ATTR Amyloid Research Articles

A case of cardiac amyloidosis incidentally detected by bone scintigraphy.

A 73-year-old man with lung cancer underwent bone scintigraphy for disease staging. Diffuse myocardial technetium hydroxymethylene diphosphonate (99mTc-HMDP) uptake was incidentally found. A diagnosis of amyloid transthyretin (ATTR) cardiac amyloidosis was suspected, although the patient had no symptoms at this time. Single-photon emission computed tomography (SPECT) showed particularly strong uptake in the ventricular septum. Cardiac magnetic resonance imaging (CMR) showed widespread subendocardial and partly transmural enhancement of the left ventricular myocardium on delayed postcontrast T1-weighted images. These findings were consistent with ATTR cardiac amyloidosis. 18F-FDG uptake in the left ventricle wall was observed on PET/CT. He was finally diagnosed with ATTR by endomyocardial biopsy. There are two major subtypes of cardiac amyloidosis: ATTR amyloidosis and amyloid light-chain (AL) amyloidosis. Endomyocardial biopsy is the gold standard for diagnosis. Recently, however, several reports have shown that bone scintigraphy using a 99mTc-labelled bone-seeking agent can detect ATTR cardiac amyloidosis and differentiate it from AL amyloidosis. Bone scintigraphy may play an important role in the detection and differentiation of ATTR cardiac amyloidosis.

Apolipoprotein AI amyloid deposits in the ligamentum flavum in patients with lumbar spinal canal stenosis

Amyloidosis is a protein-misfolding disease characterised by insoluble amyloid deposits in the extracellular space of various organs and tissues, such as the brain, heart, kidneys, and ligaments. We previously reported the frequent occurrence of amyloid deposits in the ligament flavum in the presence of lumbar spinal canal stenosis (LSCS), which is a common spinal disorder in older individuals. Our earlier clinicopathological studies revealed that amyloid deposits derived from transthyretin (TTR) were involved in the pathogenesis of LSCS. ATTR amyloid was the most common form in the ligamentum flavum, but amyloid deposits that were not identified still existed in more than 50% of patients with LSCS. In this study, we found apolipoprotein AI (AApoAI) amyloid deposits in the ligamentum flavum of patients with LSCS. The deposits occurred in 12% of patients with LSCS. Biochemical studies revealed that the amyloid deposits consisted mainly of full-length ApoAI. As a notable finding, the lumbar ligamentum flavum of patients who had LSCS with double-positive amyloid deposits—positive for both ATTR and AApoAI—was significantly thicker than that of patients who had LSCS with single-positive—that is, positive for either ATTR or AApoAI—amyloid deposits. We thus suggest that lumbar AApoAI amyloid formation may enhance the pathological changes of lumbar ATTR amyloidosis in patients with LSCS.

Non-cardiac biopsy sites with high frequency of transthyretin amyloidosis.

AimsCardiac scintigraphy, a non‐invasive technique for diagnosing ATTR cardiac amyloidosis, lacks specificity in patients with concomitant monoclonal gammopathy (up to 40% of cases). For these patients, amyloid type is often established by endomyocardial biopsy (EMB), which has clinical risk. This study aimed to investigate the frequency of ATTR in amyloid‐positive tendon/synovium, urinary bladder, and prostate biopsies, sites for which prior biopsy specimens might exist for patients suspected of having cardiac amyloidosis, and, when available, determine the amyloid type concordance rate with other anatomic sites and provide clinical data regarding subsequent development of cardiac amyloidosis.Methods and resultsWe queried our reference laboratory database of 19,298 amyloid specimens from myriad anatomic sites typed by mass spectrometry‐based proteomics (LC‐MS/MS) to investigate the frequency of ATTR amyloid in tendon/synovium, urinary bladder, and prostate. The amyloid type was ATTR in 104/138 (75.4%) tendon/synovium, 173/453 (38.0%) urinary bladder, and 27/81 (33.3%) prostate samples. Of 62 patients with available clinical data, 12 (19%) had bona fide ATTR cardiac amyloidosis prior to/concomitant with the non‐cardiac site biopsy. Of the remaining 14 with follow‐up, 8 developed bona fide and 2 probable cardiac amyloidosis; at last follow‐up 4 had no evidence of cardiac amyloidosis. Fourteen of 16 patients (87.5%) for whom we typed both non‐cardiac and cardiac sites had concordant amyloid types. There were 2 discordant cases (prostate = ASem1/heart = AL and urinary bladder = AL/heart = ATTR); only the latter is potentially clinically consequential.ConclusionsIn patients suspected of having cardiac amyloidosis based on cardiac scintigraphy, LC‐MS/MS typing of Congophilic deposits in pre‐existing biopsy specimens from non‐cardiac sites may help establish the cardiac amyloid type, obviating the need for EMB. However, if the amyloid type identified in the non‐cardiac site is not in keeping with other clinical features, then EMB for typing the cardiac amyloid might be indicated.

