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Patient Insights: Best kept secret

Our patient speakers at the Amyloidosis Speakers Bureau are powerful educators and offer compelling insights.

Have a listen to this brief clip from Ozzie on his discovery of the ‘best kept secret’ as it pertains to diagnosing amyloidosis – carpal tunnel syndrome.

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.

————————————————————
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

 

Patient Insights: Biopsy the CTR tissue!

Our patient speakers at the Amyloidosis Speakers Bureau are powerful educators and offer compelling insights.

Have a listen to this brief clip from Linda with thoughts on how orthopedic hand surgeons can be on the front line of diagnosis through CTR tissue biopsy.

Hereditary Amyloidosis: The V122I Variant

Hereditary Amyloidosis in Black Americans of African Descent: ATTR V122I Variant

Amyloidosis, still considered a relatively rare disease, can take several forms. Each slightly different, but most sharing similar debilitating symptoms of cardiac and/or neurological impairment, or both. It is viewed by many experts that amyloidosis has been presenting in plain sight and missed, or wildly underdiagnosed, for decades and, in some cases, generations. Thankfully, education to raise awareness within the healthcare community, along with improvements in diagnostic tools and testing, the journey to diagnosis and treatment is becoming more visible.

The hereditary transthyretin amyloidosis (hATTR) type results from a genetic mutation of a protein, transthyretin, which is produced in the liver and circulates throughout the body. The mutation causes the TTR protein to misfold, becoming unstable and depositing in organs and nerve systems causing impairment and eventual organ failure. Common symptoms for the disease include bilateral carpel tunnel syndrome, muscle weakness, cardiomyopathy, polyneuropathy, GI issues especially chronic diarrhea and constipation, and both nuisance and serious concerns and if untreated can lead to death. Early diagnosis, genetic testing to identify the exact genetic mutation, and treatment are important to slow the progression of the disease and conserve quality of life.

SIGNIFICANTLY UNDER-DIAGNOSED

Considered a rare disease, advances in diagnosis have shown that it is less rare than originally thought.

Familial amyloidosis caused by a transthyretin mutation occurs in approximately 1 in 100,000 Caucasians in the U.S, and more commonly in African Americans (approximately 4% in that population). This condition is prevalent in Portugal, Sweden, Japan, Ireland, Spain, France, Finland, Germany and Greece. Symptoms usually begin between 40 and 65 years of age.

https://rarediseases.org/rare-diseases/amyloidosis/

To date over one hundred variants of TTR have been identified as causing ATTR amyloidosis and they are distributed worldwide with concentrations in various ethnic populations. One variant, V122I is most commonly found in people with African and especially West African ancestry. It has been distributed worldwide but especially in North America and the Caribbean through historic slave trade and the migration of populations. This variant is most often associated with ATTR-CM (Amyloidosis with cardiomyopathy) and heart failure.

Worldwide Carrier Rates of TTR V122I in Self-Reported Countries/Regions

 From Multicenter Study JAMA 2019 Dec 10;322(22):2191-2202.

 doi: 10.1001/jama.2019.17935.

 

In an article by J. Buxdaum and F. Ruberg in the Journal Genetics in Medicine January 2017, the authors stated the following findings.

Since the identification of a valine-to-isoleucine substitution at position 122 (TTR V122I; pV142I) in the transthyretin (TTR)-derived fibrils extracted from the heart of a patient with late-onset cardiac amyloidosis, it has become clear that the amyloidogenic mutation and the disease occur almost exclusively in individuals of identifiable African descent. In the United States, the amyloidogenic allele frequency is 0.0173 and is carried by 3.5% of community-dwelling African Americans. Genotyping across Africa indicates that the origin of the allele is in the West African countries that were the major source of the slave trade to North America. At autopsy, the allele was found to be associated with cardiac TTR amyloid deposition in all the carriers after age 65 years; however, the clinical penetrance varies, resulting in substantial heart disease in some carriers and few symptoms in others. The allele has been found in 10% of African Americans older than age 65 with severe congestive heart failure. At this time there are potential forms of therapy in clinical trials. The combination of a highly accurate genetic test and the potential for specific therapy demands a greater awareness of this autosomal dominant, age-dependent cardiac disease in the cardiology community.

Genet Med advance online publication 19 January 2017

 

The prevalence and distribution of the amyloidogenic transthyretin (TTR) V122I allele in Africa.

