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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/

 

AI, Protein Folding & Amyloidosis

The Protein Folding Problem

Proteins are the building blocks of life. They are large complex molecules, made up of chains of amino acids, and what a protein does largely depends on its unique 3D structure. Figuring out what shapes proteins fold into is known as the “protein folding problem.”  For decades and decades, one of biology’s biggest challenges has been finding a solution for the “protein folding problem” and is explained in the linked video below.

AI, DeepMind and Google Find Answers

Founded in 2010, DeepMind researches and builds safe AI (Artificial Intelligence) systems that learn how to solve problems and advance scientific discovery for all. They joined forces with Google in 2014 to accelerate their work. They’re a team of scientists, engineers, machine learning experts and more, working together to advance the state of the art in AI.

In a major scientific breakthrough, DeepMind’s AI system AlphaFold has been recognized as a solution to this grandest of all biological problems – the “protein folding problem.”  Here is an excellent video explaining AlphaFold and the making of a scientific breakthrough.

According to Professor Venki Ramakrishman, Nobel laureate and President of the Royal Society,

This computational work represents a stunning advance on the protein-folding problem, a 50-year-old grand challenge in biology.  It has occurred decades before many people in the field would have predicted. It will be exciting to see the many ways in which it will fundamentally change biological research.

 

Potential Impact for Amyloidosis

For diseases which originate with misfolded proteins, such as amyloidosis, “investigators have been doing this exercise by ‘brute force’ until now,” according to Dr. Angela Dispenzieri from the Mayo Clinic.  This AI research is likely to open a whole new world of insight and answers, from which new and more effective treatments can be developed.

Marina Ramirez-Alvarado, Ph.D., whose research laboratory at the Mayo Clinic studies misfolding and amyloid formation in light chain amyloidosis, had this to say.

The protein folding problem, one of the most important scientific questions of the 20th century is making headlines today with the artificial intelligence work from DeepMind. It is clear that DeepMind will provide important basic understanding of the folding process and will significantly benefit those amyloidosis diseases that involve secreted, folded proteins, such as light chain (AL), and Transthyretin (ATTR) amyloidosis.

Dr. Morie Gertz, a hematologist/oncologist from the Mayo Clinic who has decades of clinical experience with amyloidosis, weighs in on some of the possible outcomes from this ground-breaking research.

The ability to predict protein folding in three dimensions may result in the ability to predict which protein sequences are likely to form amyloid fibrils. In light chain amyloidosis this could allow for long-term monitoring of selected patients likely to develop amyloidosis. This would permit extremely early diagnosis long before symptoms developed. It would also allow for the exploration of why wild-type TTR amyloidosis forms amyloid fibrils in the heart in some patients but not in others.

 

However, it won’t answer all questions …

Dr. Vaishali Sanchorawala, director of Boston University’s Amyloidosis Center offers these words of perspective.

The “protein folding problem” that DeepMind’s AlphaFold is designed to solve is predicting the native, functional state of a protein from just its amino acid sequence. Amyloidosis, though, is caused by our bodies’ failure to solve that problem, resulting in misfolded and aggregated proteins. AlphaFold’s remarkable achievement can definitely help to better understand native structure of amyloidogenic light chain proteins. However, amyloid fibrils are different from the native states of their precursor proteins and therefore the adaptation of AlphaFold to study protein misfolding and aggregation, perhaps by predicting the structures of complex amyloid fibrils, might be better able to predict the effects of mutations that alter people’s risk of developing amyloidosis.

 

In closing …

AI is rapidly advancing the knowledge of protein misfolding, unlocking answers for amyloidosis which should lead to earlier diagnosis, improved treatment, and better patient survival.

 

 

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Sources:

Angela Dispenzieri, M.D.

Morie A. Gertz, M.D., M.A.C.P.

Vaishali Sanchorawala, M.D.

Marina Ramirez-Alvarado, Ph.D.

 

High Accuracy Protein Structure Prediction Using Deep Learning

John Jumper, Richard Evans, Alexander Pritzel, Tim Green, Michael Figurnov, Kathryn Tunyasuvunakool, Olaf Ronneberger, Russ Bates, Augustin Žídek, Alex Bridgland, Clemens Meyer, Simon A A Kohl, Anna Potapenko, Andrew J Ballard, Andrew Cowie, Bernardino Romera-Paredes, Stanislav Nikolov, Rishub Jain, Jonas Adler, Trevor Back, Stig Petersen, David Reiman, Martin Steinegger, Michalina Pacholska, David Silver, Oriol Vinyals, Andrew W Senior, Koray Kavukcuoglu, Pushmeet Kohli, Demis Hassabis.

 

In Fourteenth Critical Assessment of Techniques for Protein Structure Prediction (Abstract Book), 30 November – 4 December 2020. Retrieved from here.

 

 

Understanding the Term “Amyloid”

Amyloid is a term that is often misunderstood. It is actually a term that is broader in meaning than generally realized. It’s easy to think that ‘amyloid = amyloidosis,’ but it’s actually associated with many diseases outside of the world of amyloidosis.

To make understanding the term amyloid a bit easier, let’s take a step back and talk briefly about proteins and their structure. An easy way to understand this process is by using an analogy to words and language. The fundamental building block of language is the alphabet and individual letters. Putting these letters together allows us to create words that have meaning, but words alone are not enough to fully communicate what we are trying to say. We must have sentences to convey our ideas. 

The same goes for proteins. The way they are able to function properly is through folding. In the graphic below, you see the progression of protein folding. It starts with an amino acid (i.e., letters), which are put together to create a string of amino acids, also known as the protein’s primary structure. This string of amino acids is then organized into an alpha helix or a pleated sheet (i.e., words) to create the protein’s secondary structure. Finally, the helix or sheet is folded into what is known as the tertiary structure (i.e., sentences). This is an essential biological step that allows proteins to carry out their natural process.

So with that rudimentary analogy, let’s bring it back to amyloid. The word amyloid simply refers to a protein folding pattern, meaning when proteins fold, they fold into an amyloid orientation. Instead of being folded into their proper orientation (i.e., tertiary structure), they are misfolded into an amyloid pattern. 

To date, scientists have discovered 37 human proteins that are capable of forming amyloid, and each of these proteins is associated with a disease it can lead to.

In the world of amyloidosis, two common forms are ATTR and AL amyloidosis. These diseases are classified by the precursor proteins that form amyloid. In the case of ATTR amyloidosis, TTR (transthyretin protein) is the amyloid-forming culprit. In AL amyloidosis, immunoglobulin (also known as antibodies) light chain fragments form amyloid. 

But as mentioned earlier, amyloid can lead to diseases other than amyloidosis. Probably one of the most well known is Alzheimer’s disease. Alzheimer’s is associated with the amyloid precursor protein that forms from the β amyloid peptide. Other well-known diseases, such as Parkinson’s and Huntington’s disease, are also associated with amyloid. In Parkinson’s disease, the α-synuclein protein forms amyloid, whereas, in Huntington’s disease, Huntingtin exon 1 forms amyloid. Each is a distinct disease, but commonly involves the folding of an associated protein into amyloid. Even a specific type of prostate cancer results when Proteins S100A8/A9 form amyloid.

 

It’s a term I never entirely understood, so I hope this short article clears a few things up!

 

 

References:
https://en.wikipedia.org/wiki/Amyloid
https://www.ptglab.com/news/blog/the-complexity-of-proteins/
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