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Heart failure is a complex and debilitating condition affecting millions of individuals worldwide. While it has several underlying causes, one often-overlooked contributor to heart failure is amyloidosis.

In this month’s piece we look to the Heart Failure Society of America and their piece titled “The Silent Intruder: Amyloidosis’ Hidden Role in Heart Failure.”

Understanding Amyloidosis

Amyloidosis is a rare but serious disease characterized by the buildup of abnormal proteins in various organs, including the heart. Amyloidosis occurs when a protein called amyloid builds up in different parts of the body, including the nervous system, tissues or even organs. These abnormal proteins (amyloids) are misfolded and can impair the normal functioning of organs, including the heart. There are different types of amyloidosis, but two forms stand out for their connection to heart failure: AL amyloidosis (immunoglobulin light chain) and ATTR amyloidosis (transthyretin). Symptoms of amyloidosis may vary, depending on which organs are affected. Signs and symptoms of amyloidosis may include:

Severe fatigue and weakness
Shortness of breath
Numbness, tingling, or pain in the hands or feet (polyneuropathy)
Swelling of the ankles and legs
Diarrhea, possibly with blood, or constipation
An enlarged tongue, which sometimes looks rippled around its edge
Skin changes, such as thickening or easy bruising, and purplish patches around the eyes

Due to the similarity of these symptoms with other heart conditions, amyloidosis is often misdiagnosed or diagnosed late, emphasizing the importance of raising awareness about its hidden role in heart failure.

The Hidden Role in Heart Failure (HF)

Amyloidosis can affect the heart in several ways, leading to heart failure:

Cardiac Amyloidosis: In cardiac amyloidosis, sometimes called stiff heart syndrome, amyloid deposits take the place of normal heart muscle, disrupting the heart’s normal structure and function. This can lead to restrictive cardiomyopathy, a condition where the heart becomes stiff and less able to pump blood effectively.
Diastolic Dysfunction: Amyloid deposits in the heart can make it difficult for the heart to relax properly during the diastolic phase, impairing its ability to fill with blood. This diastolic dysfunction can result in heart failure with preserved ejection fraction (HFpEF).
Arrhythmias: Amyloidosis can disrupt the heart’s electrical system, leading to arrhythmias (irregular heart rhythms) that can further exacerbate heart failure symptoms.

Diagnosing Amyloidosis

Amyloidosis can be confirmed through specialized tests, including tissue biopsies or imaging scans such as MRIs. Some cases of amyloidosis are hereditary, so if you or anyone else in your family has or had amyloidosis, it can be beneficial for you to take a genetic test to determine if you carry the gene.

Learn More About Amyloidosis

Amyloidosis, which can be a hidden contributor to heart failure, deserves greater recognition and awareness within the medical community and among patients. Timely diagnosis and appropriate management can make a significant difference in the prognosis of individuals affected by amyloidosis.

WATCH: Cardiac Amyloidosis from a Cardiologist

Dr. Barry Trachtenberg, cardiologist at Houston Cardiovascular Associates, shares ways that physicians can raise their awareness of cardiac amyloidosis, whether AL or ATTR. He discusses multiple organ systems and how test results may present clues to consider amyloidosis. He offers a diagnostic algorithm with early red flags that can aid in the identification and typing of amyloidosis. Dr. Trachtenberg concludes with keys to remember, including questions to ask patients, which can elevate the suspicion of amyloidosis.

SOURCE

Heart Failure Society of America

https://hfsa.org/silent-intruder-amyloidosis-hidden-role-heart-failure

Dr. Julie Rosenthal, Director of the Cardiac Amyloidosis Program at Mayo Clinic in Arizona, introduces us to the cardiovascular system and summarizes cardiac amyloidosis. She then discusses the echocardiogram and how it is used to look for abnormalities, such as thickening of the heart wall and pericardial effusion. Animated patient videos clearly convey how an impaired amyloid heart looks from multiple perspectives. She offers a tutorial on ejection fraction, what it is, how it is calculated, and why not all ejection fractions are the same despite the numbers. Importantly, she highlights that stroke volume is actually the more meaningful measurement of a patient’s cardiac output and why.