Abstract 17246: Sensitivity and Specificity of Relative Sparing of Apical Longitudinal Strain for Detection of Systemic Light-Chain Amyloidosis versus Transthyretin Amyloidosis

Introduction: Relative apical sparing of longitudinal strain (RALS, the ratio of apical strain vs the rest of the heart) on echocardiography has been found to have high sensitivity and specificity for differentiating cardiac amyloidosis (CA) from other causes of left ventricular hypertrophy. Previous studies have shown no significant difference between amyloid subtypes, systemic light-chain amyloidosis (AL) and transthyretin amyloidosis (ATTR) Hypothesis: There will be a significant difference in sensitivity and specificity of RALS to detect CA across amyloid subtypes. Methods: A cohort of patients with either AL or ATTR amyloid was identified, with a control cohort of patients with left ventricular hypertrophy (LVH) of other etiologies. Speckle tracking echocardiography was performed on EchoPAC (GE Medical Systems) software to obtain values of basal, mid, and apical longitudinal strain for each patient; relative apical strain was then calculated. Results: The TTR group (n=22) was older (66.4±7.9, 76.6±11.6, p=0.001) and more likely to be female (p=0.009) than the AL group (n=30), both groups had similar rates of hypertension, diabetes mellitus, and end stage renal disease. Echocardiographic markers of diastolic function were decreased in both groups; the AL group had decreased left ventricle end diastolic volume (60.9±25.5, 94.9±50.2, p=0.012) and mean wall thickness (1.4±0.3, 1.6±0.4 p=0.017). ROC analysis using a RALS cutoff of 2 to differentiate AL and ATTR from the LVH control group revealed similar specificity (AL 85%, ATTR 85%) and sensitivity (AL 40%, ATTR 50%). Difference in area-under-curve (AUC) was not significant (p=0.2) (figure). Conclusions: ATTR and AL amyloid have similar specificity, but ATTR has a trend towards improved sensitivity over AL for detection of CA using RALS with the previously validated threshold of 2. This might become significant with a larger sample, work that is currently on-going..

Abstract 13148: Clinical Importance of Left Atrial Infiltration in Cardiac Transthyretin Amyloidosis

Introduction: The clinical significance of left atrial (LA) involvement and dysfunction in ATTR amyloidosis cardiomyopathy (ATTR-CM) has not been characterized. We sought to study: 1) LA pathology in heart specimens from ATTR-CM patients 2) LA stiffness and mechanics using echocardiographic speckle tracking (EST) in cardiac ATTR-CM 3) the association between parameters of atrial function and mortality. Methods: Congo red staining and immunohistochemistry was performed to assess amyloid in the atria from 5 ATTR-CM heart specimens. 2D EST was used to assess LA reservoir, conduit, contractile function and stiffness in 906 ATTR-CM patients (551 wt ATTR; 93 T60A ATTR; 241 V122I ATTR; and 21 other gene variants). Results: There was extensive ATTR amyloid infiltration in the 5 atria, with loss of normal architecture, infiltration and remodelling of vessels, capillary disruption and subendocardial fibrosis. EST demonstrated increased atrial stiffness [median (25th-75th quartile) 1.83 (1.15-2.92)] that remained independently associated with reduced survival, after adjusting for known prognostic variables (lnLA stiff: HR= 1.26, CI 1.07-1.57; p=.009). There was substantial impairment of the three phasic functional atrial components [reservoir 8.86(5.94-12.97)%; conduit 6.5(4.53-9.28)%; and contraction 4.0(2.29-6.56)%]. Atrial contractile function was absent in 21.6% of patients whose ECG showed sinus rhythm (SR)-atrial electro-mechanical dissociation (AEMD). AEMD was associated with a poorer prognosis compared to SR patients who had effective mechanical contraction (p <.0001). AEMD conferred a similar prognosis to patients in AF. Conclusions: The phenotype of ATTR-CM includes clinically significant infiltration of the atrial walls characterized by progressive loss of function and increased stiffness, a strong independent predictor of mortality. AEMD emerged as a distinctive functional phenotype identifying patients in SR with poor prognosis.