1:CAS:528:DC%2BC28XhsFSlsbfJ 10.1002/mgg3.231 Mol Genet Genomic Med. 2016; 4: 548-556

 

Dr. Martha Grogan, director of the Cardiac Amyloid Clinic of Mayo Clinic in Rochester, Minnesota commented in an interview published in the Mayo News Network  (https://newsnetwork.mayoclinic.org/discussion/expert-alert-cardiac-amyloidosis-masquerades-as-other-conditions-1-type-affects-more-black-americans/) that amyloidosis can be tricky to suspect because symptoms may not be initially present and they may mimic other more common diseases. Currently there are options for free saliva or blood tests through several pharmaceutical companies. To determine the type of the disease genetic testing is important.

The University of Pennsylvania and the Icahn School of Medicine at Mount Sinai conducted a study of 52,492 participants of which 11,143 were of self-reported African ancestry. https://jamanetwork.com/journals/jama/fullarticle/2757227

An excellent discussion of the results emphasizes the conclusion that a significant association of TTR V122I and heart failure in the tested population, primarily in those of West African ancestry, exists. In addition, they confirm previous studies that have suggested a high rate of underdiagnosis of hATTR-CM in cases of cardiomyopathy and heart failure in elderly patients of African Ancestry. The discussion further suggests that this is likely due to lack of information and familiarity with the disease in the medical community.

CITATION:  Damrauer SM, Chaudhary K, Cho JH, et al. Association of the V122I Hereditary Transthyretin Amyloidosis Genetic Variant With Heart Failure Among Individuals of African or Hispanic/Latino Ancestry. JAMA. 2019;322(22):2191–2202. doi:10.1001/jama.2019.17935.  https://pubmed.ncbi.nlm.nih.gov/31821430/

 

Discussion of a different study of 7,514 African American participants in the US considered the question of the association between genetic variation and the risk of heart failure. This study was conducted by the University of Alabama, University of Colorado, Columbia University, and Cornel University. The results are similar to those in the University of Pennsylvania study discussed above, with additional comments that more subtle symptoms and changes may be apparent well before the typical onset of significant disease, average age 65, and the need for earlier screening for early detection and treatment.

An autosomal-dominant disease, hATTR-CM has a median survival of nearly 2.5 years without treatment after receiving a diagnosis.34,35 Extrapolating the hATTR-CM–associated Val122Ile variant frequency to the population level suggests that approximately 1.4 million Black individuals carry this variant implicated in the development of heart failure and reduced overall survival. Despite the possible clinical implications, the Val122Ile TTR variant, which is seen relatively more commonly among individuals of African ancestry, is not included in the list of clinically actionable deleterious variants compiled by the American College of Medical Genetics and Genomics.9 Thus, this potentially deleterious variant may not be reported as clinically actionable, thereby reducing physician vigilance for hATTR-CM.

Findings In this retrospective cohort study that included 7,514 Black participants in the US with a median 11.1 years of follow-up, the incidence of heart failure was 15.6 per 1000 person-years among Val122Ile variant carriers compared with 7.2 per 1000 person-years among noncarriers, with an adjusted hazard ratio of 2.43.

Meaning Being a carrier of the Val122Ile variant was significantly associated with an increased risk of heart failure among Black individuals living in the US.

CITATION: Parcha V, Malla G, Irvin MR, et al. Association of Transthyretin Val122Ile Variant With Incident Heart Failure Among Black Individuals. JAMA. 2022;327(14):1368–1378. doi:10.1001/jama.2022.2896

https://pubmed.ncbi.nlm.nih.gov/35377943/

SUMMARY

Despite the evidence that a meaningful 3-4% of the US Black population of West African ancestry likely carries the V122I genetic mutation, hereditary TTR amyloidosis remains significantly underdiagnosed and undertreated in this population.

Cardiac symptoms in elderly black patients have too often been treated for more common cardiomyopathy and heart conditions, resulting in lack of appropriate treatment and often death. Because of lack of awareness in the medical community and reduced access to expert medical care, more subtle symptoms in younger black patients generally have not caused the physicians to consider amyloidosis. Additionally, lack of genetic testing can mean that entire families are unaware of the implications of the disease.

