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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/

 

Expert Insights: Amyloidosis – A Brief Clinical Overview

Dr. Sarah S. Lee, Assistant Professor, Division of Hematology, at the City of Hope, provides a brief yet comprehensive clinical overview of amyloidosis. In this video Dr. Lee discusses the breadth of amyloidosis, the wide range of symptom presentations, and which organs are typically involved. Focusing on AL (light chain) and TTR (transthyretin) types, she then goes through a diagnostic workup to arrive at a diagnosis, stressing the importance of typing once the presence of amyloid has been confirmed. Concluding her overview, Dr. Lee describes treatments available and how they impact patient prognosis and quality of life.

 

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.

Bicep Bunching & Amyloidosis

 

 

 

 

 

 

 

 

Often called “Popeye Deformity,” bicep bunching is visible when the patient flexes their arm, giving the appearance of Popeye-like arms. While it is the result of a torn tendon, it can be a leading indicator of more serious issues.

 

WHAT IS IT?

When the bicep tendon is ruptured, patients develop a bunching of the biceps upon flexion of the arm against gentle resistance. Tendon ruptures occur largely in the dominant arm of each patient, with one-quarter of patients developing ruptures in both arms. Interestingly, of those who had a rupture, 37.8% didn’t know it.

 

 

 

 

 

 

 

 

 

Below watch a video from The Lancet showing what bicep bunching looks like.

 

WHAT DOES IT POTENTIALLY INDICATE?

Two things.

1.  Bicep bunching may be a marker for ATTRwt. According to MedPage Today, spontaneous ruptures of the distal biceps tendon may be a marker of wild-type transthyretin (TTR) cardiac amyloidosis, a single-center study found. The presentation of a tendon rupture, an easily elicited diagnostic sign, in a patient with HFpEF should raise suspicion for wild-type TTR cardiac amyloidosis.

The picture below (Source: JAMA September 12, 2017 Volume 318, Number 10) offers examples of ruptured biceps tendon in two patients with biopsy-proven ATTRwt Cardiac Amyloidosis. ATTRwt indicates wild-type transthyretin amyloidosis. Patient 1 with prior rupture of the biceps tendon and bunching of the biceps with flexion. Patient 2 with acute rupture of the biceps tendon in the left arm; the tendon rupture occurred with trivial trauma, five years after Cardiac Amyloidosis diagnosis.

2.  ATTRwt may contribute to heart failure. Wild-type transthyretin amyloidosis (ATTRwt) is increasingly recognized as an important cause of heart failure with preserved ejection fraction (HFpEF).

 

WHY IS IT IMPORTANT?

Bicep bunching may be a marker of wild-type transthyretin (TTR) cardiac amyloidosis, potentially giving physicians an easy way to determine the underlying cause of heart failure with preserved ejection fraction (HFpEF) in some patients. Those who were aware, reported that the distal biceps tendon ruptured approximately five years prior to heart failure diagnosis, thus perhaps offering a leading insight.

In addition, early diagnosis of wild-type TTR cardiac amyloidosis (ATTRwt) is important because treatments are now available to slow, if not halt, disease progression. Unfortunately, the diagnosis of ATTRwt is often not considered in bicep bunching cases due to the perceived rarity of the disease.

“The clinical importance [of this study] is that the detection of a ruptured distal biceps tendon may be a clue for the diagnosis of wild-type TTR amyloidosis as the cause for heart failure. This diagnosis is often overlooked in clinical practice, so this relatively simple evaluation could increase detection of the disease,” said Stuart Katz, MD, of NYU Langone Health. “Enhanced detection could lead to better treatment.”

 

EXPERT INSIGHTS VIDEO ON MUSCULOSKELETAL MANIFESTATIONS

Dr. Shari Liberman, a hand and upper extremities surgeon from Houston Methodist Orthopedics & Sports Medicine, discussed six orthopedic manifestations and their pathology as it relates to systemic amyloidosis. Published studies, coupled with her experience, has led to a belief that these manifestations can offer important evidence of amyloidosis. She concludes with thoughts regarding an orthopedic differential and biopsy considerations for each of these manifestations.