In Vivo Quantification of Myocardial Amyloid Deposits in Patients with Suspected Transthyretin-Related Amyloidosis (ATTR).

Background: Current diagnosis of Transthyretin-related Amyloidosis (ATTR) using bone scintigraphy is primarily based on visual scoring and semi-quantitative indices. With the introduction of new potential life-prolonging drugs for ATTR, a more precise quantification of myocardial amyloid burden is desirable for improved response prediction and therapy monitoring. Methods: At first, quantification experiments using an anthropomorphic thorax phantom were performed. Second, 32 patients underwent both planar whole body [99mTc]- 3,3-Diphosphono-1,2-Propanodicarboxylic Acid (DPD)-scintigraphy and quantitative Single-Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) of the thorax. SPECT/CT standardized myocardial uptake values SUVpeak and SUVpeak normalized to bone uptake (nSUVpeak) were determined. Results: Phantom measurements showed a strong linear relationship between the activity in the myocardial insert and the measured activity (r = 0.9998, p = 0.01), but the measured activity was systematically underestimated by approximately 30%. Receiver operating characteristics (ROC) analysis revealed a 100% sensitivity and specificity at a cut-off of 3.1 for SUVpeak for the differentiation of both patient groups. Conclusion: SUV quantification of ATTR amyloid burden is feasible using novel SPECT/CT technology. With a SUVpeak cut-off of 3.1, patients with Perugini grade 2 and 3 could be clearly separated from those with Perugini grade 0 and 1. Besides ATTR diagnostics, quantification of amyloid deposits could potentially be used for therapy monitoring and prognostication in patients with cardiac ATTR.

SILENT TYPE A AORTIC DISSECTION DUE TO SUSPECTED AORTIC AMYLOID

SESSION TITLE: Medical Student/Resident Critical Care Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Stanford type A dissection of the proximal aorta is considered a surgical emergency due to high early mortality (1). The weakening of the aortic wall along with elevated shear stress may predispose to an aortic dissection. Concurrently, systemic amyloidosis tends to deposit in the vasa-vasorum, which leads to the frailty of the aortic vascular layers. Here we present an unusual case in which an asymptomatic type A aortic dissection was diagnosed due to suspected aortic amyloidosis. CASE PRESENTATION: A 73 year old woman with a history of uncontrolled hypertension (HTN) and diabetes mellitus presented for elective cardiac magnetic resonance imaging (MRI) due to suspected cardiac amyloidosis after testing positive for hereditary ATTR amyloid gene mutation. Her family history was significant for amyloid cardiomyopathy in two siblings. She had no exertional symptoms, and physical exam was only notable for a soft systolic ejection murmur at the left sternal border. Her electrocardiogram showed normal sinus rhythm with normal intervals. MRI unexpectedly noted a type A aortic dissection arising at the level of the sinotubular junction extending up the ascending aorta and down to the level of the iliac bifurcation with no evidence of myocardial amyloid deposition. She remained clinically asymptomatic but was transferred to the cardiac intensive care unit for initiation of intravenous antihypertensive therapy. Cardiac surgery was consulted and performed an urgent ascending hemi-arch replacement. Aortic tissue pathology was negative for amyloid protein. Subsequent outpatient follow-up showed stable aortic repair with chronic type B aortic dissection, and she continued to remain asymptomatic. DISCUSSION: It has been observed that 6.4% of aortic dissections are clinically subtle in presentation resulting in an increased mortality (2). Although MRI & pathologic analysis did not demonstrate amyloidosis, microvascular intramural amyloid deposition in the aorta remains possible. In this case, chronic uncontrolled HTN with age related degeneration of the aortic wall were likely the primary underlying factors. CONCLUSIONS: This case illustrates an unusual clinically silent presentation of a catastrophic illness. Although the management of silent Type A dissection typically require early surgical intervention, to improve survival, late asymptomatic presentations have been observed (3) Reference #1: Mehta RH, Suzuki T, Hagan PG, Bossone E, Gilon D, Llovet A, et al. Predicting Death in Patients With Acute Type A Aortic Dissection. Circulation. 2002 Jan 15;105(2):200–6. Reference #2: Park SW, Hutchison S, Mehta RH, Isselbacher EM, Cooper JV, Fang J, et al. Association of Painless Acute Aortic Dissection With Increased Mortality. Mayo Clin Proc. 2004 Oct 1;79(10):1252–7. Reference #3: 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: Document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adultThe Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC). Eur Heart J. 2014 Nov 1;35(41):2873–926. DISCLOSURES: No relevant relationships by Benjamin Kenigsberg, source=Web Response Removed 06/24/2020 by Benjamin Kenigsberg, source=Web Response No relevant relationships by Omar Yacob, source=Web Response