Amyloidosis can be devastating to both patients and their families. Increased awareness of the disease, availability of testing, and FDA-approved therapies are slowly beginning to shift this dynamic. However, there is still much work to be done to close the gap between diagnosed cases and the population estimated to be affected.

Early diagnosis is key.

 

For additional information regarding hereditary amyloidosis:

Worldwide Hotspots of Hereditary TTR Amyloidosis (ATTRv)

Hereditary Amyloidosis: T60A Variant

CRISPR/Cas9 – ATTR Clinical Trial Update

Per the National Institute of Health, “One of the most promising areas of research in recent years has been gene editing, including CRISPR/Cas9, for fixing misspellings in genes to treat or even cure many conditions.” In this piece we provide a clinical trial update for transthyretin (TTR) amyloidosis using this technology.

 

CRISPR FIXES GENES INSIDE THE BODY (3)

Per the National Institute of Health, “One of the most promising areas of research in recent years has been gene editing, including CRISPR/Cas9, for fixing misspellings in genes to treat or even cure many conditions.”

CRISPR is a highly precise gene-editing system that uses guide RNA molecules to direct a scissor-like Cas9 enzyme to just the right spot in the genome to cut out or correct disease-causing misspellings.

 

APPLYING THE CRISPR TECHNOLOGY (3)

Science highlights a small study reported in The New England Journal of Medicine by researchers at Intellia Therapeutics, Cambridge, MA, and Regeneron Pharmaceuticals, Tarrytown, NY, in which six people with hereditary transthyretin (TTR) amyloidosis, a condition in which TTR proteins build up and damage the heart and nerves, received an infusion of guide RNA and CRISPR RNA encased in tiny balls of fat.The goal was for the liver to take them up, allowing Cas9 to cut and disable the TTR gene. Four weeks later, blood levels of TTR had dropped by at least half.”

Facts about Transthyretin (ATTR) Amyloidosis. Source: https://ir.intelliatx.com/

 

CLINICAL TRIAL UPDATE — NTLA-2001 (1)

Intellia Therapeutics and Regeneron shared a press release recently announcing initial data from the cardiomyopathy arm of the ongoing Phase 1 trial of NTLA-2001, an investigational single-dose in vivo CRISPR-Cas9 therapy for the treatment of transthyretin (ATTR) amyloidosis.

According to that press release, the interim data include 12 adult patients with ATTR amyloidosis with cardiomyopathy (ATTR-CM) with New York Heart Association (NYHA) Class I – III heart failure. Single doses of 0.7 mg/kg and 1.0 mg/kg of NTLA-2001 were administered intravenously, and the change from baseline in serum transthyretin (TTR) protein concentration was measured for each patient. The data revealed that treatment with NTLA-2001 led to rapid and deep reductions of up to 94 % in serum TTR by day 28. In February 2022, the companies reported clinical data that revealed rapid, deep and sustained responses in a cohort of 15 patients with hereditary transthyretin (TTR) amyloidosis with polyneuropathy (ATTRv-PN).

ATTR is a rare, progressive disease, in which a protein known as TTR becomes misfolded and accumulates as plaques in tissues throughout the body. This causes serious complications that mainly involve the heart and nerves, and most patients die 2-15 years after disease onset. NTLA-2001 was the first in vivo CRISPR therapy to be administered to humans via the bloodstream. It is designed to treat ATTR by selectively reducing the levels of mutated TTR protein in the blood, through CRISPR-based inactivation of the TTRgene in liver cells.

Read more about the available clinical data for NTLA-2001 in a previous CMN clinical trial update here.

BACKGROUND

Back in May, 2021 we wrote about the breakthrough gene-editing technology CRISPR being applied to hereditary transthyretin amyloidosis (hATTR), worthy of a background read for those unfamiliar with this science or those looking for a refresher.

BLOG – CRISPR/Cas9 – Editing the Code of Life

 

 

Sources:

  1. CRISPR Medicine News: Special Update: News from the Gene-Editing Clinical Trials
  2. CRISPR Medicine News: CRISPR Therapy for Transthyretin Amyloidosis Results in Rapid and Prolonged Responses
  3. NIH Director’s Blog
  4. BLOG – CRISPR/Cas9 – Editing the Code of Life

Heart Failure & Amyloidosis

 

We would like to thank the Cleveland Clinic for this information, unless specifically noted otherwise.

 

WHAT IS HEART FAILURE?