 

Sources ———————————————————————————————————————
https://www.healthline.com/health/popeye-deformity
https://www.medpagetoday.com/cardiology/chf/67850
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5818850/
https://www.researchgate.net/publication/319657750_Association_Between_Ruptured_Distal_Biceps_Tendon_and_Wild-Type_Transthyretin_Cardiac_Amyloidosis
https://www.shoulderdoc.co.uk/article/721
https://www.thelancet.com/doi/story/10.1016/vid.2019.02.26.107679
https://www.youtube.com/watch?v=fHXu_0IZ3vU

Expert Insights: The Future for Patients with Transthyretin Cardiac Amyloidosis is Looking Brighter

The treatment for patients with Transthyretin Cardiac Amyloidosis has advanced significantly since 2018 when there were no FDA-approved therapies. In this presentation, Dr. Mat Maurer from Columbia University shares how diagnostic imaging techniques have significantly improved, thereby reducing the need for an invasive heart biopsy. In addition, he shares fascinating statistics on how the age and stage of diagnosis has been evolving. Based on today’s clinical trials, providers are optimistic that the expansion of options for patient care will continue.

The future is indeed looking brighter.

Diagnosing Amyloidosis: A Two-Step Process

Amyloidosis can present in many types with the three most prevalent being light chain (AL) amyloidosis, hereditary variant transthyretin (ATTRv) amyloidosis, and wild type transthyretin (ATTRwt) amyloidosis. Being a rare disease, diagnosis can be particularly challenging, given that the general medical community is not well educated on the malady and symptoms are often associated with other more common ailments.

Successfully diagnosing the disease requires a two-step process before an appropriate treatment program can be determined and implemented for each patient.

  1. First, if amyloidosis is suspected, testing must be done to confirm the presence of amyloid.
  2. Second, once the presence of amyloid is confirmed, testing must then be done to identify and confirm the type of amyloidosis.

It is crucial that the second step, where the correct type of amyloidosis is identified, as the treatment regime can be different for each type. Here we share two different patient experiences which illustrate successful execution of the two-step diagnostic process.

Patient Case #1

The first case involved a 23-year old female. In 2017 she experienced an episode of coughing up blood, after which she looked in her throat with a flashlight and discovered a sizable lump. The patient met with a local ENT, who incorrectly diagnosed allergies, and prescribed over-the-counter medicine. With no improvement, she met with a second ENT. Testing was performed on the patient’s left oral pharynx utilizing a Congo red staining biopsy process which confirmed the presence of amyloid in the tissue. Additionally, mass spectrometry was performed which successfully differentiated the type of amyloidosis as being ALH (lambda light chain and delta heavy chain). Subsequently, she was referred to a hematologist who ordered a bone marrow biopsy and blood testing. The bone marrow biopsy summary notes read “….in conjunction with the concurrent finding of monoclonal lambda light chain restricted plasma cells in the marrow by flow cytometry, the findings are consistent with involvement of the marrow by a plasma cell neoplasm.”

Additionally, the blood testing confirmed elevated light chains as shown below.

Patient Case #2

The second case involved a man in his mid-fifties. He began experiencing disease symptoms approximately 6-7 years prior to being diagnosed in early 2019. He initially experienced gradually progressing numbness in his feet, legs, hands and forearms, as well as bilateral carpal tunnel syndrome. Soon after, he began experiencing symptoms of lightheadedness and fainting. Additionally, he started experiencing progressive gastro-intestinal issues such as acid reflux, chronic coughing, and frequent bouts of constipation and diarrhea. By 2018, his physical condition was rapidly deteriorating, including a total weight loss of approximately 80 pounds. During this extended period of time he was seen by a variety of physicians including internal medicine, neurology, endocrinology, gastroenterology, oncology, and cardiology, none of who were successful in arriving at a conclusive diagnosis. His list of maladies included cardiomyopathy, peripheral neuropathy, autonomic neuropathy, bilateral carpal tunnel syndrome, and gastroparesis, all which are classic symptoms of amyloidosis.

Finally, in early 2019 his condition was successfully diagnosed by an amyloidosis specialist. An echocardiogram was performed as well as a cardiac MRI (utilizing a gadolinium tracer) to identify amyloid fibrils and related damage in the heart tissue. These tests confirmed the presence of amyloid. A free light chain serum test was performed which ruled out AL amyloidosis, and Transthyretin DNA sequencing was performed to differentiate between the hereditary variant and wild-type of ATTR, which identified the T80A (legacy T60A) variant of transthyretin (ATTRv) amyloidosis. The two tests were successful in identifying the type of amyloidosis. The associated testing results are show below.

