Amyloid Cardiomyopathy
Courtney M. Campbell
Rami Kahwash
Ajay Vallakati
INTRODUCTION
Amyloid cardiomyopathy is increasingly recognized as an underdiagnosed cause of heart failure. Amyloidosis occurs when proteins misfold, form amyloid fibrils, and then deposit in the body resulting in organ dysfunction. Although many proteins can form amyloid fibrils, two proteins are primarily responsible for amyloid cardiomyopathy: light chains and transthyretin. Amyloid deposition of these proteins results in light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR), with the latter due to a wild-type (ATTRwt) or an inherited form (ATTRv) caused by pathogenic variants in the transthyretin gene. The amyloid fibrils have variable organ tropism that results in a range of initial presentations. Most often amyloidosis is a multisystem disease. The extent of cardiac involvement is most closely associated with overall survival. Recent advances in the treatment of AL and ATTR have substantially improved morbidity and mortality, but early diagnosis of amyloidosis is key to achieving maximal benefits.
Epidemiology
Amyloidosis is considered a rare disease. However, the true prevalence of amyloid cardiomyopathy is not known because it is underdiagnosed. Based on 2012 data from billing codes in Medicare beneficiaries, the prevalence of amyloid cardiomyopathy is estimated at 17 per 100,000 person-years with an incidence of 55 per 100,000 person-years.1 In a study of amyloidosis-related mortality based on U.S. death certificates, the average reported mortality was calculated at 4.95 per 1 million people.2 Significant geographic differences were noted, with the counties surrounding Mayo Clinic in Minnesota reporting rates of 31.73 and 25.43 per 1 million people. Specific demographics and epidemiology for AL, ATTRv, and ATTRwt are considered in Table 30.1.
AL is slightly more common in men compared to women, and the majority of patients with AL are over the age of 65 years.3 Based on 2015 claims data, the prevalence is estimated at 40.5 cases per million and incidence at 14.0 cases per million person-years.4 Extrapolated from this data, at least 12,000 adults in the United States are estimated to be living with AL amyloidosis.
ATTRwt has a strong male predominance, and most patients are diagnosed with ATTR in their 60s and 70s,5 although cases have been reported in patients in their 40s.6 Autopsy data suggest a high prevalence of ATTRwt in older individuals of Northern European descent: 25% of 85 consecutive Swedish patients older than 80 years,7 25% of 256 Finnish patients older than 85 years,8 and 37% of 63 Finnish patients older than 95 years.9 A high prevalence of ATTRwt has also been seen in recent studies screening specific patient populations: 13.3% of 120 hospitalized patients admitted with heart failure with preserved ejection fraction (EF), left ventricular hypertrophy, and age older than 60 years10; 16% of 151 patients with severe aortic stenosis undergoing transcatheter aortic valve replacement11; 5% of patients with presumed hypertrophic cardiomyopathy12; and 10% of older patients undergoing bilateral carpal tunnel release.13
ATTRv is an inherited autosomal dominant disease and affects an estimated 50,000 people worldwide.14 Onset is earlier than ATTRwt with a significant male predominance in amyloid cardiomyopathy. The most common mutations in the United States are Val122Ile (p.Val142Ile), Thr60Ala (p.Thr80Ala), and Val30Met (p.Val50Met); the “p” notation is indicative of the 20 amino acid precursor protein inclusion. Val122Ile is primarily found in patients of African Caribbean descent older than 65 years. Among African Americans, 3% to 4% are estimated to carry the Val122Ile mutation,15 but the penetrance is not known. Thr60Ala occurs in an estimated 1% of a Northwest Ireland population and with an onset older than 45 years.16 Overall, it is most common in the United Kingdom and Ireland. Thr60Ala can also be found in U.S. descendants, many located in the Appalachia region. Val30Met is the most prevalent ATTRv mutation worldwide with a predominance in Japan, Sweden, and Portugal.17 In those populations, the prevalence is estimated at 1:1000. The onset is older than 50 years, but there is variable gene penetrance and clinical presentation.
Risk Factors
Populations at higher risk of amyloidosis include the following:
Age: Most common in those older than 60 years, but earlier onset occurs.