Heart failure occurs when the heart muscle doesn’t pump blood as well as it should. Heart failure can occur if the heart cannot pump (systolic) or fill (diastolic) adequately.

Almost six million Americans have heart failure, and more than 870,000 people are diagnosed with heart failure each year. Heart failure (congestive heart failure) is the leading cause of hospitalization in people older than 65.

 

WHAT ARE THE TYPES OF HEART FAILURE?

There are many causes of heart failure, but the condition is generally broken down into these types:

Left-sided heart failure

Heart failure with reduced left ventricular function (HF-rEF)

The lower left chamber of the heart (left ventricle) gets bigger and cannot squeeze (contract) hard enough to pump the right amount of oxygen-rich blood to the rest of the body.

Heart failure with preserved left ventricular function (HF-pEF)

The heart contracts and pumps normally, but the bottom chambers of the heart (ventricles) are thicker and stiffer than normal. Because of this, the ventricles can’t relax properly and fill up all the way. Because there’s less blood in the ventricles, the heart pumps out less blood to the rest of the body when it contracts.

Right-sided heart failure

Heart failure can also affect the right side of the heart. Left-sided heart failure is the most common cause of this. Other causes include certain lung problems and issues in other organs.

 

WHAT ARE THE SYMPTOMS OF HEART FAILURE?

Symptoms of heart failure include:

  • Shortness of breath.
  • Feeling tired (fatigue) and having leg weakness when active.
  • Swelling in ankles, legs and abdomen.
  • Weight gain.
  • Need to urinate while resting at night.
  • Rapid or irregular heartbeats (palpitations).
  • A dry, hacking cough.
  • A full (bloated) or hard stomach, loss of appetite or upset stomach (nausea).

Symptoms of heart failure can range from mild to severe and may come and go. Unfortunately, heart failure usually gets worse over time. As it worsens, patients may have more or different signs or symptoms.

 

WHAT CAUSES HEART FAILURE?

Although the risk of heart failure doesn’t change with age, you’re more likely to have heart failure when older. Many medical conditions that damage the heart muscle can cause heart failure. Common conditions include:

 

WHAT TYPES OF TESTS ARE USED TO DIAGNOSE HEART FAILURE?

Common tests include:

 

WHAT IS THE IMPORTANCE OF EJECTION FRACTION?

Ejection fraction (EF) is one way to measure the severity of the condition. If it’s below normal, it can mean the patient has heart failure. The ejection fraction tells the healthcare provider how good of a job the left or right ventricle is doing at pumping blood. Usually, the EF number is talking about how much blood the left ventricle is pumping out because it’s the heart’s main pumping chamber.

Several non-invasive tests can measure the EF. A normal left ventricular ejection fraction (LVEF) is 53% to 70%. An LVEF of 65%, for example, means that 65% of the total amount of blood in the left ventricle is pumped out with each heartbeat. The EF can go up and down, based on the heart condition and how well the treatment works.

 

HOW IS AMYLOIDOSIS RELATED TO HEART FAILURE?

As stated by the Cleveland Clinic, cardiomyopathy is one of the medical conditions that damage the heart muscle and can cause heart failure. Cardiomyopathy refers to conditions that affect the myocardium (heart muscle). Cardiomyopathy can make your heart stiffen, enlarged or thickened and can cause scar tissue. As a result, your heart can’t pump blood effectively to the rest of your body. In time, your heart can weaken and cardiomyopathy can lead to heart failure. 

One of the common types of cardiomyopathy is Transthyretin amyloid cardiomyopathy (ATTR-CM), characterized by an abnormal protein buildup (ATTR amyloidosis) in the heart’s left ventricle (primary blood-pumping chamber). ATTR-CM is a life-threatening, underrecognized, and underdiagnosed type of amyloidosis that affects the heart and is associated with heart failure. It was once considered a rare disease, but recently, improved diagnostic tools and greater attention to early manifestations of the disease are leading to an increasing number of diagnosed cases. (3)

 

Listen to an American Heart Association podcast (12 minutes) titled “What is ATTR-CM?”

 

ATTR-CM Basics (5)

 

Recent Research (4)

Davies et al.(2022) published an informative paper titled “A Simple Score to Identify Increased Risk of Transthyretin Amyloid Cardiomyopathy in Heart Failure with Preserved Ejection Fraction.” In conclusion, they believe their findings can increase recognition of ATTR-CM among patients with HFpEF in the community.

