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Amyloidosis is a group of diseases that have a common feature where proteins behave abnormally, with the breakdown products of these proteins folding upon themselves and depositing in various organs. Hereditary transthyretin amyloidosis is caused by a genetic mutation which causes misfolding of transthyretin (TTR) proteins (which originate from the liver). There are over 100 genetic variants of hereditary amyloidosis.

One such variant, called T60A, is the most common variant in Ireland (and the UK).

Symptoms of hereditary amyloidosis, specifically the T60A variant, include a variety of peripheral neuropathic, autonomic, and cardiac maladies, including:

carpal tunnel syndrome
numbness and tingling in hands, feet, arms, and legs
muscular weakness
excessive sweating
dizziness/fainting (orthostatic hypotension)
sexual disfunction
unintentional weight loss
indigestion
acid reflux
bouts of constipation and diarrhea
fatigue
shortness of breath
leg swelling
chest pain

One Patient’s Story

“Do you have an ancestor from Donegal?” is a question frequently asked by doctors who are investigating the possibility that a patient may have hereditary amyloidosis type T60A. With its origins in a short ribbon of coastline in North-West Donegal (Ireland), the condition wandered worldwide with Irish migration.”

_{(Callaghan, Donegal Amy, 2022.)}

Donegal Ireland was one of the worst affected areas of Ireland’s “Great Hunger” of the mid to late 1800’s. 123,000 emigrants left the Donegal area between 1851-1900. A great many of them migrated to the United States, many to the Appalachian region of the country. The T60A variant, as it now appears in the United States, has been traced back to those settling in Appalachia. Sean Riley is a T60A amyloidosis patient who has ancestorial connections to Appalachia and the Donegal area.

Sean’s journey to diagnosis began in the fall of 2012 when he had bilateral carpal tunnel surgery. His job required quite a bit of typing and handwriting so he assumed that the condition was related to repetitive motion, which is a common cause of carpal tunnel syndrome. Little did he or the attending hand surgeon know that bilateral carpal tunnel syndrome may be an early neurological symptom of amyloidosis.

Concurrently, Sean started experiencing numbness in his left foot and lower left leg. He previously had vascular surgery on the left leg, and incorrectly assumed that the foot and leg numbness might be associated with nerve damage from the surgery. In actuality the numbness was due to the onset of peripheral neuropathy, yet another early symptom of the disease.

Between 2014 and 2017 he was taken to the hospital by ambulance on three separate occasions. In each instance he felt extreme dizziness and discomfort in his chest and assumed that the events were due to a cardiac issue, but no obvious signs of cardiac issues could be identified in any of the events. He now knows that what he was experiencing was orthostatic hypotension due to the onset of progressive autonomic neuropathy, another signature malady associated with the disease.

In the fall of 2017 Sean started being treated for severe acid reflux and gastrointestinal issues. Over time he had an endoscopy and colonoscopy performed, each which indicated normal results. These conditions likely indicated the onset of amyloidosis impact on nerves and tissue of the gastro-intestinal system.

Over the period of time from 2012 through 2017 Sean was seen by a hand surgeon, cardiology, oncology, endocrinology, neurology, and gastroenterology, along with his primary care physician. Nobody was able to connect the dots to amyloidosis, a product of the rarity of the disease and resulting lack of disease expertise by the general medical community.

In 2018 Sean moved overseas to Abu Dhabi to pursue a career opportunity. Shortly after arriving he started experiencing more frequent hypotensive episodes as well as progressive muscle wasting and weight loss. Fortunately for Sean the Cleveland Clinic has a hospital facility in Abu Dhabi. The attending cardiologist had a working knowledge of amyloidosis and ordered a series of tests, including an echocardiogram, a cardiac MRI, and a neuropathic evaluation, all of which concluded a preliminary positive diagnosis for the disease. As a result, the cardiologist recommended that Sean travel back to the United States and be seen at the amyloidosis center at Brigham and Women’s hospital in Boston. In February of 2019 he received a definitive diagnosis of hereditary transthyretin amyloidosis, specifically the T60A mutation. Excerpts of the confirming echocardiogram, cardiac MRI, and genetic testing results are shown below.

