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A Life-Threatening Disease That Can Go Undetected

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A Life-Threatening Disease That Can Go Undetected TRANSTHYRETIN AMYLOID CARDIOMYOPATHY (ATTR-CM) A LIFE-THREATENING DISEASE THAT CAN GO UNDETECTED ATTR-CM: The Disease • ATTR-CM is a rare condition that is life-threatening, underrecognized, and underdiagnosed1-6 Suspect the Signs of ATTR-CM • The diagnosis of ATTR-CM is often delayed or missed1-3 Detect ATTR-CM Utilizing Nuclear Scintigraphy • Tools used to diagnose ATTR-CM include nuclear scintigraphy (eg, PYP cardiac imaging), endomyocardial biopsy (EMB), and genetic testing4,7-10 PYP = 99mTc-pyrophosphate. ATTR-CM: The Disease UNDERSTANDING TRANSTHYRETIN A CLOSER LOOK AT WILD-TYPE AND HEREDITARY ATTR-CM AMYLOID CARDIOMYOPATHY WILD-TYPE ATTR-CM HEREDITARY ATTR-CM Wild-type ATTR-CM (wtATTR) is idiopathic1 and is Hereditary ATTR-CM (hATTR)* occurs due to a not considered to be a hereditary disease.5 It is mutation in the TTR gene.5 In the United States, (ATTR-CM) thought to account for the majority of all the most common mutation causing ATTR is ATTR-CM cases.3 the valine-to-isoleucine substitution at position 122 (V122I).3 This mutation affects almost exclusively the African American population, with a prevalence of about 3-4%.4,17 Not all patients SOME PATIENT CONSIDERATIONS who carry this mutation will go on to have clinical signs and symptoms of this disease. • Ethnicity: predominantly white1,3 UNDERSTANDING ATTR-CM *Also known as variant ATTR (ATTRv).14 • Mostly men1-3 Amyloidosis is a group of diseases in which amyloid fibrils deposit into the extracellular space of the heart. • Symptom onset typically over the 11 The amyloid fibrils are formed by an aggregation of misfolded proteins. The most common amyloid fibril age of 60 years15 SOME PATIENT CONSIDERATIONS 12 proteins that can infiltrate the heart and lead to cardiac amyloidosis are immunoglobulin light chain (AL), • Heart failure1-3 • African American, African, or a hematological emergency, and transthyretin (ATTR).4,7,11,12 • Cardiac arrhythmias, particularly Afro-Caribbean descent3,4 atrial fibrillation1-4 • Men and women3 As for ATTR-CM specifically, it is found mostly in older patients, in whom misfolded transthyretin proteins • History of carpal tunnel syndrome, • Symptom onset may occur as 1,2,16 15,18 deposit in the heart.13 This rare condition is life-threatening, underrecognized, and underdiagnosed.1-6 often bilateral early as 50-60 years of age • Heart failure3 PROGNOSIS • Neurological symptoms (peripheral and autonomic)3 • Without treatment, median survival: • Gastrointestinal symptoms3 ~3.5 years1,2,16 • History of carpal tunnel syndrome, Most Common Types of Cardiac Amyloidosis often bilateral3 PROGNOSIS COMMON SIGNS AND SYMPTOMS • Without treatment, median survival: ~2 to 3 years4 IN wtATTR AND hATTR1-3,11,19-22* Transthyretin amyloidosis (ATTR)12 Immunoglobulin light chain amyloidosis (AL)12 wtATTR hATTR* • Fatigue • Arrhythmias Cardiac • Shortness of breath • HFpEF • Edema • Aortic stenosis Wild-type ATTR Hereditary ATTR 12 12 • Lumbar stenosis Cardiac Cardiac (wtATTR) (hATTR) Soft Tissue Previously known Also known as variant14 • Biceps tendon rupture as senile or umar senosis Neurologic age-related • Diarrhea • Nausea GI Neurologic CS • Constipation • Early satiety CS GI • Carpal Tunnel • Orthostasis Neurologic Syndrome • Weakness • Peripheral neuropathy IT IS CRITICAL TO CLINICALLY DIFFERENTIATE BETWEEN ATTR AND AL, AS AL REQUIRES IMMEDIATE TREATMENT AND HAS A DIFFERENT CLINICAL COURSE. CTS, carpal tunnel syndrome; GI, gastrointestinal; hATTR, hereditary ATTR; HFpEF, heart failure with preserved ejection fraction; wtATTR, wild-type ATTR, previously known as senile cardiac amyloidosis, senile systemic amyloidosis, or age-related amyloidosis. *Also known as variant ATTR.14 2 3 Suspect The Signs Of ATTR-CM HIDDEN IN PLAIN SIGHT SUSPECT ATTR-CM CLUES THAT MAY RAISE SUSPICION OF CARDIAC AMYLOIDOSIS ATTR-CM is an underdiagnosed cause of heart failure, particularly heart failure with preserved ejection fraction (HFpEF) in older adults.23 HFpEF: heart failure with preserved ejection fraction in patients typically over 60 • In ATTR-CM, diastolic function is impaired due to amyloid fibril deposition in the myocardium CONSIDER THE FOLLOWING CLINICAL CLUES, ESPECIALLY IN COMBINATION, TO RAISE resulting in thicker and inelastic ventricles thereby decreasing the stroke volume. It is not until the 34,35 SUSPICION FOR ATTR-CM AND THE NEED FOR FURTHER TESTING later stages of ATTR-CM disease that ejection fraction drops • Imaging clues, such as reduced longitudinal strain with apical sparing, may help increase suspicion7,36 heart failure with preserved ejection INTOLERANCE to standard HF therapies, ie, ACEi/ARBs and beta blockers fraction in patients typically over 60 years