Echocardiogram Summary Notes

Associated Cardiac MRI Interpretation

DNA Sequencing Result

 

Once Diagnosed, Next is a Treatment Plan

Once the presence of amyloid is confirmed, and the type is identified, then it is time to treat the disease. In each of these patient cases the disease was diagnosed utilizing the two-step process to identify and confirm the type of amyloidosis. In both cases, successful treatment regimens were implemented which were effective in putting the disease into remission and/or halting disease progression.

Treatment options for amyloidosis have been vastly improved over the past several years. What was previously considered to be a foregone fatal disease can now be a manageable chronic disease. To ensure the best patient outcome, a timely diagnosis utilizing the two-step process, is essential.

 

Expert Insights: Neurological Complications of ATTR Amyloidosis

Patients with ATTR amyloidosis are commonly faced with neurological complications. In this presentation, Dr. Chafic Karam from the University of Pennsylvania goes through four areas: an overview of the neurological systems, how amyloid damages the nerves, neurological signs of ATTR amyloidosis, and how to detect amyloid and diagnose ATTR amyloid neuropathy.

 

A Patient Guide for Understanding Amyloidosis

Amyloidosis is a multi-system disease, making diagnosis challenging. In this informative patient guide, the American Society of Nuclear Cardiology (ASNC) discusses common symptoms, types of amyloidosis, red flags to be aware of, diagnostic tests and available treatment options. 

CLICK HERE to read/download ASNC’s Guide for Understanding Amyloidosis

 

Multidisciplinary Care for Cardiac Amyloidosis Patients

Multi-systemic diseases such as amyloidosis are complex to diagnose, but also complex in treatment and ongoing patient care. It takes a village. In this seminal piece, the American College of Cardiology (ACC) provides an Expert Consensus Decision Pathway on Comprehensive Multidisciplinary Care for the Patient With Cardiac Amyloidosis. 

According to Dr. Vaishali Sanchorawala, Director of the Amyloidosis Center at Boston Medical Center, “The results and progress in the therapeutic landscape of systemic amyloidosis are unbelievable, unprecedented and unheard of for this uniformly fatal disease of the 1990s. But they are not enough, and therefore we need to work together to make a difference.

This paper is an absolute must-read for cardiologists and other specialties such as neurology, gastroenterology, nephrology and hematology.

To read, CLICK HERE.

 


Thank you.

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Source:
Kittleson M, Ruberg F, et al. 2023 ACC Expert Consensus Decision Pathway on Comprehensive Multidisciplinary Care for the Patient With Cardiac Amyloidosis. J Am Coll Cardiol. 2023 Mar, 81 (11) 1076–1126.
https://www.jacc.org/doi/10.1016/j.jacc.2022.11.022



ATTR-CM: Don’t Assume it’s Wild-Type TTR Amyloidosis

Historically it has been thought that the majority of elderly cardiomyopathy patients diagnosed with amyloidosis, ATTR-CM, transthyretin amyloid cardiomyopathy, suffered from wild-type, a non-genetic version of the disease that most commonly affects but is not exclusive to men over seventy years of age. A study in the UK conducted from January 2010 through August 2022 was conducted to determine whether this was true. It is thought that this study was the first time such a large population of ATTR-CM patients was studied to consider the actual prevalence of the differing disease types. The researchers stated purpose was “ …to estimate the prevalence, clinical characteristics and prognostic implications of transthyretin (TTR) variants among elderly patients diagnosed with ATTR-CM.”1

A paper detailing the results of the study, ‘Prevalence, characteristics and outcomes of older patients with hereditary versus wild-type transthyretin amyloid cardiomyopathy’ by A. Porcari et al.1, published January 16, 2023 in the European Journal of Heart Failure provide specifics about the methodology, statistical analysis of the results, and an analysis of the findings. An invited editorial about that article, ‘Variant and wild type transthyretin amyloidosis: two sides of the same coin or different currencies in different pockets?’, by Osnat Itzhaki Ben Zadok and Rodney H. Falk provides comments and an assessment of the study discussed in the A. Porcari paper.2  A helpful summary of the differences between wild-type and hereditary amyloidosis can be found here.3

With increased awareness of amyloidosis and the various types as well as developments in the technology used to diagnose and type ATTR amyloidosis, it has now become relatively easy to determine whether a patient is suffering from the hereditary version or the wild-type. Imaging has become preferred over the previous “gold standard” of endomyocardial biopsy. The study population was selected from those for whom ATTR-CM was established as the diagnosis using echocardiography, nuclear scintigraphy, and TTR gene sequencing at the National Amyloidosis Center (NAC) in London, the single center for diagnosing and treating amyloidosis patients in the UK. Correct diagnosis and typing of the disease could allow for appropriate treatment to begin resulting in the likelihood of an improved disease management and outcome for the patient.