Echocardiogram Summary Notes

Associated Cardiac MRI Interpretation

DNA Sequencing Result

Shortly after diagnosis, Sean started treatment with a state-of-the-art FDA-approved amyloidosis drug. The treatment is administered every three weeks and is designed to slow or stop disease progression. The drug is an RNA signal blocker which stops the transthyretin proteins from misfolding and creating amyloid fibrils.

Sean continues this therapy to this day, and all indications show that disease progression has stopped. There is no cure for the disease, so he must contend with and manage the damage that has been done; however, he is thrilled that the disease progression is being kept in check.

For more information on hereditary amyloidosis worldwide, visit our blog — Click Here

Bibliography

“Donegal Amy-A Rare Inherited Disease from Ireland”, Rosaline Callaghan, Roscara Books, 2022.

“Unraveling the Lineage: The Genetic Basis of Familial ATTR Cardiomyopathy Ronald Witteles”, MD Professor of Medicine (Cardiovascular Medicine).

“Cardiac Amyloidosis Part 1: Understanding Types and Risks”, Dr. Rodney Falk, Brigham and Women’s Hospital, YouTube, July 2018.

Obi CA, Mostertz WC, Griffin JM, Judge DP. ATTR Epidemiology, Genetics, and Prognostic Factors. Methodist Debakey Cardiovasc J. 2022 Mar 14;18(2):17-26. doi: 10.14797/mdcvj.1066. PMID: 35414855; PMCID: PMC8932385.

Transthyretin Amyloidosis, or ATTR, is considered a single disease, however the diversity in its clinical presentation is staggering. In this blog, we’ll discuss some of the most common hereditary variants and how the disease manifestation differs around the world in documented hotspots.

Source: Epidemiology, Genetics, and Prognostic Factors (1)

There are two distinct forms of Transthyretin Amyloidosis (ATTR), the hereditary form (ATTRv), and the non-hereditary form (ATTR-wt) commonly referred to as wild-type amyloidosis. Disease manifestation is considered a spectrum involving aspects of cardiomyopathy, neuropathy, or more frequently a mixture of both.

Below we’ll discuss the hereditary form and the various genetic variants and how they differ based on geographical location.

WHAT IS TRANSTHYRETIN (TTR)

Transthyretin, also known as prealbumin, is a protein produced primarily in the liver that is responsible for the transport of thyroxine and retinol. Interesting enough, this is how it got its name.

In steady state, the protein circulates primarily as a tetramer (i.e., monomeric form), but unfortunately, its monomeric form is inherently amyloidogenic (prone to breakdown and formation of amyloid aggregates). Couple that with mutations that increase the amyloidogenicity of the protein, these tetramers dissociate into monomers that will misfold, aggregate, and form the insoluble fibrils (“amyloid”) that are resistant to the body’s inherent protective mechanisms like proteolysis.

SPECIFIC TTR PATHOGENIC VARIANTS

As of today, there have been over 145 reported variants related to hereditary transthyretin amyloidosis. Interestingly, these genetic variants have a tendency to cluster in both geographic and ethnic groups around the world. We’ll discuss some of the most prevalent mutations below.

Val122Ile

This is the most common TTR mutation in the United States, with a prevalence of roughly 3.4% in the African American community. The disease is primarily cardiac in nature, typically present when patients are in their 60s. It is thought that this mutation arose from the region of West Africa and has worked its way to the United States over time, where it has become the predominant form.

Val30Met

This is the most commonly recognized TTR mutation worldwide and the first TTR variant discovered. It is most commonly found in the regions of Portugal, Spain, France, Japan, Sweden, and Brazil. Interestingly, between these regions where this mutation dominates, there is variability in age of onset and parent-of-origin. For example, age of onset was found to be earlier in the Swedish population in comparison to Portugal and Japan. As for the parent-of-origin, it was found that the mother was more likely than the father to pass along the mutation (153 vs. 138), whereas in the French population the father was more likely to pass on the mutation (219 vs. 216), although not by much. The one thing these populations do have in common is this form of the disease is almost exclusively neurologic in nature.