old1,3,23,24 • Patients can develop a decrease in stroke volume, which can lead to low blood pressure. As a HFpEF 13,25 result, they can develop an intolerance to blood pressure–lowering therapies to standard HF therapies, ie, ACEi/ARBs and beta DISCORDANCE between QRS voltage and LV wall thickness blockers7,13,25 • The classic ECG feature of ATTR-CM is a discordance between QRS voltage to LV INTOLERANCE mass ratio7,15,28 between QRS voltage and left ventricular (LV) DIAGNOSIS of carpal tunnel syndrome or lumbar spinal stenosis wall thickness26-28 DISCORDANCE • Carpal tunnel syndrome and lumbar spinal stenosis are often seen in ATTR-CM due to amyloid deposition in these areas1,13,21,22,29,30,37 of carpal tunnel syndrome1,12,13,16,29 or 2,16,38 DIAGNOSIS lumbar spinal stenosis21,22,30 • Carpal tunnel syndrome in ATTR-CM often precedes cardiac manifestations by several years ECHOCARDIOGRAPHY showing increased LV wall thickness • Increased wall thickness without a clear explanation (eg, hypertension) should raise suspicion for showing increased LV wall thickness3,12,26,31,32 ECHO cardiac amyloidosis7,12 • Extracellular amyloid deposition results in an increased LV wall thickness that tends to be greater in ATTR-CM than in AL cardiac amyloidosis, with reported thicknesses for ATTR-CM often being NERVOUS SYSTEM over 15 mm12,26,28,32 NERVOUS SYSTEM—autonomic nervous system dysfunction, including gastrointestinal —autonomic nervous system dysfunction, including gastrointestinal complaints or complaints or unexplained weight loss unexplained weight loss3,12,18,33 • Gastrointestinal complaints due to autonomic dysfunction include diarrhea and constipation11 • Orthostatic hypotension due to autonomic dysfunction is another symptom that may occur with ATTR-CM1-4,12 ACEi, angiotensin-converting enzyme inhibitors; ARBs, angiotensin receptor blockers. 4 5 Detect ATTR-CM Utilizing PYP Nuclear Scintigraphy IF YOU SUSPECT ATTR-CM TOOLS FOR DIAGNOSIS ADVANCED IMAGING TECHNIQUES TO HELP RAISE SUSPICION DETECT TRANSTHYRETIN AMYLOID CARDIOMYOPATHY (ATTR-CM) ALTHOUGH THESE TECHNIQUES CANNOT DIAGNOSE ATTR-CM,39 ABNORMAL PYP CARDIAC IMAGING (NUCLEAR SCINTIGRAPHY) FINDINGS SHOULD PROMPT FURTHER TESTING TO ESTABLISH A DIAGNOSIS • A noninvasive, widely available diagnostic tool with high OF ATTR-CM. NONINVASIVE IMAGING TECHNIQUES INCLUDE: sensitivity and specificity for ATTR-CM • Advanced echocardiography with speckle tracking strain imaging7,36,37,40 • Both Planar and SPECT imaging should be reviewed and – Relative apical sparing of global longitudinal strain7 interpreted using visual and quantitative approaches – “Ice cream cone with a cherry on top” sign7 – SPECT imaging is necessary for studies that show planar myocardial uptake because they can help differentiate myocardial uptake from blood pool or overlying bone uptake • Uses 99mtechnetium-pyrophosphate (99mTc-PYP), a radioactive tracer utilized as an adjunct in the diagnosis of ATTR-CM, though not FDA approved for that use • A multicenter international study of scintigraphy at amyloid centers of excellence demonstrated 100% specificity for ATTR-CM using visual grade 2 or 3 with concurrent testing to rule out AL • American Society of Nuclear Cardiology (ASNC) Practice Points highlight the importance of PYP cardiac imaging in diagnosing ATTR-CM noninvasively and thereby guide patient management • If clinical suspicion remains high for cardiac amyloidosis in spite of a negative or inconclusive 99mTc-PYP scan, biopsy should be considered Reprinted from Siddiqi OK, Ruberg FL, Cardiac amyloidosis: an update on pathophysiology, diagnosis, and treatment. Trends Cardiovasc Med. 28/1, 10-21, 2018, with permission from Elsevier.35 ENDOMYOCARDIAL BIOPSY (EMB) • CMR, with late gadolinium enhancement, and distinct T1 mapping7,36,40 • Requires histology with Congo red staining with apple-green birefringence to diagnose – Increased extracellular volume, ECV7 cardiac amyloidosis7,8 5 Pre-contrast T1 LGE ECV • To determine amyloid type, immunohistochemistry testing and/or mass spectrometry should be performed7 • Patients may experience diagnostic delay for a number of reasons, including risk of complications and the need for specialized centers and expertise7,8 GENETIC TESTING IS USED TO DETERMINE IF THE DISEASE IS HEREDITARY DUE TO A MUTATION IN THE TTR GENE. GENETIC COUNSELING AND GENE SEQUENCING ARE RECOMMENDED FOLLOWING THE CONFIRMATION OF ATTR-CM.4 Reprinted by permission from Fontana M, Chung R, Hawkins PN, Moon JC. Springer: Heart Failure Reviews, Cardiovascular magnetic resonance for amyloidosis. 2015;20(2):133-144. PYP, pyrophosphate. CMR, cardiac magnetic resonance imaging; ECV, extracellular volume; LGE, late gadolinium enhancement. *Please consult individual labeling for risks. 6 7 Detect ATTR-CM Utilizing PYP Nuclear Scintigraphy IF YOU SUSPECT ATTR-CM TOOLS
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