Dr. Morie Gertz, hematologist, professor of medicine at the Mayo Clinic in Rochester and world renowned expert in amyloidosis, provides the ABCs of AL amyloidosis. His “Weeds in the Garden” is a legendary story explaining the biology behind this disease and how mis-folded proteins are created and evolve. He concludes with how treatments seek to deal with these mis-folded proteins and the goal of improving patients’ quality of life. This is a must-watch video for healthcare professionals from an esteemed expert.

WHAT IS IT?

According to the NIH ⁽¹⁾, macroglossia is the abnormal enlargement of the tongue in proportion to other structures in the mouth. It usually occurs secondary to an underlying disorder that may be present from birth (congenital) or acquired.

SYMPTOMS

Symptoms associated with macroglossia may include drooling, speech impairment, difficulty eating, noisy and/or high-pitched breathing (stridor), snoring, airway obstruction, abnormal growth of the jaw and teeth, and ulceration. In some cases, the tongue may protrude from the mouth. ⁽¹⁾⁽³⁾

Talking may be affected. The large size of the tongue may also cause abnormal development of the jaw and teeth, resulting in misaligned or protruding teeth. Ulceration and dying tissue on the tip of the tongue may be other symptoms of the disorder. ⁽³⁾

In addition to an enlarged tongue it is common to see indentations around the tongue perimeter from the constant pressure against the teeth.

Patients who graciously offered their picture for this blog reinforce many of these symptoms, including TMJ, difficulty swallowing, and breathing. Reiterated almost unanimously, eating is a problem – chewing and swallowing, clearing food from their mouth. Food gets stuck in front of their teeth. Speech is affected, and they often sound “slushy.” Snoring can get so bad it wakes them (and partners) up during the night. In addition, sometimes, their tongue gets sore from rubbing against their teeth.

WHAT CAUSES IT?

Macroglossia can be associated with a wide range of congenital (present from birth) and acquired conditions (e.g., malignancies, metabolic/endocrine disorders, inflammatory or infectious diseases; amyloidosis), or it can occur as an isolated feature (with no other abnormalities). In most cases, it is due to vascular malformations (blood vessel abnormalities) and muscular hypertrophy (an increase in muscle mass). ⁽¹⁾

Macroglossia is the most frequent oral manifestation of amyloidosis and may be found as the only presenting symptom of the disease or included in a longer list of other symptoms. In addition, while occurring much more frequently in AL Light Chain amyloidosis, it can also accompany hereditary ATTR Transthyretin amyloidosis. ^{(2, 4)}

HOW IS IT TREATED?

There is no cure, but treatments can manage the symptoms. Treatment depends upon the underlying cause and severity and may range from speech therapy in mild cases, to orthodontic procedures, to surgical reduction in more severe cases. ^{(1) (3)}

Sources

National Institutes of Health
NIH National Library of Medicine
National Organization for Rare Disorders
https://ashpublications.org/blood/article/116/21/5007/66459/Macroglossia-Not-Always-AL-Amyloidosis

Ref 5 (picture only)

https://www.mayoclinic.org/diseases-conditions/amyloidosis/multimedia/enlarged-tongue/img-20008056

Dr. Morie Gertz, professor of medicine at the Mayo Clinic in Rochester and world renowned expert in amyloidosis, shares his views on the past, present, and future treatments of AL (light chain) amyloidosis. Over his four decades of experience with this disease, he has diagnosed and treated thousands of patients, advanced research, and managed countless clinical trials. This makes him the perfect professor to orate on the dramatic evolution of treating this historically devastating disease to the optimism of today, and the breakthrough world of tomorrow. This is a must-watch video from a legendary expert.

Dr. Mat Maurer, cardiologist at Columbia University Irving Medical Center, discusses the importance of developing a broad differential in order to diagnose this rare, potentially life-threatening, yet treatable disease. He shares a typical but unfortunate case of cardiac amyloidosis, along with statistics of misdiagnosis and delayed diagnosis. He shares his view on the appropriate process for diagnosis based on Dr. David Eddy’s 1982 New England Journal of Medicine piece “The Art of Diagnosis” and the need to create a broad enough differential in order to consider less common diseases such as systemic amyloidosis. Dr. Maurer lists common reasons for missing diagnosis of cardiac amyloidosis all clinicians should be aware of, punctuated by his concluding point … “The Key to Correct Treatment is Diagnosis, Diagnosis, and Diagnosis.” It’s simple … you cannot treat what has not been diagnosed.