Thr60Ala

This variant is most commonly found in the UK and Irish populations, and is also seen in the Appalachian region of the United States. This variant presents as a mixture of both cardiomyopathy and neuropathy symptoms. It seems to be that in early stages of the disease the neurologic symptoms are most prevalent, but cardiac symptoms present at diagnosis seem to indicate poorer patient outcomes.

Thr119Met

This is arguably the most interesting variant that was investigated in a large study of the Danish population. The presence of this mutation actually confers a protective benefit. When this mutation occurs along with the Val30Met mutation, it has the effect of stabilizing and delaying, even preventing transthyretin amyloidosis.

PROGNOSIS

While the prognosis is by no means near perfect, it is improving. There is continued advancement in the field of transthyretin amyloidosis, whether it be improving diagnostic methods, drug development, or a potential cure on the horizon with CRISPR gene-editing technology. Having said that, there continue to be significant barriers to diagnosis. The importance of being an astute clinician to suspect and work up for amyloidosis remains at the forefront of the challenge.

CONCLUSION

The geographic nature of this disease plays an important role in identifying and diagnosing amyloidosis. Having an understanding of how the presentation of the disease is heavily related to the patient’s ancestry and location around the world. The hardest part is suspecting amyloidosis, from there don’t forget the value of the diagnostic tools at your disposal, including genetic testing. Use this knowledge to strengthen and guide your suspicions of amyloidosis!

Over the upcoming months we’ll post blogs delving deeper into some of these variants, so stay tuned.

Thanks for reading,

Mackenzie

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SOURCES

Let us begin by saying we are super grateful for our growing list of supporters, many of whom are becoming repeat donors (which of course, we love), investing in our effort from year to year. THANK YOU for supporting Mackenzie’s Mission and the Amyloidosis Speakers Bureau, as without your support we could not have achieved new highs.

HOW DID WE DO IN 2022?

This was our fifth full year of operation (shocking how fast time passes), busy and loaded with lots of activities to advance our mission — to make a difference in the fight against Amyloidosis. Operationally, we continued to run extremely efficient and lean, and laser-focused on making a difference in two ways.

Raising awareness about Amyloidosis, which we believe can lead to earlier diagnosis and better outcomes for patients.
Supporting medical research on Amyloidosis, seeking the cause of the disease and more effective treatments to improve and extend lives.

RAISING AWARENESS

Amyloidosis Speakers Bureau (ASB): Since launching the Amyloidosis Speakers Bureau in February 2019, the ASB is front and center for our raising awareness effort.

Amyloidosis is considered a rare disease and is not well known. However, there is a belief within the medical community that this disease is not rare, it is underdiagnosed or diagnosed when it is too late to make a difference. The complexity of this disease makes diagnosis one of the biggest challenges affecting patient lives. It is not uncommon to hear from patients that it took multiple years and multiple doctors to ultimately arrive at a correct diagnosis, all the while the disease continued to progress. Until a cure is found, it is imperative to raise awareness within the medical community so that a diagnosis can be determined much sooner, enabling effective treatments and therapies to slow the disease progression and improve patient survival.

Our response to this crisis is the Amyloidosis Speakers Bureau (ASB), an initiative focused on educating the medical community about this disease through presentations from amyloidosis patients, an educational video from medical experts, and our monthly information mailing. Our target audience is the next generation of doctors during their first/second year of medical school, as well as internal medicine residency programs for physicians beginning their career post-medical school.

During 2022, we saw presentations exceed our target, and in-person events slowly returning. With our target set at 65 presentations, we were pleased to close the year at 68 presentations to more than 3,500 medical students and resident physicians. We’re also excited to say we surpassed a massive milestone this year — since we started, we have now given over 215 presentations to more than 10,000 medical students and residents!!