Key Points

Question.  Which patients with heart failure and preserved ejection fraction (HFpEF) have an increased risk of transthyretin amyloid cardiomyopathy (ATTR-CM) warranting technetium Tc 99m pyrophosphate scintigraphy?

Findings.  The study team developed and validated an ATTR-CM score comprising of 3 clinical (age, male sex, hypertension diagnosis) and 3 echocardiographic (ejection fraction, posterior wall thickness, relative wall thickness) variables to predict increased risk of ATTR-CM in HFpEF cohorts with variable ATTR-CM prevalence.

Meaning.  Because specific and highly effective therapy for ATTR-CM exists, the ATTR-CM score can provide a simple tool to guide use of technetium Tc 99m pyrophosphate scintigraphy and increase recognition and appropriate therapy of ATTR-CM in patients with HFpEF.

Abstract

Importance.  Transthyretin amyloid cardiomyopathy (ATTR-CM) is a form of heart failure (HF) with preserved ejection fraction (HFpEF). Technetium Tc 99m pyrophosphate scintigraphy (PYP) enables ATTR-CM diagnosis. It is unclear which patients with HFpEF have sufficient risk of ATTR-CM to warrant PYP.

Objective  To derive and validate a simple ATTR-CM score to predict increased risk of ATTR-CM in patients with HFpEF.

Design, Setting, and Participants.  Retrospective cohort study of 666 patients with HF (ejection fraction ≥ 40%) and suspected ATTR-CM referred for PYP at Mayo Clinic, Rochester, Minnesota, from May 10, 2013, through August 31, 2020. These data were analyzed September 2020 through December 2020. A logistic regression model predictive of ATTR-CM was derived and converted to a point-based ATTR-CM risk score. The score was further validated in a community ATTR-CM epidemiology study of older patients with HFpEF with increased left ventricular wall thickness ([WT] ≥ 12 mm) and in an external (Northwestern University, Chicago, Illinois) HFpEF cohort referred for PYP. Race was self-reported by the participants. In all cohorts, both case patients and control patients were definitively ascertained by PYP scanning and specialist evaluation.

Main Outcomes and Measures.  Performance of the derived ATTR-CM score in all cohorts (referral validation, community validation, and external validation) and prevalence of a high-risk ATTR-CM score in 4 multinational HFpEF clinical trials.

Results.  Participant cohorts included were referral derivation (n = 416; 13 participants [3%] were Black and 380 participants [94%] were White; ATTR-CM prevalence = 45%), referral validation (n = 250; 12 participants [5%]were Black and 228 participants [93%] were White; ATTR-CM prevalence = 48% ), community validation (n = 286; 5 participants [2%] were Black and 275 participants [96%] were White; ATTR-CM prevalence = 6% ), and external validation (n = 66; 23 participants [37%] were Black and 36 participants [58%] were White; ATTR-CM prevalence = 39%). Score variables included age, male sex, hypertension diagnosis, relative WT more than 0.57, posterior WT of 12 mm or more, and ejection fraction less than 60% (score range −1 to 10). Discrimination (area under the receiver operating characteristic curve [AUC] 0.89; 95% CI, 0.86-0.92; P < .001) and calibration (Hosmer-Lemeshow; χ2 = 4.6; P = .46) were strong. Discrimination (AUC ≥ 0.84; P < .001 for all) and calibration (Hosmer-Lemeshow χ2  = 2.8; P = .84; Hosmer-Lemeshow χ2  = 4.4; P = .35; Hosmer-Lemeshow χ2 = 2.5; P = .78 in referral, community, and external validation cohorts, respectively) were maintained in all validation cohorts. Precision-recall curves and predictive value vs prevalence plots indicated clinically useful classification performance for a score of 6 or more (positive predictive value ≥25%) in clinically relevant ATTR-CM prevalence (≥10% of patients with HFpEF) scenarios. In the HFpEF clinical trials, 11% to 35% of male and 0% to 6% of female patients had a high-risk (≥6) ATTR-CM score.

Conclusions and Relevance  A simple 6 variable clinical score may be used to guide use of PYP and increase recognition of ATTR-CM among patients with HFpEF in the community.

 

In closing … a known condition of heart failure is cardiomyopathy, of which one type – Transthyretin Amyloid Cardiomyopathy (ATTR-CM) – may be the underlying cause. In seeking answers to heart failure, keep this in mind.