Sex: The majority of patients are male.
Family history: Hereditary amyloidosis has an autosomal dominant inheritance pattern.
Race: 3% to 4% of African Americans may carry a mutation that predisposes them to amyloidosis.
TABLE 30.1 Comparison of AL, ATTRwt, and ATTRv Epidemiology, Clinical Findings, and Prognosis | ||||||||||||||||||||||||||||||||||||||||||||
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PATHOGENESIS
In amyloidosis, proteins misfold, aggregate into beta-sheets, and form amyloid fibrils that are deposited extracellularly, leading to organ dysfunction. When the amyloid is deposited in the heart, the patient initially develops a nonischemic, restrictive cardiomyopathy. Later systolic dysfunction occurs. Over 100 proteins in the body can misfold and result in amyloid deposition. However, only two precursor proteins are primarily involved in amyloid cardiomyopathy: immunoglobulin light chain and transthyretin protein.
In AL, clonal immunoglobulin light chains are secreted by aberrant monoclonal plasma cells or B-cell dyscrasia from the bone marrow. These light chains form insoluble amyloid fibrils that are then deposited in tissue. The fibrils tend to be highly inflammatory. Cardiac impairment can occur prior to significant accumulation and is rapidly progressive.
In ATTR, the tetrameric transthyretin protein, primarily synthesized in the liver, dissociates and misassembles, resulting in amyloid fibrils that deposit in tissue. Functional transthyretin transports thyroxine and retinol-binding protein. ATTRwt is linked to advanced age and occurs when native transthyretin protein misfolds. In hereditary ATTRv, the transthyretin misfolding is linked to a destabilizing transthyretin mutation. Over 120 pathogenic mutations have been identified.18 Compared to AL amyloidosis, ATTR fibrils are less inflammatory. Disease progression relates more highly to cumulative fibril deposition over a longer period of time.
CLINICAL PRESENTATION
Common Signs and Symptoms
Amyloidosis can smolder subclinically for years to over a decade. Some amyloidosis manifestations reach clinical significance but often are attributed to other causes and are not investigated for amyloidosis. Restrictive cardiomyopathy with diastolic heart failure and dilated cardiomyopathy with systolic heart failure are some of the final amyloidosis manifestations in the disease cascade. The progression of symptoms and involved organs varies by the subtype of amyloidosis. Generally, AL symptoms are more varied and are specific to the organ systems involved. ATTRwt tends to have primarily musculoskeletal and cardiac involvement. In ATTRv, the phenotype can range from neuropathy predominant, cardiac predominant, or a mixed phenotype.
Skin: Easy bruising can accompany amyloidosis. In AL amyloidosis, periorbital purpura is a pathognomonic sign that should prompt diagnostic testing.
Musculoskeletal: The earliest initial symptoms of amyloidosis are often musculoskeletal. Amyloid deposits can build up in the transverse carpal ligament and impinge on the median nerve, resulting in carpal tunnel syndrome. If these deposits build up in the ligamentum flavum of the spine, patients can present with back pain and radiculopathy from lumbar spinal stenosis. Biceps tendon rupture can also occur with amyloid deposition. A high rate of knee and hip replacements has been noted in amyloidosis.19 ATTR seems to have high rates of musculoskeletal complaints, and these can present 5 to 15 years prior to cardiac manifestations.
Gastrointestinal: Indigestion, gastroesophageal reflux, gastrointestinal immobility, constipation, and diarrhea can all be related to amyloid deposition. An enlarged tongue can also be present. These symptoms are seen most commonly in patients with AL and some variants of ATTRv (specifically T60A, G89Q). When these symptoms are present, they can be prominent and significantly affect quality of life. Patients often seek gastrointestinal specialty care and undergo endoscopy or colonoscopy, at which time tissue from these procedures can be screened for amyloid deposits.
Renal: The kidneys are frequently affected by systemic amyloidosis. Patients with AL can initially present with nephrotic syndrome with or without renal dysfunction. Amyloidosis frequently is diagnosed after renal biopsy. Other patients with less severe deposition may have an elevated creatinine because of reduced glomerular filtration rate.