ASB Effectiveness and Impact Study: We have long been interested in understanding the effectiveness and impact of the Amyloidosis Speakers Bureau. With the valuable assistance from one of our speakers Dr. Kathy Rowan of George Mason University, along with Dr. Adebanke Adebayo of Washburn University and expert medical advisor Dr. Vaishali Sanchorawala of Boston University, we designed and launched a study in 2021. Our study explored responses across four variables:

Behavioral intentions
Attitudes
Knowledge
And patient/physician communication

We randomly formed two groups from over 250 respondents: half that had not seen an ASB presentation, and half that had. In analyzing the data, the results were striking. The data shows higher significant mean differences (where the p value < .05) between these two groups. We also found that those who heard the presentation had nearly unanimous agreement about their experience regarding speaker effectiveness and finding value from the ASB presentation. So yes, we do believe the evidence indicates we are making a difference. YAY!

Our manuscript has been submitted for publication consideration with Medical Teacher, an international journal of education in the health sciences.

ASB Briefs: After every presentation we invite medical students interested in continuing to learn about amyloidosis to join our ASB Briefs mailing list. Today, that list numbers over 600! Each month we send a brief discussion about some aspect of the disease with a growing library of links to informative presentations / videos by medical experts, and announcements regarding advancements in treatment. The intention is to keep amyloidosis more front-of-mind and educate on the many facets of this complex and multi-systemic disease.

Blogs: We publish periodic blogs on our website about amyloidosis on topics such as symptoms, diagnosis, treatment, expert updates, resources, and caregiver support.

Conferences: Chaired by Dr. Vaishali Sanchorawala, we spoke on a panel at the recent International Society of Amyloidosis (ISA) in Heidelberg, Germany. Our presentation was titled “Patients are Powerful Educators,” introducing the ASB and our focus on educating medical students. We received strong positive feedback from attendees around the world, showcasing how patients can contribute to raising awareness about this disease.

Mailings, Social Media & Miscellaneous: We spread this information across our platform which includes: our website, our mailing lists, our Facebook page, our LinkedIn page, our new Twitter account (@Amyloidosis_ASB), and our YouTube channel. We welcome you following us on any of these platforms.

SUPPORTING MEDICAL RESEARCH

As we have said over and over, nothing happens in research without money. And knowing the NIH funds only 11% of its applications, this leaves a heavy burden on private foundations and individuals to help close the shortfall gap. So, our work to raise money matters.

Monies we send to research institutions are derived from two sources: general donations to Mackenzie’s Mission and proceeds from our Play FORE The Cure charity golf tournament. It’s a competitive 24-player Presidents Cup format at the Robert Trent Jones Golf Club, with two teams of twelve competing for the title. We’re proud to say the event this year raised over $150,000, bringing our cumulative total raise from our Play FORE The Cure tournaments to over $830,000!

To help advance medical research we donated to five world-class research institutions.

Mayo Clinic’s Amyloidosis Research Fund
Boston University’s Amyloid Research Fund
Tufts Medical Center’s Amyloid and Myeloma Research Fund
Scripps Research’s Kelly Lab
Cleveland Clinic Foundation’s Amyloidosis Research & Education Fund

WHAT ARE OUR GOALS FOR 2023?

In short, to keep doing what we are doing, and do more of it.

Raising Awareness

Focus our energies on the Amyloidosis Speakers Bureau (ASB), expanding our medical school and residency program outreach. This is where we believe we can make the biggest impact from our efforts. Engagement from the amyloidosis patient community, securing meaningful grant support, and proceeds from donations/fundraisers will be key to complement the operational and legal infrastructure required.
Publish educational blogs to the growing medical student mailing list, as well as to our broad mailing list and website.
Explore additional opportunities, both large and small, which enable us to further spread the word on the importance of early diagnosis.

Supporting Medical Research

From our general donations and charity golf tournament proceeds we support leading research institutions whom we know are working to advance the knowledge and find answers about this disease.

WITH MUCH APPRECIATION AND GRATITUDE

You may have donated cash or securities, played in our charity Play FORE The Cure charity golf tournament, participated in one of our raising awareness campaigns, or given us a grant to support our Amyloidosis Speakers Bureau medical education initiative. You may have been an Amyloidosis Speakers Bureau speaker, liked/shared our Facebook posts, or taken the time to read our blogs to learn about amyloidosis. Whether you did one of these or many, you helped us push forward our fight against this disease and we appreciate your support.

