AL Amyloidosis for Cardiologists: Awareness, Diagnosis, and Future Prospects: JACC: CardioOncology State-of-the-Art Review

Amyloid light chain (AL) amyloidosis is a rare, debilitating, often fatal disease. Symptoms of cardiomyopathy are common presenting features, and patients often are referred to cardiologists. Cardiac amyloid infiltration is the leading predictor of death. However, the variable presentation and perceived rarity of the disease frequently lead to delay in suspecting amyloidosis as a cause of heart failure, leading to misdiagnoses and a marked delay in diagnosis, with devastating consequences for the patient. A median time from symptom onset to correct diagnosis of about 2 years is often too long when median survival from diagnosis for patients with AL amyloidosis and cardiomyopathy is 4 months to 2 years. The authors highlight the challenges to diagnosis, identify gaps in the current knowledge, and summarize novel treatments on the horizon to raise awareness about the critical need for early recognition of symptoms and diagnosis of AL amyloidosis aimed at accelerating treatment and improving outcomes for patients

Left atrial structure and function in cardiac amyloidosis

Aims: Although cardiac amyloidosis (CA) is characterized by significant left atrial (LA) dilatation, the characteristics of LA function remain to be fully investigated. // Methods and results: We assessed LA function by speckle-tracking echocardiography in 124 patients with CA and sinus rhythm: 68 with light chain (AL), 29 with mutant (ATTRm), 27 with wild-type (ATTRwt) transthyretin amyloidosis. Conventional and strain-derived parameters, including LA peak longitudinal strain (LS) and strain rate (peak LSR: reservoir function; early LSR: conduit function; late LSR: active function), were assessed compared between CA patients and 20 healthy controls of similar age and gender. All LA function phases, including LA longitudinal strain, peak LSR, early and late LSR were significantly impaired in CA compared to healthy controls after adjusting for LA size, LV ejection fraction and LV filling pressures (E/E’) (all P < 0.05). Peak LA LS was moderately correlated with LV global LS (R = −0.60, P < 0.001); late LSR was correlated with A wave at the level of LV inflow (R = −0.69, P < 0.001). Among the different CA subtypes, peak LS and LA active emptying fraction were worse in ATTRwt than AL and ATTRm [P < 0.05 after adjustment for age, sex, body mass index, systolic blood pressure, heart rate, LA volume index, severity of mitral regurgitation, left ejection fraction, and left ventricular end-diastolic pressure (E/E’)]. // Conclusion: In CA, LA function was severely impaired and highly correlated with LV deformation. Differences in LA function between amyloid subtypes suggest that amyloid aetiology plays a role in the pathophysiology of cardiac dysfunction in CA

Left atrial structure and function in cardiac amyloidosis

Aims: Although cardiac amyloidosis (CA) is characterized by significant left atrial (LA) dilatation, the characteristics of LA function remain to be fully investigated. // Methods and results: We assessed LA function by speckle-tracking echocardiography in 124 patients with CA and sinus rhythm: 68 with light chain (AL), 29 with mutant (ATTRm), 27 with wild-type (ATTRwt) transthyretin amyloidosis. Conventional and strain-derived parameters, including LA peak longitudinal strain (LS) and strain rate (peak LSR: reservoir function; early LSR: conduit function; late LSR: active function), were assessed compared between CA patients and 20 healthy controls of similar age and gender. All LA function phases, including LA longitudinal strain, peak LSR, early and late LSR were significantly impaired in CA compared to healthy controls after adjusting for LA size, LV ejection fraction and LV filling pressures (E/E’) (all P < 0.05). Peak LA LS was moderately correlated with LV global LS (R = −0.60, P < 0.001); late LSR was correlated with A wave at the level of LV inflow (R = −0.69, P < 0.001). Among the different CA subtypes, peak LS and LA active emptying fraction were worse in ATTRwt than AL and ATTRm [P < 0.05 after adjustment for age, sex, body mass index, systolic blood pressure, heart rate, LA volume index, severity of mitral regurgitation, left ejection fraction, and left ventricular end-diastolic pressure (E/E’)]. // Conclusion: In CA, LA function was severely impaired and highly correlated with LV deformation. Differences in LA function between amyloid subtypes suggest that amyloid aetiology plays a role in the pathophysiology of cardiac dysfunction in CA