Nervous system: In addition to nerve compression from thickened ligaments, patients can develop peripheral and autonomic neuropathy. Often the etiology of peripheral neuropathy is not investigated. Some patients with amyloidosis have been on gabapentin for years, but are not diagnosed with amyloidosis until cardiac symptoms develop. If a patient has underlying diabetes, the degree of neuropathy is often out of proportion and more rapidly progressive than otherwise anticipated. Neuropathy can also manifest as erectile dysfunction and sweating abnormalities. For patients that develop autonomic neuropathy, the most prominent symptom is orthostatic hypotension. The first sign of autonomic neuropathy may be improvement of their baseline hypertension that may no longer require antihypertensive medications. For many amyloidosis patients, neuropathy is the most prominent symptom. Neuropathy is common in AL and certain variants of ATTRv (Val-30Met). Peripheral neuropathy is less common in ATTRwt.
Cardiac: Early progression of amyloid heart disease is subclinical and subtle. Amyloid cardiomyopathy becomes more prominent as the disease progresses. Patients can present with mild dyspnea on exertion, fatigue, and exercise intolerance. These symptoms can be accompanied by angina, likely related to coronary microvascular dysfunction. Almost all patients with cardiac amyloidosis (>95%) had significantly reduced peak stress myocardial blood flow (<1.3 mL/g/min).20 When the conduction system is involved, arrhythmias, bundle branch block, and sinoatrial disease are common. Patients can also present at later stages with heart failure. Most often, patients have heart failure with preserved EF. Yet many patients can present with mildly reduced ejected fraction. In end-stage amyloid cardiomyopathy, severely reduced EF with dilated cardiomyopathy can be seen. Common cardiac tests can reveal signs of amyloidosis and should prompt diagnostic testing. A single normal cardiac test should not stop pursuit of diagnostic testing if clinical suspicion is otherwise present.
Echocardiogram: In the early stages of the disease, a patient may have no obvious abnormalities on echocardiogram—particularly for AL. Subsequently, the heart develops concentric remodeling or mild left ventricular hypertrophy (Figures 30.1A and B). As the disease progresses, the walls become thicker and the patient develops diastolic dysfunction. On longitudinal strain imaging, apical sparing can be present (“cherry red spot”) (Figures 30.2A-C). Next, the patient develops an infiltrative phenotype with biventricular concentric hypertrophy, valve thickening, interatrial septal thickening, and pericardial effusion. The left ventricle is often described as having a granular sparkling pattern, although this is neither sensitive nor specific for cardiac amyloidosis and is dependent on the imaging technique. Severe diastolic dysfunction with restrictive physiology ensues. Eventually, the patient develops systolic dysfunction with a nondilated left ventricle. Special attention should also be paid to patients with paradoxical low-flow/low-gradient aortic stenosis that is accompanied by a right ventricular thickening.
Electrocardiogram (ECG): In early stages of amyloidosis, the ECG is unremarkable (Figure 30.1B). Even in patients with amyloid cardiomyopathy, the ECG can be unremarkable, particularly in those with ATTRwt. When they do occur, the initial changes can be a mild first-degree atrioventricular block. As the left ventricle thickens, there is no commensurate increase in voltage on ECG; the voltage remains normal. A pseudo-infarct pattern of Q waves unrelated to prior myocardial infarction is common. Only in late stages of the disease is the classic sign of low QRS voltages in the limb leads sometimes present (Figure 30.3). Atrial fibrillation is common in amyloid cardiomyopathy and can present in early or late stages of the disease. Complete heart block and the need for a pacemaker can also occur at late stages.