We also want to extend a special thank you to our volunteers who passionately and graciously devote their time and expertise. Whether to help at our charity golf tournament, or one of many facets of the Amyloidosis Speakers Bureau (e.g., speaker development, running Zoom presentations, researching contacts, writing ASB Briefs, leading the charge for our ASB impact study, professionalizing our videos, and running our webinars), we can’t begin to accomplish all we have without them. Thank you!

I am encouraged by the impact Mackenzie’s Mission is already making after just a few short years. Connecting with the amyloidosis community and working together to make an impact is extremely rewarding. There is much work to be done, but with so much help from the community and our supporters I know we can win this fight!

With warm regards for a wonderful and hopeful 2023,

Mackenzie

AN UPDATE ON ME

This past year I devoted my time largely to Mackenzie’s Mission and the work of the Amyloidosis Speakers Bureau. Outside of the foundation, I am busy in the midst of my first year of graduate school at Northeastern University, studying to be a Physician Assistant. I’m so proud of what we’ve accomplished and am excited about what lies ahead. Many thanks and appreciation to all of our speakers and volunteers who work passionately to keep advancing our efforts. As for my disease, I am on a regimen that keeps my disease under control, and I continue to feel great.

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)

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:

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:

Coronary artery disease.
Heart attack.
Cardiomyopathy.
Heart issues present at birth (congenital heart disease).
Diabetes.
High blood pressure (hypertension). This is a common cause in people assigned female at birth.
Arrhythmia (abnormal heart rhythms, including atrial fibrillation).
Kidney disease.
Having obesity.
Tobacco and recreational drug use.
Medications. Some drugs used to fight cancer (chemotherapy) can lead to heart failure.

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:

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

Today, with our 215th presentation, we surpassed a huge milestone — presenting to 10,000 medical students and residents!

What a great accomplishment for all of us, and to reach this level in just over three years! We are so proud of what we have accomplished, and thank our speakers, advisors, and supporters for their contributions. Without question, we could not have done it without them!

Each of these physicians, and future physicians, will go on to see hundreds, if not thousands, of patients during their career — so there is an astounding multiplier impact! We know that among those 10,000 attendees there were many who will never forget their patient speaker who shared their journey through symptoms, diagnosis, and treatment. We also know there will be future amyloidosis diagnoses among this group; perhaps diagnoses that are made sooner than had they not attended an ASB presentation? We believe there will be.

Until we are no longer needed, there remains much work to do, and we are thrilled to help raise awareness to the healthcare community.

Have a great day!

Mackenzie, Lane and Deb

Operating Committee Members

We are super proud to have presented the story about the Amyloidosis Speakers Bureau at last week’s International Symposium on Amyloidosis (ISA) in Heidelberg, Germany.

Ours was not the typical presentation at such a prestigious global medical conference, but our message “PATIENTS ARE POWERFUL EDUCATORS” was seemingly super well received. Afterwards we heard words such as “transformative” and “brilliant” … opening minds about the impact that patients can bring to raise awareness. Hopefully, there will be good actions to come from this! Meanwhile, we press on to educate U.S. medical students and residents.

THE PANEL INCLUDED (Thank you to Alexion Pharmaceuticals for sponsoring our panel):

– Professor JULIAN GILLMORE and Professor ASHUTOSH WECHALEKAR from the National Amyloidosis Centre, UCL – University College of London, UK
– Professor GIOVANNI PALLADINI, Director of the Amyloidosis Research and Treatment Center at the University Hospital San Matteo in Pavia, Italy
– DR. VAISHALI SANCHORAWALA, Director of Amyloidosis Center at Boston University
– DR. RODNEY FALK, Director of the Cardiac Amyloidosis Program at Brigham and Women’s Hospital (BWH)

– DEBORAH BOEDICKER, Board Member at Mackenzie’s Mission and Operating Committee Member of the Amyloidosis Speakers Bureau
– KRISTEN HSU, Executive Director of Clinical Research at the Amyloidosis Research Consortium

We are proud of the work we collectively do at the ASB and the impact we are making. Now into our fourth academic year, we have given over 200 presentations to more than 9,600 medical students and residents!

