Signs that Suggest Transthyretin Amyloidosis: Non-cardiac Clues – Part II
In part 2 of a 2-part series, Sarah Paciulli, Heart Failure Nurse Practitioner from VCU Health’s cardiac amyloidosis care team, continues from where Dr. Keyur Shah ended in Part I and discusses here in Part II the non-cardiac clues of transthyretin (TTR) amyloidosis. She expands the list of clinical clues and “red flags” that clinicians should be alert to, including orthopedic manifestations, erectile dysfunction, and polyneuropathy. See Part I: “Cardiac Clues that Suggest Transthyretin Amyloidosis” for more.
Closing the Underdiagnosis Gap of Transthyretin Cardiac Amyloidosis Among African Americans
Dr. Kevin Alexander, advanced heart failure and transplant cardiologist at the Stanford Amyloid Center, discusses transthyretin cardiac amyloidosis (ATTR-CM) and how today this is a “common rare disease,” more prevalent than previously appreciated. He summarizes findings from a study to understand diagnosis across the U.S. and how ATTR-CM disproportionately affects black individuals. This statistic is driven by the belief that 3-4% of African descendants carry the V122I TTR variant – translating to over 1 million carriers. Kevin offers a screening algorithm for who to screen for ATTR-CM, and examines sub-groups of African Americans that are important not to overlook.