 FIGURE 30.1 Cardiac tests in early amyloid cardiomyopathy. A: Transthoracic echocardiogram showing concentric remodeling on the parasternal long axis view. B: Normal electrocardiogram in a patient with biopsy proven amyloid cardiomyopathy with no evidence of low voltages, a classic amyloidosis red flag. |
 FIGURE 30.2 Transthoracic echocardiogram red flags in late amyloid cardiomyopathy. A: Parasternal long axis view demonstrating thick right ventricular walls, thick left ventricular walls (1.5 cm), and granular sparkling appearance of the myocardium. B: Four chamber view demonstrating thick mitral and tricuspid valves and thick interatrial septum. Pericardial effusion, another red flag, is not seen in this example. |
 FIGURE 30.2 (continued) C: Global longitudinal strain demonstrating apical sparing, also known as “cherry on top” sign. |
 FIGURE 30.3 Electrocardiogram red flags in late amyloid cardiomyopathy. Electrocardiogram demonstrating low voltage in limb leads and normal voltage in the lateral leads despite known left ventricular hypertrophy. |
Cardiac magnetic resonance imaging (CMR): On CMR, amyloidosis in the heart is seen as diffuse subendocardial or transmural late gadolinium enhancement. The extracellular volume is increased (typically >0.4). The native T1 can be elevated greater than 1100 ms with difficulty, nulling the myocardium (Figure 30.4A-C).
Labs: Troponin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are useful biomarkers in amyloid cardiomyopathy.
In early stages, both tests are normal. As diastolic dysfunction develops, the NT-proBNP elevates commensurate with heart failure with preserved EF. In later stages of the disease, the troponin can be persistently, mildly elevated with little change on repeat testing.
In early stages, both tests are normal. As diastolic dysfunction develops, the NT-proBNP elevates commensurate with heart failure with preserved EF. In later stages of the disease, the troponin can be persistently, mildly elevated with little change on repeat testing.
 FIGURE 30.4 Cardiac MRI red flags in late amyloid cardiomyopathy. A: Native T1 is >1100 ms. B: Diffuse late gadolinium enhancement. |
 FIGURE 30.4 (continued) C: Extracellular volume >27% in the short axis view. LV, left ventricle. |
Differential Diagnosis
From a cardiac perspective, patients with amyloid cardiomyopathy are often misdiagnosed as hypertrophic cardiomyopathy, hypertensive heart disease, or undifferentiated heart failure with preserved EF. They may also carry an undifferentiated peripheral neuropathy diagnosis.
 ALGORITHM 30.1 Part A: Clinical suspicion for amyloidosis. |
DIAGNOSIS
Diagnosis of amyloidosis begins with a high index of suspicion (Algorithm 30.1A and B). Early diagnosis of amyloidosis is critical because early therapy translates to decreased mortality. Understanding the array of noncardiac manifestations in addition
to cardiac “red flags” can help identify patients who should be screened for amyloidosis. In all suspected cases of amyloidosis, AL must be ruled out first before consideration of ATTR. Once cardiomyopathy develops in AL, the median survival is 6 months if left untreated; therefore, early diagnosis is critical (Table 30.1).
to cardiac “red flags” can help identify patients who should be screened for amyloidosis. In all suspected cases of amyloidosis, AL must be ruled out first before consideration of ATTR. Once cardiomyopathy develops in AL, the median survival is 6 months if left untreated; therefore, early diagnosis is critical (Table 30.1).
 ALGORITHM 30.1 (continued) Part B: Clinical suspicion for amyloidosis. AL, AL, light chain amyloidosis ATTR, transthyretin amyloidosis; FLC, free light chain; H:CL, heart-to-contralateral lung MGUS, monoclonal gammopathy of uncertain significance; SPECT, single-photon emission computed tomography SPEI, serum protein electrophoresis and immunofixation; UPEI, urine protein electrophoresis and immunofixation. |
Diagnosis of Light Chain Amyloidosis
Laboratory tests: For AL, initial laboratory tests of choice are serum free light chain quantification, serum protein electrophoresis and immunofixation (SPEI), and urine protein electrophoresis and immunofixation (UPEI). Generally, a kappa-lambda ratio greater than 1.7 with evidence of a monoclonal protein on SPEI or UPEI can be indicative of AL; in the absence of monoclonal protein, a kappa-lambda ratio of up to 2.5 can be considered normal. With chronic kidney disease, mild kappa predominance can occur with a ratio of approximately 2:1. Up to 40% of patients may have monoclonal gammopathy of uncertain significance (MGUS) on immunofixation,21 and the demographics of MGUS and amyloidosis overlap. In addition, an estimated 10% of patients with multiple myeloma can develop AL.22 Abnormal results of any of these tests must be discussed with a hematologist.
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