Our speakers, and their willingness to share their authentic story, are the cornerstone of this powerful educational initiative.

With endless appreciation for your support and engagement,

Deb Boedicker

Drugs are the lifeblood of patient treatments, and the development of new drugs is critical. Overseen by the FDA (U.S. Food and Drug Administration), they define a drug as “any product that is intended for use in the diagnosis, cure mitigation, treatment, or prevention of disease; and that is intended to affect the structure or any function of the body.”

The FDA’s Center for Drug Evaluation and Research (CDER): “The center’s evaluation not only prevents quackery, but also provides doctors and patients the information they need to use medicines wisely. CDER ensures that drugs, both brand-name and generic, are effective and their health benefits outweigh their known risks.”

There are several phases (comprising twelve steps) of the FDA drug development and approval process, depicted in a two-page graphic here, and described below.

PRE-CLINICAL RESEARCH

This is the drug sponsor’s discovery and screening phase, comprising two steps.

The Start. The sponsor develops a new drug compound and seeks to have it approved by the FDA for sale in the U.S.

Step 1: Animals Tested. The sponsor must test the new drug on animals for toxicity. Multiple species are used to gather basic information on the safety and efficacy of the compound being investigated/researched.

Step 2: IND Application. The sponsor submits an Investigational New Drug (IND) application to the FDA based on the results from initial testing that includes the drug’s composition and manufacturing, and develops a plan for testing the drug on humans (aka a clinical trial).

The FDA reviews the IND to assure that the proposed studies, generally referred to as clinical trials, do not place human subjects at unreasonable risk of harm. The FDA also verifies that there are adequate informed consent and human subject protection.

CLINICAL

This phase is all about the clinical trial, all of which must be approved by the FDA before they can begin. In an earlier blog – Clinical Trials 101 – we offer an expanded discussion along multiple facets regarding clinical trials which you may find informative.

According to the National Institutes of Health (NIH), clinical trials are research studies performed on people that are aimed at evaluating a medical, surgical, or behavioral intervention. Clinical trials are the primary way that researchers find out if a new treatment, like a new drug or medical device (e.g., a pacemaker) is safe and effective in people. Often a clinical trial is used to learn if a new treatment is more effective and/or has less harmful side effects than the standard treatment. Other clinical trials test ways to find a disease early, sometimes before there are symptoms. Still, others test ways to prevent a health problem before it begins. A clinical trial may also look at how to make life better for people living with a life-threatening disease or a chronic health problem.

Clinical trials are comprised of four phases to test a treatment, find appropriate dosages, and detect side effects. If following the completion of the first three phases, researchers find the drug or intervention to be safe and effective, the FDA approves it for clinical use and continues to monitor its effects. The fourth phase continues post-FDA approval. Overall, the duration of a clinical trial spans years.

Step 3: Phase I Trial. A Phase I trial tests an experimental treatment on a small group of often healthy people (20 to 80 in number) to judge its safety and side effects and to find the correct drug dosage.

Step 4: Phase 2 Trial. A Phase II trial uses more people (100 to 300 in number). While the emphasis in Phase I is on safety, the emphasis in Phase II is on effectiveness. This phase aims to obtain preliminary data on whether the drug works in people who have a certain disease or condition. These trials also continue to study safety, including short-term side effects. This phase can last several years.

Step 5: Phase 3 Trial. A Phase III trial gathers more information about safety and effectiveness, studying different populations and different dosages, using the drug in combination with other drugs. The number of subjects usually ranges from several hundred to about 3,000 people. If the FDA agrees that the trial results are positive, it will approve the experimental drug or device.

NDA (NEW DRUG APPLICATION) REVIEW

This phase covers the FDA’s New Drug Application (NDA) review.

Step 6: Review Meeting. The FDA meets with the sponsor prior to submission of the NDA.