Diagnostic sensitivity of abdominal fat aspiration in cardiac amyloidosis

Aims: Congo red staining of an endomyocardial biopsy is the diagnostic gold-standard in suspected cardiac amyloidosis (CA), but the procedure is associated with the risk, albeit small, of serious complications, and delay in diagnosis due to the requirement for technical expertise. In contrast, abdominal fat pad fine needle aspiration (FPFNA) is a simple, safe and well-established procedure in systemic amyloidosis, but its diagnostic sensitivity in patients with suspected CA remains unclear. Methods and results: We assessed the diagnostic sensitivity of FPFNA in 600 consecutive patients diagnosed with CA [216 AL amyloidosis, 113 hereditary transthyretin (ATTRm), and 271 wild-type transthyretin (ATTRwt) amyloidosis] at our Centre. Amyloid was detected on Congo red staining of FPFNAs in 181/216 (84%) patients with cardiac AL amyloidosis, including 100, 97, and 78% of those with a large, moderate, and small whole-body amyloid burden, respectively, as assessed by serum amyloid P (SAP) component scintigraphy (P < 0.001); the deposits were successfully typed as AL by immunohistochemistry in 102/216 (47%) cases. Amyloid was detected in FPFNAs of 51/113 (45%) patients with ATTRm CA, and only 42/271 (15%) cases with ATTRwt CA. Conclusions: FPFNA has reasonable diagnostic sensitivity in cardiac AL amyloidosis, particularly in patients with a large whole-body amyloid burden. Although the diagnostic sensitivity of FPFNA is substantially lower in transthyretin CA, particularly ATTRwt, it may nevertheless sometimes obviate the need for endomyocardial biopsy

99mTc-DPD scintigraphy in immunoglobulin light chain (AL) cardiac amyloidosis

AIMS: Technetium-99m-labelled 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD scintigraphy) is recognized as highly accurate for the non-invasive diagnosis of transthyretin (ATTR) cardiac amyloidosis (CA). A proportion of patients with immunoglobulin light chain (AL) CA have also been reported to show cardiac 99mTc-DPD uptake. Herein, we assessed the frequency and degree of cardiac 99mTc-DPD uptake and its clinical significance among patients with AL CA. METHODS AND RESULTS: Between 2010 and 2017, 292 consecutive patients with AL CA underwent 99mTc-DPD scintigraphy and were included in this study: 114 (39%) had cardiac 99mTc-DPD uptake: grade 1 in 75%, grade 2 in 17%, and grade 3 in 8% of cases. Patients with cardiac 99mTc-DPD uptake had poorer cardiac systolic function and higher N-terminal pro-brain natriuretic peptide. No differences were noted in cardiac magnetic resonance parameters between patients with and without cardiac 99mTc-DPD uptake (N = 19 and 42, respectively). Patients with cardiac 99mTc-DPD uptake showed a trend to worse survival than those with no uptake (log-rank P = 0.056). Among 22 patients who underwent serial 99mTc-DPD scintigraphy, 5 (23%) showed reduction in the grade of cardiac uptake. CONCLUSIONS: In this large cohort of patients with AL CA, 99mTc-DPD scintigraphy ∼40% of cases showed cardiac uptake, including grade 2-3 in 10% of all patients (25% of those with cardiac 99mTc-DPD uptake). Cardiac 99mTc-DPD uptake was associated with poorer cardiac function and outcomes. These data highlight the critical importance of ruling out AL amyloidosis in all patients with cardiac 99mTc-DPD uptake to ensure such patients are not assumed to have ATTR CA

