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Cardiomyopathy & Amyloidosis

Cardiomyopathy is a broad term that is used to describe disease of the heart muscle, making it difficult for the heart to provide the body with an adequate blood supply. It can lead to heart failure and even death. In this article, we’ll discuss the types of cardiomyopathy and its connection to amyloidosis. 

 

Risk Factors 

It has no ideal target, as it can affect a person of any age, race, or gender. However, there are a number of risk factors that can put one at an increased chance of developing cardiomyopathy. 

  • Genetic History → Family history of cardiomyopathy, heart failure, or sudden cardiac arrest
  • High Blood Pressure → Over a long period of time
  • Heart Conditions → Past history of heart attack, coronary artery disease, or infection of the heart
  • Obesity → Tends to make the heart work harder to perform its normal function
  • Alcohol Use → Long period of alcohol use
  • Drug Use → Use of illicit drugs, such as cocaine, amphetamines, and anabolic steroids
  • Medications → Drugs used in the treatment of cancer, such as chemotherapy and radiation

Additionally, there are a number of diseases that increase the risk of developing cardiomyopathy, including:

  • Amyloidosis
  • Connective Tissue Disorders
  • Diabetes
  • Hemochromatosis (excess iron storage)
  • Sarcoidosis
  • Thyroid Disease

 

Types of Cardiomyopathy

  • Dilated Cardiomyopathy → Dilation of the left ventricle prevents the heart from pumping effectively. It most commonly occurs in middle-aged men and is typically the result of coronary artery disease, heart attack, or genetic defects.

  • Hypertrophic Cardiomyopathy → Abnormal thickening of heart muscle, most commonly affecting the muscles surrounding the left ventricle. This type of cardiomyopathy is strongly associated with a family history of the disease. There have been genetic mutations linked specifically with this type of cardiomyopathy.

  • Restrictive Cardiomyopathy → Stiffening of the heart muscle results in an inelasticity, making it difficult for the heart to expand and fill. It is most commonly seen in the elder population. The disease can be of idiopathic origin or of disease such as amyloidosis. This is the least common type of cardiomyopathy. 
  • Arrhythmogenic Right Ventricular Dysplasia → Scar tissue replaces healthy tissue of the right ventricle. This form of cardiomyopathy is rare and often the result of genetic mutations.
  • Unclassified Cardiomyopathy → All other forms of cardiomyopathy fall within this category.

 

Amyloidosis

Cardiomyopathy is one of the hallmarks of amyloidosis, often seen in the transthyretin form of amyloidosis (ATTR). ATTR-CM, or transthyretin amyloid cardiomyopathy, is a disease where the transthyretin protein becomes unstable and misfolds. This unstable protein (“amyloid”) then deposits in the heart muscle, resulting in thickening and stiffening of the heart. 

The two types of ATTR-CM are wild-type ATTR-CM (wtATTR) or hereditary ATTR-CM (hATTR). wtATTR-CM is the most common form of ATTR-CM, affecting predominantly white males 60+ years old. hATTR-CM is genetic affecting both men and women, and presents as early as 50+ years old. Interestingly, one of the mutations causing hATTR, V122I, is seen almost exclusively in individuals of African ancestry. It is believed that approximately 3-4% of African Americans carry this mutation, regardless of whether or not they develop symptoms. 

Most importantly, these are the most common and important signs and symptoms to be aware of, in order to diagnose ATTR amyloidosis.

 

Expert Insights – Cardiac Clues and Clinical Signs

In part 1 of a 2-part series, Dr. Keyur Shah, cardiologist from VCU Health’s cardiac amyloidosis care team, discusses the two most common types of transthyretin (TTR) amyloidosis: hereditary and wild-type. He details how ATTR cardiomyopathy amyloidosis presents and manifests itself to impair the heart. Dr. Shah lists clinical clues, “red flags,” and biomarkers which can raise suspicion of the presence of amyloidosis. Next he discusses insights that can be gained from echocardiograms, electrocardiograms, and cardiac MRIs and how they offer possible indicators of the disease presence. Once amyloidosis is suspected, definitive diagnosis testing is next.

In part 2 of a 2-part series, Sarah Paciulli, Heart Failure Nurse Practitioner, from VCU Health’s cardiac amyloidosis care team, continues from where Dr. Keyur Shah ended in Part I and discusses here in Part II the non-cardiac clues of transthyretin (TTR) amyloidosis. She expands the list of clinical clues and “red flags” that clinicians should be alert to, including orthopedic manifestations, erectile dysfunction, and polyneuropathy.

 

 

 

 

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References:

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

https://www.yourheartsmessage.com

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

 

Mackenzie’s Mission at the Bradley Z Naifeh Amyloidosis Conference 2024!