Step 7: NDA Application. The sponsor formally asks the FDA to approve a drug for marketing in the United States by submitting an NDA. An NDA includes all animal and human data and analyses of the data, as well as information about how the drug behaves in the body and how it is manufactured.

Steps 8-9: Application Reviewed. After an NDA is received, the FDA has 60 days to decide whether to file it so it can be reviewed. If the FDA files the NDA, the FDA Review Team is assigned to evaluate the sponsor’s research on the drug’s safety and effectiveness.

Step 10: Drug Labeling. The FDA reviews the drug’s professional labeling and assures appropriate information is communicated to health care professionals and consumers.

Step 11: Facility Inspection. The FDA inspects the facilities where the drug will be manufactured.

Step 12: Drug Approval. The FDA reviews will approve the application or issue a response letter.

POST-MARKETING RISK ASSESSMENTS

Phase IV clinical trial for drugs or devices takes place after the FDA approves their use. A device or drug’s effectiveness and safety are monitored in large, diverse populations, where the sponsor is required to submit periodic safety updates to the FDA. Sometimes, the side effects of a drug may not become clear until more people have taken it over a longer period of time.

WHO REVIEWS NEW DRUG SUBMISSIONS?

A team of CDER physicians, statisticians, chemists, pharmacologists, and other scientists review the drug sponsor’s data and proposed labeling of drugs.

WHAT OTHER DRUG PRODUCTS ARE REGULATED BY THE FDA?

Drugs include more than just medicines. For example, fluoride toothpastes, antiperspirants (not deodorant), dandruff shampoos, and sunscreens are all considered drugs.

CONCLUSION

FDA approval of a drug means that data on the drug’s effects have been reviewed by CDER, and the drug is determined to provide benefits that outweigh its known and potential risks for the intended population.

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SOURCE

National Institutes of Health

U.S. Food and Drug Administration

Drugs.com

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:

Over the course of the past two months, we spent time discussing two of the most common hallmark symptoms of ATTR amyloidosis: cardiomyopathy and peripheral neuropathy. In this article, we’ll briefly recap both hallmark symptoms as well as bring it all together by discussing the two most common forms of ATTR amyloidosis: ATTR cardiomyopathy (ATTR-CM) and ATTR peripheral neuropathy (ATTR-PN).

To recap …

Cardiomyopathy

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 is a common cause of sudden cardiac arrest and sudden cardiac death, which can lead to heart failure and even death.

Types of Cardiomyopathy:

Dilated Cardiomyopathy → dilation of the left ventricle prevents the heart from pumping effectively
Hypertrophic Cardiomyopathy → abnormal thickening of the heart muscle most commonly surrounding the left ventricle
Restrictive Cardiomyopathy → stiffening of the heart muscle results in an inelasticity
Arrhythmogenic Right Ventricular Dysplasia → scar tissue replaces healthy tissue of the right ventricle
Unclassified Cardiomyopathy → all other forms of cardiomyopathy fall within this category

Peripheral Neuropathy

Peripheral neuropathy, also referred to as polyneuropathy, is a very broad term used to describe damage of the peripheral nerves. Damage to these nerves most commonly causes numbness, pain, and weakness but can affect other areas of the body including, but not limited to, circulation, digestion, and urination.

Types of Neuropathy:

Motor Neuropathy → damage to the motor nerves
Sensory Neuropathy → damage to sensory nerves
Autonomic Nerve Neuropathy → damage to autonomic nerves that control involuntary functions
Combination Neuropathies → damage to a mix of 2 or 3 of these other types of neuropathies

ATTR Amyloidosis

The origin of this disease can be genetic (hATTR) or non-genetic, or “wild-type” (wtATTR). Regardless, in ATTR amyloidosis, the transthyretin (TTR) protein is misfolded and aggregates, forming amyloid fibers that deposit into tissues and organs. The deposition of protein causes organ dysfunction and can even cause organ failure and death.

ATTR-CM and ATTR-PN

Depending on the location of protein deposition, the disease is referred to in different ways. For instance, when the primary location of amyloid deposit is in the heart, the disease is referred to as ATTR cardiomyopathy (ATTR-CM). On the other hand, when the primary location of amyloid deposit is in the nerves, the disease is referred to as ATTR peripheral neuropathy (ATTR-PN).