 

 

Sources:

  1. https://my.clevelandclinic.org/health/diseases/17069-heart-failure-understanding-heart-failure
  2. https://my.clevelandclinic.org/health/diseases/16841-cardiomyopathy
  3. https://www.emergency-live.com/health-and-safety/cardiac-amyloidosis-what-it-is-and-tests-for-diagnosis/?fbclid=IwAR0lNrxqubUbFAhNcew233YU_CqN6Udf_RYj1FhBAErSrqou5CKjypZPk4A
  4. Davies DR, Redfield MM, Scott CG, et al. A Simple Score to Identify Increased Risk of Transthyretin Amyloid Cardiomyopathy in Heart Failure With Preserved Ejection Fraction. JAMA Cardiol. 2022;7(10):1036–1044. doi:10.1001/jamacardio.2022.1781
  5. https://www.yourheartsmessage.com/about-attr-cm 
  6. American Heart Association – What is ATTR-CM

https://www.heart.org/-/media/Files/Health-Topics/Answers-by-Heart/What-Is-ATTRCM.pdf

 

Carpal Tunnel & Amyloidosis – An Update

The connection between carpal tunnel and amyloidosis is one that is already established. In fact, carpal tunnel syndrome is one of many potential symptoms of amyloidosis, but it is a symptom that tends to present early. It is not uncommon to hear patients started experiencing carpal tunnel five to ten years before they were diagnosed with amyloidosis.

TWO STUDIES

Clinicians are becoming aware of this connection and are starting to investigate the connection. Two studies have been published that investigate the connection between carpal tunnel and amyloidosis.

The first study from 2018 was a “prospective, cross-sectional, multidisciplinary study of consecutive men age ≥ 50 years and women ≥ 60 years undergoing carpal tunnel release surgery. Biopsy specimens of tenosynovial tissue were obtained and stained with Congo red.”3 Of the patients that were eligible for Congo red staining (n=98), a total of 10 came back positive for amyloidosis.3 That is a hit rate of just over 10%.

In a larger second study from 2022, a total of 185 patients underwent carpal tunnel release surgery, where 54 biopsies confirmed evidence of amyloidosis with Congo red staining.1 That is a hit rate of 29%.

The results of these studies are powerful and provide an opportunity to change the trajectory of diagnosing amyloidosis, particularly doing so much earlier. According to the Bureau of Labor and Statistics and the National Institute for Occupational Safety and Health, carpal tunnel release surgery is the second most common type of surgery, performed over 230,000 times every year.4

PERSPECTIVE FROM AN ORTHOPEDIC SURGEON

“Since carpal tunnel syndrome is often one of the earliest signs of underlying amyloidosis, those with undiagnosed disease could greatly benefit from tissue biopsies at the time of surgery. A positive biopsy result could initiate the road to disease stabilization and hopefully future cures, avoiding the all-too-often rapid decline of health before final recognition. Bringing the surgeon into the arena of amyloidosis diagnosis and care broadens the net for catching this disease early and prepares the surgeon as a team-player for future medical support.”

Charles Williams Sr., MD

Retired Orthopedic Surgeon

 

CONCLUSION

Screening for amyloidosis in carpal tunnel release surgery can be a low-cost method of detecting amyloidosis that should be considered.2

Most importantly, identifying and diagnosing amyloidosis early has the potential to significantly improve patient outcomes and substantially alter the course of disease.

Truly life changing.

P.S. Click here to read our previous post on Carpal Tunnel & Amyloidosis

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Resources:

  1. https://pubmed.ncbi.nlm.nih.gov/35469694/
  2. https://consultqd.clevelandclinic.org/cardiac-amyloidosis-look-to-the-wrist-for-an-early-diagnostic-clue/
  3. https://www.sciencedirect.com/science/article/pii/S0735109718381634?via%3Dihub
  4. https://www.orthoarlington.com/contents/patient-info/conditions-procedures/11-astounding-carpal-tunnel-statistics
  5. https://www.verywellhealth.com/open-surgery-or-endoscopic-carpal-tunnel-surgery-4083069
  6. https://mailchi.mp/ea0a0bb441eb/carpal-tunnel-amyloidosis

Carpal Tunnel & Amyloidosis

Cardiac 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.”

Closing Words



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