A total of 2,029 patients were accepted into the study, none of whom had previously received genetic testing for the disease. Patients identified through gene sequencing as having the hereditary version of the disease, 141 total, were moved to medication as soon as it became available. Of note, all patients who had been treated with any of the then available medication for ATTR amyloidosis — tafamidis, inotersen, diflunisal, or patisiran, and all patients who were participating in clinical trials for therapies for the disease — were excluded from the study. This was to remove the possibility of the therapies skewing the results. All participants were 70 years of age or older. The patients were all followed at the NAC in London, the only center for the diagnosis and treatment of Amyloidosis in the UK. This allowed for unprecedented access to what is thought to be the majority of ATTR-CM in the country. All causes of death were tracked for the duration of the study.

The table below illustrates the number of ATTM-CM patients in the study who were thought to be suffering from wild-type amyloidosis but after testing were actually found to have a hereditary, variant, version of the disease instead. Specific data from the tests used to make this determination can be found in the article where the following table is found.

Correcting the diagnosis then allowed the patients to be moved to more appropriate therapies.

Further discussion in the Porcari article considers the study population and those currently listed in the THAOS registry4  by percentage of total ATTR-CM  patients in the United Kingdom, the United States, and the rest of the World for both wild-type and variant disease with the more common variants also identified. It is thought that as many as 20% of ATTR-CM identified as having the wild-type disease likely have a variant version but have not had genetic testing to correctly determine that.1

The article goes on to discuss the most commonly seen demographics and presentations of  ATTRwt-CM and ATTRv-CM in the elderly, and the effects of the various therapies currently available as well as their mechanisms and limitations.

While some symptoms of wild-type amyloidosis and hereditary, variant, amyloidosis are similar, it is easy to differentiate between the two diseases. With careful testing, as noted in the article, this then allows for the proper management and treatment of the disease. The concluding paragraph of the paper really sums up the findings and sends an important message.

In conclusion, up to 20.7% of elderly patients with ATTR-CM carry a pathogenic TTR mutation with a higher proportion still among specific ethnic groups. Among patients diagnosed with ATTR-CM, younger age at diagnosis, female gender, Afro-Caribbean ethnicity, AF, IHD, polyneuropathy and orthostatic hypotension are independently associated with ATTRv-CM. A diagnosis of ATTR-CM should prompt sequencing of the TTR gene in all patients, regardless of age, gender and ethnicity.”1

 

Sources:
1.     https://onlinelibrary.wiley.com/doi/full/10.1002/ejhf.2776  Prevalence, characteristics and outcomes of older patients with hereditary versus wild-type transthyretin amyloid cardiomyopathy, Aldostefano Porcari, Yousuf Razvi, Ambra Masi, Rishi Patel, Adam Ioannou, Muhammad U. Rauf, David F. Hutt, Dorota Rowczenio, Janet Gilbertson, Ana Martinez-Naharro, Lucia Venneri, Carol Whelan, Helen Lachmann, Ashutosh Wechalekar, Candida Cristina Quarta, Marco Merlo, Gianfranco Sinagra, Philip N. Hawkins, Marianna Fontana, Julian D. Gillmore, January 2023

2.     https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2808  Variant and wild type transthyretin amyloidosis: two sides of the same coin or different currencies in different pockets?
Osnat Itzhaki Ben Zadok, Rodney H. Falk, February 2023

3.     https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500251/   Transthyretin Amyloidosis: Update on the Clinical Spectrum, Pathogenesis, and Disease-Modifying Therapies
Haruki Koike  and Masahisa Katsuno, September 2020

4.     https://www.jns-journal.com/article/S0022-510X(15)00745-5/fulltext THAOS – The Transthyretin Amyloidosis Outcome Survey , F. Barroso, M. Waddinton-Cruz, et. Al., October 2015

 

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