ATTR-CM impairs the heart’s ability to pump effectively. A major challenge surrounding this disease is that symptoms of ATTR-CM are often similar to other heart conditions like enlarged heart and heart failure. This makes diagnosing the disease increasingly more difficult. Individuals with hATTR typically present symptoms in their 50s and 60s, whereas those with wtATTR may not present symptoms until their 70s and later.

Common Symptoms of ATTR-CM:

Fatigue
Swelling of legs, ankle, or abdomen
Shortness of breath with activity
Orthostatic hypotension
Difficulty breathing when lying down
Arrhythmia

ATTR-PN impairs the function of the nervous system. While amyloid most commonly builds up in the peripheral nervous system, deposition can also occur in the autonomous system. This results in a diversity of symptoms that are specific to the site of amyloid deposition. Symptom presentation is much more diverse, occurring as early as the 20s, or as late in life as the 70s.

Common Symptoms of ATTR-PN:

Carpal tunnel syndrome
Diarrhea and/or constipation
Nausea, vomiting
Loss of appetite
Sexual dysfunction
Muscle weakness
Eye problems
Orthostatic hypotension

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References:

https://www.pfizer.com/news/articles/understanding_this_rare_disease_called_attr_amyloidosis

https://www.mayoclinic.org/diseases-conditions/cardiomyopathy/symptoms-causes/syc-20370709

https://www.yourheartsmessage.com

https://healthjade.net/familial-amyloidosis/

https://my.clevelandclinic.org/health/diseases/14737-neuropathy

https://www.hopkinsmedicine.org/health/conditions-and-diseases/peripheral-neuropathy

https://www.mayoclinic.org/diseases-conditions/peripheral-neuropathy/symptoms-causes/syc-20352061

https://practicalneurology.com/articles/2021-july-aug/neuromuscular-amyloidosis

https://healthjade.net/familial-amyloidosis/

Header

Slider

WHAT IS TRANSTHYRETIN (TTR)

SPECIFIC TTR PATHOGENIC VARIANTS

Val122Ile

Val30Met

Thr60Ala

Thr119Met

PROGNOSIS

CONCLUSION

HOW DID WE DO IN 2022?

RAISING AWARENESS

SUPPORTING MEDICAL RESEARCH

WHAT ARE OUR GOALS FOR 2023?

Raising Awareness

Supporting Medical Research

WITH MUCH APPRECIATION AND GRATITUDE

AN UPDATE ON ME

CRISPR FIXES GENES INSIDE THE BODY (3)

APPLYING THE CRISPR TECHNOLOGY (3)

CLINICAL TRIAL UPDATE — NTLA-2001 (1)

BACKGROUND

WHAT IS HEART FAILURE?

WHAT ARE THE TYPES OF HEART FAILURE?

Left-sided heart failure

Right-sided heart failure

WHAT ARE THE SYMPTOMS OF HEART FAILURE?

WHAT CAUSES HEART FAILURE?

WHAT TYPES OF TESTS ARE USED TO DIAGNOSE HEART FAILURE?

WHAT IS THE IMPORTANCE OF EJECTION FRACTION?

HOW IS AMYLOIDOSIS RELATED TO HEART FAILURE?

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

ATTR-CM Basics (5)

Recent Research (4)

Key Points

Abstract

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.

PRE-CLINICAL RESEARCH

CLINICAL

NDA (NEW DRUG APPLICATION) REVIEW

POST-MARKETING RISK ASSESSMENTS

WHO REVIEWS NEW DRUG SUBMISSIONS?

WHAT OTHER DRUG PRODUCTS ARE REGULATED BY THE FDA?

CONCLUSION

TWO STUDIES

PERSPECTIVE FROM AN ORTHOPEDIC SURGEON

CONCLUSION

Cardiomyopathy

Types of Cardiomyopathy:

Peripheral Neuropathy

Types of Neuropathy:

ATTR Amyloidosis

ATTR-CM and ATTR-PN

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