TTR gene silencing therapy in post liver transplant hereditary ATTR amyloidosis patients

Objective Patients with hereditary transthyretin (TTR) amyloidosis (hATTR) often experience disease progression after orthotopic liver transplant (POLT) due in part to wild type ATTR amyloid deposition. The management strategy is not defined. We propose that TTR gene silencing with an antisense oligonucleotide or a small interfering ribonucleic acid may be a treatment for these patients. Methods We reviewed the charts of hATTR patients POLT treated with a TTR gene silencing agent at 7 different Amyloid Clinics between 2018–2020. Results Nine hATTR patients with POLT were treated with TTR gene silencing therapy (Inotersen). The median age was 61 years. The median time from OLT to initiation of TTR gene silencing therapy was 7.5 years. The median duration of therapy was 12 months. Neuropathy impairment score remained stable or improved in all patients. Five patients stopped treatment: 3 because of thrombocytopenia, 2 because of reversible liver rejection. Three patients who discontinued treatment subsequently experienced worsening of their neuropathy. Conclusion TTR gene silencing therapy in hATTR patients with POLT could be a treatment option. Vigilant monitoring of renal, liver and bone marrow functions is necessary because of frequent complications. Further studies are needed to determine efficacy.

The value of screening biopsies in light-chain (AL) and transthyretin (ATTR) amyloidosis.

Systemic amyloidosis is a histological diagnosis, often achieved via critical organ biopsy. Screening biopsies represent a low-risk approach to diagnosis. All patients with systemic AL and ATTR amyloidosis who underwent abdominal fat aspiration (AFA) and either a bone marrow (BM) or gastrointestinal (GI) biopsy at the UK National Amyloidosis Centre (2006-2019) were identified. We sought to determine diagnostic sensitivity in relation to whole body amyloid burden, amyloid type and organ involvement. Diagnostic sensitivity established in 471 patients with AL (n=321) and ATTR (n=150) amyloidosis, respectively, was 73.2% and 27.3% for AFA (P<.001), 59.7% and 42.2% for BM (P<.001), and 74.6% and 44.6% for GI biopsy (P<.001). ATTR amyloid deposits were detected in 35.4% BMs and 33.3% of GI biopsies when AFA did not demonstrate amyloid. In AL amyloidosis, sensitivity of combined AFA and BM biopsy in AL amyloidosis was 82.9%. There was a strong association between whole body amyloid burden and sensitivity of each screening biopsy method. The diagnostic sensitivity of screening biopsies ranged from 80.0% to 90.5% for patients with a large amyloid load on 123 I-SAP scintigraphy in comparison with 53.9%-79.0% in those with no visceral amyloid visible on imaging. Performing both AFA and BM biopsy should be considered in suspected AL amyloidosis to substantially reduce the clinical risk associated with critical organ biopsy. The sensitivity of screening biopsies in ATTR amyloidosis is poor.