We were proud to be part of the 2nd annual Bradley Z. Naifeh Amyloidosis Conference 2024 at Houston Methodist! On day 1 the auditorium was filled with healthcare professionals who learned about the many facets of the clinical side of amyloidosis from experts such as Dr. Ron Witteles of Stanford and Dr. Angela Dispenzieri of Mayo Clinic.

On day 2 the auditorium was packed with patients and caregivers of all types of amyloidosis, offering a wonderful opportunity to learn about the disease, resources available, and network with other patients and caregivers.

Mackenzie and Deb had the chance for a photo op with Megan Fleischfresser Naifeh (daughter of Bradley Z. Naifeh who lost his battle with AL Amyloidosis) and Dr. Arvind Bhimaraj (co-host of the conference).

We thank the Naifeh family for their support of this valuable annual conference.

ASB Participates in Rare Disease Day 2024!

The Amyloidosis Speakers Bureau was thrilled to participate on Rare Disease Day! One way we were part of the celebration was for our patient educator Sean to share his journey at Keck Graduate Institute’s Rare Disease Awareness Fair.

 

Proteinuria & Amyloidosis

According to the Cleveland Clinic, “Proteinuria is due to increased levels of protein in the urine.” Your kidneys filter waste products from your blood while retaining what your body needs — including proteins. However, some diseases and conditions allow proteins to pass through the filters of your kidneys, causing protein in the urine.

 

HOW DOES PROTEIN GET INTO URINE? (1)

Protein gets into the urine if the kidneys aren’t working properly. Normally, glomeruli, which are tiny loops of capillaries (blood vessels) in the kidneys, filter waste products and excess water from the blood.

Glomeruli pass these substances, but not larger proteins and blood cells, into the urine. If smaller proteins sneak through the glomeruli, tubules (long, thin, hollow tubes in the kidneys) recapture those proteins and keep them in the body.

However, if the glomeruli or tubules are damaged, if there is a problem with the reabsorption process of the proteins, or if there is an excessive protein load, the proteins will flow into the urine.

 

WHAT ARE THE SYMPTOMS OF PROTEINURIA? (2)

Often, someone with proteinuria doesn’t experience symptoms, especially if kidneys are just beginning to have problems. However, if proteinuria is advanced, symptoms can include:

  • More frequent urination
  • Shortness of breath
  • Tiredness
  • Nausea and vomiting
  • Swelling in the face, belly, feet or ankles
  • Lack of appetite
  • Muscle cramping at night
  • Puffiness around the eyes, especially in the morning
  • Foamy or bubbly urine

Conditions that can cause a temporary rise in the levels of protein in urine, but don’t necessarily indicate kidney damage, include:

  • Dehydration
  • Emotional stress
  • Exposure to extreme cold
  • Fever
  • Strenuous exercise

However, according to the Mayo Clinic (2), there are diseases and conditions that can cause persistently elevated levels of protein in urine, which might indicate kidney disease, such as:

TESTING FOR PROTEINURIA

The only way to know if you have protein in your urine, an established marker for chronic kidney disease, is to have a urine test.

“Integral to the process of evaluating for proteinuria is quantification of the total amount of protein spilling into the urine. The various methods to detect proteinuria include urine dipstick and sulfosalicyclic acid test (SSA); quantification methods include the ratio of albumin or protein to creatinine (UACR or UPCR) and the 24-hour urine protein collection.

The gold standard for quantification of proteinuria is the 24-hour urine collection. The test is performed by voiding upon waking and then collecting all urine on subsequent voids until the first void of the next day.“ (11)

In a retrospective study (5), researchers evaluated data from 265 patients with systemic AL amyloidosis who visited the Amyloidosis Center at Boston University Medical Center between July 1, 2018, and Jan. 1, 2020. This study examined the correlation between 24-hour urine testing and [urine protein-to-creatinine ratio] UPCR at various proteinuria levels in patients with AL amyloidosis. All patients underwent proteinuria measurement by 24-hour collection and UPCR in the same day. According to Andrea Havasi, MD, “In summary, although 24-hour urine collection is cumbersome, we continue to recommend it in patients with AL amyloidosis and kidney involvement.

 

CONCLUSION (12)

Amyloidosis can be a life-threatening disease because it can cause progressive organ damage and irreversible failure. Although it may affect any organ, one of the most frequently involved organs is the kidney, and clinically evident renal disease occurs in about 50-80% of cases. Typical manifestations of renal involvement are proteinuria, nephrotic syndrome (i.e., concomitant proteinuria, hypoalbuminemia, and peripheral edema), renal insufficiency, and end-stage renal disease (ESRD) requiring hemodialysis. All forms of systemic amyloidosis can lead to renal involvement. AL amyloidosis induces proteinuria and renal insufficiency in up to 73% and 50% of cases, respectively. ATTR amyloidosis typically does not involve the kidneys, but it can induce proteinuria and ESRD in some patients.