This is a MUST VIEW video for clinicians who diagnose patients, regardless of sub-specialty.

Dr. Gurbakhash Kaur, co-director of the amyloidosis program at UT Southwestern Medical Center, opens with a brief overview of the disease. Focusing on AL Amyloidosis, she shares how heterogeneously this disease presents – it can be very different from patient to patient, amplifying the diagnostic challenge. Symptoms may also be more commonly associated with other diseases. For example, proteinuria is often associated with diabetes and hypertension. However, clinicians should look at the bigger picture to be sure, as amyloidosis can also be a cause. Dr. Kaur reviews what should be in a basic workup when one has a clinical suspicion for amyloidosis. Once tested positive for amyloidosis, a second necessary step is to determine the type of amyloidosis. This is critical as it will determine the appropriate course of treatment. In closing Dr. Kaur summarizes the goals of treatment, what is available today, and what drugs are in clinical trials, giving lots of hope to the AL amyloidosis community.

Dr. J. Mark Sloan, Associate Professor of Medicine, Boston University Chobanian & Avedisian School of Medicine. He is a member of the BU Amyloidosis Center, the Evans Center for Interdisciplinary Biomedical Research at BU, and the program director for the hematology/oncology fellowship at Boston University. In this video, developed exclusively for the Amyloidosis Speakers Bureau, he provides a comprehensive clinical overview of diagnosing amyloidosis, from cardiology to neurology, and when to think about amyloidosis.

Neuropathy, also known as peripheral neuropathy, is a broad term that is used to describe damage to the nerves outside of the brain and spinal cord. There are over 100 types of peripheral neuropathy that can be classified into four categories, with each type having their own symptoms and prognosis. In this article, we’ll discuss the types of peripheral neuropathy and its connection to amyloidosis.

Symptoms

One of the challenges with neuropathy is the fact that symptoms can vary significantly based on what nerve is damaged. Additionally, symptoms can develop over the course of months to years (chronic neuropathy) or come on suddenly (acute neuropathy). Some of the most commonly seen symptoms are listed below:

Muscle weakness
Cramps
Muscle twitching
Loss of muscle and bone
Changes in skin, hair, or nails
Numbness
Loss of sensation or feeling in body parts
Loss of balance or other functions as a side effect of the loss of feeling in the legs, arms, or other body parts
Emotional disturbances
Sleep disruptions
Loss of pain or sensation that can put you at risk, such as not feeling an impending heart attack or limb pain
Inability to sweat properly, leading to heat intolerance
Loss of bladder control, leading to infection or incontinence
Dizziness, lightheadedness, or fainting because of a loss of control over blood pressure
Diarrhea, constipation, or incontinence related to nerve damage in the intestines or digestive tract
Trouble eating or swallowing
Life-threatening symptoms, such as difficulty breathing or irregular heartbeat

Types of Neuropathy

Motor Neuropathy → Damage to the motor nerves control how you move.
Sensory Neuropathy → Damage to sensory nerves control what you feel.
Autonomic Nerve Neuropathy → Damage to autonomic nerves that control functions that are involuntary (ie. you do not consciously control).
Combination Neuropathies → Damage to a mix of 2 or 3 of these other types of neuropathies. For example, damage to both sensory and motor nerves would result in sensory-motor neuropathy.

Amyloidosis

Peripheral Neuropathy is one of the hallmarks of amyloidosis, often seen in the transthyretin form of amyloidosis (ATTR). ATTR-PN, or transthyretin amyloid polyneuropathy, is a disease where the transthyretin protein becomes unstable and misfolds. This unstable protein (“amyloid”) then deposits in the nerve tissue, resulting in damage to these nerves. While amyloid deposits primarily in the peripheral nerves, it is not uncommon for amyloid deposition in the autonomic nerves as well.

While peripheral neuropathy is most commonly associated with ATTR amyloidosis, it should be noted that peripheral neuropathy is also seen in 15-35% of patients with AL amyloidosis.

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

Neurological Complications of ATTR Amyloidosis

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

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References:

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/

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/

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Amyloidosis’ Hidden Role in Heart Failure

Ejection Fraction: It’s Just a Fraction

Weeds in the Garden: ABCs of AL Amyloidosis