An Analysis of Our Ten-Year Cohort of Patients with Cardiac Amyloidosis Supported by the Continuous-Flow Left Ventricular Assist Device

Limited data exists on the use continuous-flow left ventricular assist device (CF-LVAD) in patients with cardiac amyloidosis (CA). The largest single center analysis on CF-LVAD support in patients with CA reports a 50% mortality at 6-months. Our primary aim was to examine the survival and morbidity of our patients with diagnosed CA and supported by CF-LVAD. Data on demographics, type of cardiac amyloidosis, pre-implant echocardiographic features, and post-implant survival and morbidity outcomes was retrospectively extracted on patients with CA and supported by CF-LVAD at our institution from January 2009-October 2019. Descriptive statistics are reported. Six patients with diagnosed CA (mean age 64 ± 9 years) were supported by CF-LVAD (3 centrifugal, 3 axial) for a median 32.3 months (range 8.4, 48.3). Table 1 depicts pertinent patient demographics, survival and morbidity. Four patients had ATTR amyloid, and 2 had AL amyloidosis. LV ejection fraction (10-45%) and end-diastolic dimension (4.4-6.0 cm) varied pre-implant. All 6 patients were alive at 6-months on CF-LVAD support. Overall, 2 patients died, 2 were bridged to heart transplant, and 2 remain on destination therapy. One patient required a right ventricular assist device and dialysis immediately post-implant, and two patients had hospital re-admission for right heart failure. Various etiologies contributed to re-hospitalizations post-implant (data not shown). With CF-LVAD support, the patients with AL amyloid survived for a median 47.8 months. Our limited experience in patients with cardiac amyloidosis highlights the feasibility of supporting these patients with CF-LVAD as bridge to transplant or destination therapy. Future analyses are warranted to refine careful patient selection to improve outcomes, with particular consideration to the interplay between right ventricular hemodynamics and renal function.

Amyloid and the Heart.

While morbidity and mortality remain high for amyloid cardiomyopathy (AC), increased awareness, earlier diagnosis, and advances in treatment have improved patient outcomes. This review will discuss the pathophysiology, contemporary diagnostic strategies, and novel and investigational therapeutic strategies for light-chain (AL) and transthyretin (ATTR) AC. Diagnostic strategies for AC now include cardiac magnetic resonance imaging and bone scintigraphy. Proteosome inhibitor therapy is now front-line therapy for AL AC followed by autologous stem cell transplantation. Emerging disease-modifying strategies for ATTR AC include the recently FDA-approved TTR-stabilizer, tafamadis. ATTR gene-silencing therapy and amyloid fibril degradation therapy are two other strategies under investigation. Heart transplantation and durable mechanical circulatory support remain a final potential option; however, contemporary outcomes are improving with better patient selection. Patient outcomes for AC are expected to improve as increased awareness leads to earlier diagnosis and prompt treatment with emerging pharmacotherapy or advanced heart therapies.

Cryo-EM structure of a transthyretin-derived amyloid fibril from a patient with hereditary ATTR amyloidosis

ATTR amyloidosis is one of the worldwide most abundant forms of systemic amyloidosis. The disease is caused by the misfolding of transthyretin protein and the formation of amyloid deposits at different sites within the body. Here, we present a 2.97 Å cryo electron microscopy structure of a fibril purified from the tissue of a patient with hereditary Val30Met ATTR amyloidosis. The fibril consists of a single protofilament that is formed from an N-terminal and a C-terminal fragment of transthyretin. Our structure provides insights into the mechanism of misfolding and implies the formation of an early fibril state from unfolded transthyretin molecules, which upon proteolysis converts into mature ATTR amyloid fibrils.

Mechanical circulatory support for cardiac amyloidosis.

Cardiac amyloidosis, typically from abnormal deposition of AL or ATTR amyloid protein, can result in heart failure requiring transplantation (HTx). The role of mechanical circulatory support (MCS) is not well-established. The purpose of this study was to present our experience with MCS in patients with cardiac amyloidosis. Consecutive patients with cardiac amyloidosis who received MCS at Cedars-Sinai Medical Center between 2010 and 2018 were reviewed. Clinical characteristics and outcomes were compared to a control group of MCS patients without amyloid matched 2:1 for age and INTERMACS Profile. 11 amyloid patients underwent durable MCS, two with paracorporeal biventricular assist devices and 9 with total artificial hearts. No patients received isolated left ventricular assist device support. By 1year, 9 (82%) of patients in the MCS-Amyloid group had been transplanted and 2 (18%) had died. In the MCS-No Amyloid group, by 1year, 8 (36%) of patients had been transplanted, 10 (46%) had died, and 4 (18%) were still living with MCS. Over a 9-year period, patients with amyloid cardiomyopathy who required MCS at our institution all received durable biventricular MCS. For carefully selected patients, this approach is feasible with acceptable outcomes as bridge to transplantation.