 

Therefore, when you have a patient with proteinuria, investigate why and don’t assume a benign origin. There are many serious causes, one of which may be amyloidosis.

 

Stay curious.

 

 

 

======== References  =========

  1. https://my.clevelandclinic.org/health/diseases/16428-proteinuria
  2. https://my.clevelandclinic.org/health/diseases/16428-proteinuria
  3. https://www.mayoclinic.org/symptoms/protein-in-urine/basics/causes/sym-20050656
  4. https://www.kidneyfund.org/kidney-disease/kidney-problems/protein-in-urine.html
  5. https://www.kidney.org/atoz/content/proteinuriawyska
  6. https://www.healio.com/news/nephrology/20220209/researchers-regard-24hour-proteinuria-collection-best-for-amyloid-light-chain-amyloidosis
  7. https://medlineplus.gov/lab-tests/albumin-blood-test/#:~:text=Albumin%20is%20a%20protein%20made,and%20enzymes%20throughout%20your%20body.
  8. https://www.kidney.org/content/kidney-failure-risk-factor-urine-albumin-to-creatinine-ration-uacr
  9. https://www.hopkinsmedicine.org/health/treatment-tests-and-therapies/24hour-urine-collection#:~:text=A%2024%2Dhour%20urine%20collection%20is%20a%20simple%20lab%20test,is%20returned%20to%20the%20lab
  10. https://www.kidneyfund.org/all-about-kidneys/tests-for-kidney-disease/urine-tests
  11. https://www.mdedge.com/clinicianreviews/article/210146/nephrology/proteinuria-and-albuminuria-whats-difference
  12. https://emedicine.medscape.com/article/238158-workup
  13. Talamo G, Mir Muhammad A, Pandey MK, Zhu J, Creer MH, Malysz J. Estimation of Daily Proteinuria in Patients with Amyloidosis by Using the Protein-To-Creatinine ratio in Random Urine Samples. Rare Tumors. 2015 Feb 18;7(1):5686. doi: 10.4081/rt.2015.5686. PMID: 25918613; PMCID: PMC4387359.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387359/#:~:text=AL%20amyloidosis%20induces%20proteinuria%20and,50%25%20of%20cases%2C%20respectively.&text=ATTR%20amyloidosis%20typically%20does%20not,and%20ESRD%20in%20some%20patients

 

 

Patient Insights: West African Descent – BE AWARE!

Our patient speakers at the Amyloidosis Speakers Bureau are powerful educators and offer compelling insights. Have a listen to this brief clip from Greg with his call out to those of West African descent — BE AWARE there is a high prevalence believed to be carriers of hereditary amyloidosis.

Patient Insights: Stay Curious

Our patient speakers at the Amyloidosis Speakers Bureau are powerful educators and offer compelling insights. Have a listen to this brief clip from Ozzie with his words of recommendation to all physicians — stay curious — and you will save lives.

Patient Insights: Not Every Symptom is Amyloidosis

Our patient speakers at the Amyloidosis Speakers Bureau are powerful educators and offer compelling insights. Have a listen to this brief clip from Dan with his reminder to PCPs — not every symptom is due to amyloidosis!

The Story Behind the Amyloidosis Speakers Bureau

The story behind the Amyloidosis Speakers Bureau (ASB) is very special. In this video we hear where the original concept of patients presenting to medical students came from — Dr. Gordon Huggins of Tufts University School of Medicine. Hear how he was “auditioning” his patients to speak to his class of second year cardiovascular medical students, and then he met Charolotte Raymond. It was an experience so meaningful it inspired Charolotte to conceptualize a program whereby patients would educate medical students across the country. She partnered with Mackenzie’s Mission in 2018, where together we took her original concept and collectively developed it into the Amyloidosis Speakers Bureau. The ASB was officially founded February 1, 2019.

Clinical Trials

Clinical research is simply medical research involving people. Here we explore clinical trials and the basics of what you need to know, and how clinicians are working to improve racial and ethnic representation in amyloidosis clinical trials.

 

WHAT ARE CLINICAL TRIALS?

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.

 

WHY CLINICAL TRIALS ARE IMPORTANT

Clinical trials permit researchers to test the safety and effectiveness of new therapies. They also allow for a rigorous evaluation through patient participation. Bottom line: it is only after the extensive evaluation and testing from a clinical trial that the FDA will approve the widespread use of any new therapy.

 

WHAT ARE THE PHASES OF CLINICAL TRIALS?

All clinical trials must be approved by the U.S. Food and Drug Administration (FDA) before they can begin. Prior to that decision, scientists perform laboratory tests and studies in animals to test a potential therapy’s safety and efficacy. Assuming favorable outcomes, the FDA then gives approval for a clinical trial involving humans.