The Amyloidogenic V122I Transthyretin Variant in Elderly Black Americans

BACKGROUND: Approximately 4% of black Americans carry a valine-to-isoleucine substitution (V122I) in the transthyretin protein, which has been associated with late-onset restrictive amyloid cardiomyopathy and increased risks of death and heart failure. METHODS: We determined genotype status for the transthyretin gene (TTR) in 3856 black participants in the Atherosclerosis Risk in Communities study and assessed clinical profiles, mortality, and the risk of incident heart failure in V122I TTR variant carriers (124 participants [3%]) versus noncarriers (3732 participants). Cardiac structure and function and features suggestive of cardiac amyloidosis were assessed in participants who underwent echocardiography during visit 5 (2011 to 2013), when they were older than 65 years of age. RESULTS: After 21.5 years of follow-up, we did not detect a significant difference in mortality between carriers (41 deaths, 33%) and noncarriers (1382 deaths, 37%; age- and sex-stratified hazard ratio among carriers, 0.99; 95% confidence interval [CI], 0.73 to 1.36; P=0.97). The TTR variant was associated with an increased risk of incident heart failure (age- and sex-stratified hazard ratio, 1.47; 95% CI, 1.03 to 2.10; P=0.04). On echocardiography at visit 5, carriers (46 participants) had worse systolic and diastolic function, as well as a higher level of N-terminal pro–brain natriuretic peptide, than noncarriers (1194 participants), although carriers had a low prevalence (7%) of overt manifestations of amyloid cardiomyopathy. CONCLUSIONS: We did not detect a significant difference in mortality between V122I TTR allele carriers and noncarriers, a finding that contrasts with prior observations; however, the risk of heart failure was increased among carriers. The prevalence of overt cardiac abnormalities among V122I TTR carriers was low. (Funded by the National Heart, Lung, and Blood Institute and others.

Cardiac Structural and Functional Consequences of Amyloid Deposition by Cardiac Magnetic Resonance and Echocardiography and Their Prognostic Roles

OBJECTIVES: This cross-sectional study aimed to describe the functional and structural cardiac abnormalities that occur across a spectrum of cardiac amyloidosis burden and to identify the strongest cardiac functional and structural prognostic predictors in amyloidosis using cardiac magnetic resonance (CMR) and echocardiography. BACKGROUND: Cardiac involvement in light chain and transthyretin amyloidosis is the main driver of prognosis and influences treatment strategies. Numerous measures of cardiac structure and function are assessed by multiple imaging modalities in amyloidosis. METHODS: Three hundred twenty-two subjects (311 systemic amyloidosis and 11 transthyretin gene mutation carriers) underwent comprehensive CMR and transthoracic echocardiography. The probabilities of 11 commonly measured structural and functional cardiac parameters being abnormal with increasing cardiac amyloidosis burden were evaluated. Cardiac amyloidosis burden was quantified using CMR-derived extracellular volume. The prognostic capacities of these parameters to predict death in amyloidosis were assessed using Cox proportional hazards models. RESULTS: Left ventricular mass and mitral annular plane systolic excursion by CMR along with strain and E/e' by echocardiography have high probabilities of being abnormal at low cardiac amyloid burden. Reductions in biventricular ejection fractions and elevations in biatrial areas occur at high burdens of infiltration. The probabilities of indexed stroke volume, myocardial contraction fraction, and tricuspid annular plane systolic excursion (TAPSE) being abnormal occur more gradually with increasing extracellular volume. Ninety patients (28%) died during a median follow-up of 22 months (interquartile range: 10 to 38 months). Univariable analysis showed that all imaging markers studied significantly predicted outcome. Multivariable analysis showed that TAPSE (hazard ratio: 1.46; 95% confidence interval: 1.16 to 1.85; p < 0.01) and indexed stroke volume (hazard ratio: 1.24; 95% confidence interval: 1.04 to 1.48; p < 0.05) by CMR were the only independent predictors of mortality. CONCLUSIONS: Specific functional and structural abnormalities characterize different burdens of cardiac amyloid deposition. In a multimodality imaging assessment of a large cohort of amyloidosis patients, CMR-derived TAPSE and indexed stroke volume are the strongest prognostic cardiac functional markers