Therapeutic Potential of Polyamidoamine Dendrimer for Amyloidogenic Transthyretin Amyloidosis.

Amyloidogenic transthyretin (ATTR) amyloidosis is caused by a formation of ATTR amyloid fibrils. Because ATTR misfolding triggers the formation of aggregates and amyloid fibrils, which are considered to deposit on the tissues, novel clinically effective therapeutic strategies targeted to those processes are urgently needed. In this study, to discover a new drug candidate for ATTR amyloidosis therapy, we focused on polyamidoamine dendrimer (dendrimer), a 3D-structural nanomaterial, which has a branched cationic polymer repeating polyamidoamine units. Dendrimer (G2) not only inhibited ATTR V30M amyloid fibril formation, but also reduced already formed ATTR V30M amyloid fibrils by reducing β-sheet structure of ATTR V30M protein. Moreover, intravenous administration of dendrimer (G2) reduced TTR deposition in human ATTR V30M transgenic rats. These results indicate that dendrimer (G2) may possess both inhibitory and breaking effects on ATTR V30M amyloid, suggesting that dendrimer has the potential as a dual effective agents against TTR amyloidosis.

Quantitation of 99mTc-DPD uptake in patients with transthyretin-related cardiac amyloidosis

Purpose: Transthyretin (ATTR) amyloidosis is a rare but serious infiltrative disease associated with a wide spectrum of morphologic and functional cardiac involvement. 99mTc-labelled 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD), initially developed as a bone-seeking radiotracer, is remarkably sensitive for imaging cardiac ATTR amyloid deposits. Our aim was to investigate the feasibility and utility of estimating 99mTc-DPD uptake in myocardial tissue; this has the potential to yield reliable quantitative information on cardiac amyloid burden, which is urgently required to monitor disease progression and response to novel treatments.Methods: Three methods of quantitation were developed and tested on 74 patients with proven cardiac ATTR amyloidosis who had recently undergone 99mTc-DPD planar whole-body imaging and SPECT-CT. Quantitative results were compared to measurements of extracellular volume fraction (ECV) by cardiac magnetic resonance imaging, a validated technique for measuring amyloid burden.Results: An experienced clinician graded uptake using a widely-used visual scoring system as 1 (n = 15), 2 (n = 39) or 3 (n = 20). Linear correlations between the SPECT and ECV data (p < .001) were demonstrated. None of the methods showed that 99mTc-DPD uptake in the heart was significantly greater in patients with grade-3 uptake than in those with grade-2 uptake.Conclusions: Quantitation of 99mTc-DPD uptake in cardiac transthyretin amyloid deposits is complex and is hindered by competition for radiotracer with amyloid in skeletal muscle. The latter underlies differences in uptake between grade-2 and grade-3 patients, not cardiac uptake.

Seven factors predict a delayed diagnosis of cardiac amyloidosis

Introduction: Diagnostic delay of cardiac amyloidosis (CAm) continues to challenge clinicians. We investigated features associated with delay and ascertained if a diagnostic delay had negative implications for the patient.Methods: We performed a retrospective chart review identifying 82 subjects with biopsy-proven and mass-spectrometry-identified CAm with clinical and epidemiologic data including first potential symptom of amyloidosis. Pathology slides were scored for extent of amyloid. Robust statistical analyses including generalized linear and ordered logistic regression analysis were performed.Results: There was a 22 month (median) delay in diagnosis, more pronounced (34 months) in subjects with transthyretin (ATTR) amyloidosis. Seven factors predict a delayed diagnosis including ATTR amyloid type (ratio =2.17, 95% CI 1.31–3.59), having carpal tunnel syndrome (2.13, CI 1.49–3.03) and age <70 at first symptom (1.85, CI 1.30–2.61). Individuals with delays of 1+ years had higher levels of NT proBNP (4451 vs. 2559 pg/mL, p = .016) and longer PR intervals (225 vs. 162 ms, p < .001) at the time of diagnosis.Conclusions: Diagnostic delays negatively affect cardiac function. Of the predictive clinical features, carpal tunnel syndrome was frequent and its presence should lead to a more aggressive analysis for CAm in the appropriate clinical settings.

Cardiac ATTR amyloid nuclear imaging—not all bone scintigraphy radionuclide tracers are created equal

Cardiac ATTR amyloid nuclear imaging—not all bone scintigraphy radionuclide tracers are created equal

MALDI Mass Spectrometry Imaging: A Novel Tool for the Identification and Classification of Amyloidosis.

