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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/

Often called “Popeye Deformity,” bicep bunching is visible when the patient flexes their arm, giving the appearance of Popeye-like arms. While it is the result of a torn tendon, it can be a leading indicator of more serious issues.

WHAT IS IT?

When the bicep tendon is ruptured, patients develop a bunching of the biceps upon flexion of the arm against gentle resistance. Tendon ruptures occur largely in the dominant arm of each patient, with one-quarter of patients developing ruptures in both arms. Interestingly, of those who had a rupture, 37.8% didn’t know it.

Below watch a video from The Lancet showing what bicep bunching looks like.

WHAT DOES IT POTENTIALLY INDICATE?

Two things.

1. Bicep bunching may be a marker for ATTRwt. According to MedPage Today, spontaneous ruptures of the distal biceps tendon may be a marker of wild-type transthyretin (TTR) cardiac amyloidosis, a single-center study found. The presentation of a tendon rupture, an easily elicited diagnostic sign, in a patient with HFpEF should raise suspicion for wild-type TTR cardiac amyloidosis.

The picture below (Source: JAMA September 12, 2017 Volume 318, Number 10) offers examples of ruptured biceps tendon in two patients with biopsy-proven ATTRwt Cardiac Amyloidosis. ATTRwt indicates wild-type transthyretin amyloidosis. Patient 1 with prior rupture of the biceps tendon and bunching of the biceps with flexion. Patient 2 with acute rupture of the biceps tendon in the left arm; the tendon rupture occurred with trivial trauma, five years after Cardiac Amyloidosis diagnosis.

2. ATTRwt may contribute to heart failure. Wild-type transthyretin amyloidosis (ATTRwt) is increasingly recognized as an important cause of heart failure with preserved ejection fraction (HFpEF).

WHY IS IT IMPORTANT?

Bicep bunching may be a marker of wild-type transthyretin (TTR) cardiac amyloidosis, potentially giving physicians an easy way to determine the underlying cause of heart failure with preserved ejection fraction (HFpEF) in some patients. Those who were aware, reported that the distal biceps tendon ruptured approximately five years prior to heart failure diagnosis, thus perhaps offering a leading insight.

In addition, early diagnosis of wild-type TTR cardiac amyloidosis (ATTRwt) is important because treatments are now available to slow, if not halt, disease progression. Unfortunately, the diagnosis of ATTRwt is often not considered in bicep bunching cases due to the perceived rarity of the disease.

“The clinical importance [of this study] is that the detection of a ruptured distal biceps tendon may be a clue for the diagnosis of wild-type TTR amyloidosis as the cause for heart failure. This diagnosis is often overlooked in clinical practice, so this relatively simple evaluation could increase detection of the disease,” said Stuart Katz, MD, of NYU Langone Health. “Enhanced detection could lead to better treatment.”

EXPERT INSIGHTS VIDEO ON MUSCULOSKELETAL MANIFESTATIONS

Dr. Shari Liberman, a hand and upper extremities surgeon from Houston Methodist Orthopedics & Sports Medicine, discussed six orthopedic manifestations and their pathology as it relates to systemic amyloidosis. Published studies, coupled with her experience, has led to a belief that these manifestations can offer important evidence of amyloidosis. She concludes with thoughts regarding an orthopedic differential and biopsy considerations for each of these manifestations.

Sources ———————————————————————————————————————

https://www.healthline.com/health/popeye-deformity

https://www.medpagetoday.com/cardiology/chf/67850

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5818850/

https://www.researchgate.net/publication/319657750_Association_Between_Ruptured_Distal_Biceps_Tendon_and_Wild-Type_Transthyretin_Cardiac_Amyloidosis

https://www.shoulderdoc.co.uk/article/721

https://www.thelancet.com/doi/story/10.1016/vid.2019.02.26.107679

https://www.youtube.com/watch?v=fHXu_0IZ3vU

Dr. Grodin, a cardiologist and co-director of the UT Southwestern Multidisciplinary Amyloidosis Program, goes through the diagnostic process for AL and ATTR cardiac amyloidosis. Understanding that there are key differences and typing of amyloidosis which are paramount to consider in order to subsequently develop a treatment plan. He concludes with diagnostic algorithms to help clinicians arrive at an accurate diagnosis.

Understanding that amyloidosis exists BEFORE organs become involved is critical to developing an early diagnosis. Dr. Grodin, a cardiologist and co-director of the UT Southwestern Multidisciplinary Amyloidosis Program, discusses these early symptoms, family history, and red flags to be aware of in order to build an index of suspicion.

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.

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

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

Multi-systemic diseases such as amyloidosis are complex to diagnose, but also complex in treatment and ongoing patient care. It takes a village. In this seminal piece, the American College of Cardiology (ACC) provides an Expert Consensus Decision Pathway on Comprehensive Multidisciplinary Care for the Patient With Cardiac Amyloidosis.

According to Dr. Vaishali Sanchorawala, Director of the Amyloidosis Center at Boston Medical Center, “The results and progress in the therapeutic landscape of systemic amyloidosis are unbelievable, unprecedented and unheard of for this uniformly fatal disease of the 1990s. But they are not enough, and therefore we need to work together to make a difference.”

This paper is an absolute must-read for cardiologists and other specialties such as neurology, gastroenterology, nephrology and hematology.

To read, CLICK HERE.

Thank you.

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Source:

Kittleson M, Ruberg F, et al. 2023 ACC Expert Consensus Decision Pathway on Comprehensive Multidisciplinary Care for the Patient With Cardiac Amyloidosis. J Am Coll Cardiol. 2023 Mar, 81 (11) 1076–1126.

https://www.jacc.org/doi/10.1016/j.jacc.2022.11.022

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

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

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

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

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

SIGNIFICANTLY UNDER-DIAGNOSED

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

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

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

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

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

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

doi: 10.1001/jama.2019.17935.

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

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

Genet Med advance online publication 19 January 2017

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

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

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

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

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

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

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

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

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

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

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

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

SUMMARY

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

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

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

Early diagnosis is key.

For additional information regarding hereditary amyloidosis:

Worldwide Hotspots of Hereditary TTR Amyloidosis (ATTRv)

Hereditary Amyloidosis: T60A Variant

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

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