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. Overall, the duration of a clinical trial spans years.

 

WHY PEOPLE CHOOSE TO JOIN A CLINICAL TRIAL

There are many reasons why people choose to join a clinical trial. Some join a trial because the treatments they have tried for their health problem did not work. Others participate because there is no treatment for their health problem. Some studies are designed for, or include, people who are healthy but want to help find ways to prevent a disease that may be common in their family. By being part of a clinical trial, participants may access new treatments before they are widely available. Especially with a rare disease such as amyloidosis, clinical trials may offer a meaningful impact to a patient’s quality of life.

In addition, people may feel that participating in a clinical trial allows them to play a more active role in their own health care. Participants may receive more frequent health check-ups and closer monitoring through the clinical trial. Other people say they want to help researchers learn more about certain health problems. Whatever the motivation, when choosing to participate in a clinical trial, one becomes a partner in scientific discovery. This can also help future generations lead healthier lives. Major medical breakthroughs could not happen without the generosity of clinical trial participants—young and old.

 

POTENTIAL RISKS OF A CLINICAL TRIAL

There are no guarantees of success from a clinical trial, and there are risks. For starters, there may be serious side effects. Also, the therapy may not improve upon current treatment, or may not even work at all. Finally, as a clinical trial participant, you may be part of the control group, which means either standard treatment or no-treatment placebo. In other words, there are no assurances you would receive the new therapy.

 

FINDING A CLINICAL TRIAL

Thanks to the internet, folks can find lots of information regarding the wide array of open clinical trials. So much so that it may be overwhelming. Particularly with regards to amyloidosis, casting such a wide net may not be the most productive. Since finding an appropriate clinical trial is not easy for such a rare disease, here are a few excellent places to start.

  • My Amyloidosis Pathfinder (MAP). Developed by the Amyloidosis Research Consortium (ARC), MAP helps patients discover and learn about amyloidosis-related clinical trials. After answering a short questionnaire, MAP matches patients to trials specific to their condition and ones for which they may be eligible.
  • Amyloidosis Treatment Centers. The list of amyloidosis centers participating in clinical trials in the U.S. is growing. Below we list three active participating centers.
  • ClinicalTrials.gov. This resource, provided by the U.S. National Library of Medicine, is a database of over 250,000 privately and publicly funded clinical studies conducted around the world (in all 50 states in the U.S. and 204 countries).

 

DECIDING WHO PARTICIPATES IN CLINICAL TRIALS

After signing the informed consent form, the clinical staff will screen the candidate against the clinical trial criteria. The screening may involve cognitive and physical tests. Inclusion criteria for a trial might include age, stage of disease, gender, genetic profile, family history, and whether or not the candidate has a study partner who can accompany them to future visits. Exclusion criteria might include factors such as specific health conditions or medications that could interfere with the treatment being tested. Generally, individuals can participate in only one trial or study at a time. Different trials have different criteria, so being excluded from one trial does not necessarily mean exclusion from another.

In the following video, Dr. Frederick Ruberg, cardiologist at the Boston University Amyloidosis Center, discusses the diversity of racial and ethnic occurrences of amyloidosis, and why this should parallel patient representation in clinical trials. He illustrates the persistent disparities observed by race and ethnicity and how un-recognized ATTR amyloidosis, for example, could be contributing to such differences. Adding more evidence, he shares how published clinical trials of ATTR-CM agents are insufficiently diverse. He summarizes possible solutions for improving future clinical trial participation.

 

Clinical trials need numbers and diversity of patients that reflect the patient community.  Many volunteers must be screened to find enough people for a study, and with rare diseases such as amyloidosis, important trials are often significantly delayed due to a lack of participants. This can seriously slow down the rate at which new drugs are discovered, tested, and made available to patients.

 

CONCLUSION

Not all clinical trials have successful outcomes. However, every disease drug and therapy treatment prescribed today is the result of clinical research. Clinical trials are absolutely necessary to determine that a treatment is safe and that it has a real positive effect on a particular disease, better than that observed by a placebo or the current standard of care. In addition, ensuring participant diversification adequately reflects the patient population is an important consideration when recruiting for clinical trials. Clinical trials are how we will learn more about amyloidosis, discover new drugs and treatment therapies, and find a cure.

Additional information regarding clinical trials, including where to find clinical trials and participant protection and safety, can be found in Clinical Trials 101.

 

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SOURCES

Amyloidosis Research Consortium

Boston University / Boston Medical Center, Amyloidosis Center

The Clinical Study Center

Mayo Clinic

National Institute on Aging

National Institutes of Health

Stanford University Amyloid Center

U.S. National Library of Medicine

 

Expert Insights: Amyloidosis – A Brief Clinical Overview

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

 

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