Amyloidosis is a group of diseases caused by extracellular accumulation of fibrillar polypeptide aggregates. So far, diagnosis is performed by Congo red staining of tissue sections in combination with polarization microscopy. Subsequent identification of the causative protein by immunohistochemistry harbors some difficulties regarding sensitivity and specificity. Mass spectrometry based approaches have been demonstrated to constitute a reliable method to supplement typing of amyloidosis, but still depend on Congo red staining. In the present study, we used matrix‐assisted laser desorption/ionization mass spectrometry imaging coupled with ion mobility separation (MALDI‐IMS MSI) to investigate amyloid deposits in formalin‐fixed and paraffin‐embedded tissue samples. Utilizing a novel peptide filter method, we found a universal peptide signature for amyloidoses. Furthermore, differences in the peptide composition of ALλ and ATTR amyloid were revealed and used to build a reliable classification model. Integrating the peptide filter in MALDI‐IMS MSI analysis, we developed a bioinformatics workflow facilitating the identification and classification of amyloidosis in a less time and sample‐consuming experimental setup. Our findings demonstrate also the feasibility to investigate the amyloid's protein composition, thus paving the way to establish classification models for the diverse types of amyloidoses and to shed further light on the complex process of amyloidogenesis.

A new staging system for cardiac transthyretin amyloidosis.

Cardiac transthyretin (ATTR) amyloidosis is an increasingly recognized, progressive, and fatal cardiomyopathy, the natural history of which remains unclear. We sought to establish and validate a new prognostic staging system applicable to patients with both wild-type ATTR (ATTRwt) and hereditary variant ATTR (ATTRv) amyloid cardiomyopathy. Eight hundred and sixty-nine patients with cardiac ATTR amyloidosis (553 with ATTRwt and 316 with ATTRv) attending the UK National Amyloidosis Centre were stratified into three disease stages at baseline on the basis of cut points in two universally measured biomarkers, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and estimated glomerular filtration rate (eGFR). Stage I was defined as NT-proBNP ≤3000 ng/L and eGFR ≥45 ml/min, Stage III was defined as NT-proBNP >3000 ng/L and eGFR <45 ml/min, and the remainder were Stage II. The staging system was validated in a cohort of 318 patients with cardiac ATTR amyloidosis from France. Median survival among 393 (45%) Stage I patients was 69.2 months, 334 (38%) Stage II patients was 46.7 months, and 142 (16%) Stage III patients was 24.1 months (P < 0.0001). After adjusting for age, compared with Stage I, the hazard ratio (HR) for death for Stage II was 2.05 [confidence interval (CI) 1.54-2.72, P < 0.001] and for Stage III was 3.80 (CI 2.73-5.28, P < 0.001). HRs and statistical significance were little altered by transthyretin genotype and were maintained in the validation cohort. This simple, universally applicable staging system stratifies patients with both ATTRwt and ATTRv amyloid cardiomyopathy into prognostic categories. It will be of value in the design of forthcoming clinical trials of novel amyloid-specific therapies.

Cardiac Amyloidosis: Diagnosis and Treatment Strategies.

Cardiac amyloidosis in the United States is most often due to myocardial infiltration by immunoglobulin protein, such as in AL amyloidosis, or by the protein transthyretin, such as in hereditary and senile amyloidosis. Cardiac amyloidosis often portends a poor prognosis especially in patients with systemic AL amyloidosis. Despite better understanding of the pathophysiology of amyloid, many patients are still diagnosed late in the disease course. This review investigates the current understanding and new research on the diagnosis and treatment strategies in patients with cardiac amyloidosis. Myocardial amyloid infiltration distribution occurs in a variety of patterns. Structural and functional changes on echocardiography can suggest presence of amyloid, but CMR and nuclear imaging provide important complementary information on amyloid burden and the amyloid subtype, respectively. While for AL amyloid, treatment success largely depends on early diagnosis, for ATTR amyloid, new investigational agents that reduce production of transthyretin protein may have significant impact on clinical outcomes. Advancements in the non-invasive diagnostic detection and improvements in early disease recognition will undoubtedly facilitate a larger proportion of patients to receive early therapy when it is most effective.