High prevalence of recurrent nocturnal desaturations in systemic AL amyloidosis: a cross-sectional pilot study

Objectives: Cardiac involvement and/or macroglossia with soft tissue deposits are risk factors for central sleep apnoea (CSA) and obstructive sleep apnoea (OSA), and common features of systemic AL amyloidosis. Little data exist on the occurrence of sleep-disordered breathing (SDB) or recurrent nocturnal hypoxia in amyloidosis, which this study sought to investigate. Methods: A total of 72 consecutive patients with systemic amyloidosis (mean age 69 years and mean BMI 25) were evaluated for occurrence of SDB, by overnight continuous pulse oximetry, and completed Epworth Sleepiness Score (ESS) and STOPBANG questionnaires. Patients included: AL cardiac (AL-C), AL macroglossia (AL-M), AL both (AL-CM) and transthyretin (ATTR). Results: Mean overnight oxygen saturations were 93% (SD ± 2, 95% CI 87–96) with abnormal oximetry (4% oxygen desaturation index (ODI) >5/hour): AC-C 84%, AL-M 57%, AL-CM 62% and ATTR 47%. NYHA class directly correlated with a higher 4% ODI, NYHA class I vs 3, (p = 0.01). Two-thirds of patients had STOPBANG scores >3 and abnormally high ESS scores (>10) were seen in up to 30% of patients. Conclusion: Recurrent nocturnal hypoxaemia, suggestive of sleep-disordered breathing, is frequent in systemic AL amyloidosis. The higher incidence in cardiac amyloidosis highlights CSA and recurrent hypoxia as possible mechanisms for morbidity/mortality in these cases. A detailed polysomnography study is planned to clarify and further investigate these findings

A targeted proteomics approach to amyloidosis typing

Background: Amyloidosis is a life threatening disease caused by deposition of various types of blood serum proteins in organs and tissues. Knowing the type of protein involved is the basis of a correct diagnosis and personalized medical treatment. While the classical approach uses immunohistochemistry, in recent years, laser micro-dissection, followed by high resolution LC-MS/MS, has been shown to provide superior diagnostic sensitivity and specificity. This techniques, however, is only available at major reference proteomics centers. // Objective: To perform clinical amyloid protein typing using low-resolution mass spectrometry and no laser micro dissection (LMD), we developed a targeted proteomics approach for the determination of both frequently encountered amyloid proteins (i.e., κ and -λ immunoglobulin light chains and transthyretin (TTR)) and specific reference proteins (i.e., actin (A) for cardiac muscle tissue, or fatty acid binding protein 4 (FBP4) for subcutaneous adipose tissue) in histologic specimens. // Method: Small tissue fragments and/or histological sections were digested to yield a protein mixture that was subsequently reduced, alkylated and trypsinized to obtain a peptide mixture. After SPE purification and LC separation, proteotypic peptides were detected by their MRM transitions. // Results: The method showed high specificity and sensitivity for amyloid protein proteotypic peptides. LODs were 1.0, 0.1, 0.2 picomoles in cardiac muscle tissue (CMT) and 0.1, 0.2, 0.5 picomoles in subcutaneous adipose tissue (SAT) for TTR, κ-, and λ-LC proteins, respectively. Amyloid to tissue-specific protein signal ratios correlated with the presence of amyloid deposits in clinical samples. // Conclusions: This targeted proteomics approach enables sensitive and specific discrimination of amyloidosis affected tissues for the purpose of clinical research