Diagnosis Of ATTR Research Articles

Abstract 12278: A Case of Hereditary Transthyretin Amyloidosis Caused by a Rare Mutation

Introduction: Transthyretin amyloidosis (ATTR) is an underdiagnosed multisystem disease caused by dissociation of the tetrameric structure, misfolding, and deposition of the protein transthyretin. More than 100 known mutations that decrease the stability of transthyretin have been implicated in hereditary ATTR (ATTRv). Organ tropism and disease progression can vary significantly depending on the specific mutation, though cardiomyopathy and neuropathy are the most common phenotypes (Figure 1b). Reproducibly tracking the pattern of end organ dysfunction in ATTRv caused by novel mutations may help elucidate the mechanism of mutation-specific organ tropism and predict the potential disease course for patients with the same mutation. Case: The index patient is an 86-year-old male with a history of atrial fibrillation, tachy-brady syndrome requiring a pacemaker, orthostatic hypotension, peripheral neuropathy, and left ventricular hypertrophy (interventricular septum 1.4 cm prior to diagnosis) on echocardiogram. The constellation of symptoms raised the clinical suspicion for amyloidosis which was confirmed on endomyocardial biopsy. Given his age, he was presumed to have wild type ATTR by the local team. Upon referral to our center, genetic testing was performed which revealed the missense mutation c.229G>A which results in the amino acid substitution p.Gly77Arg, and has previously only been reported in one patient in Sweden. We initiated family screening and identified multiple family members with the mutation with varying phenotypes including no symptoms, cardiomyopathy, and neuropathy (figure 1a). Discussion: We identified a family with a rare c.229G>A mutation, and report on a mixed cardiomyopathy and neuropathy phenotype. Our report highlights the importance of screening for pathologic genetic variants in all patients with a diagnosis of ATTR given the treatment and prognostic implications for patients and their family members.

Assessment of incidental cardiac uptake in bone scintigraphy across Spain. ECCINGO study

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Pfizer SLU Introduction Myocardial uptake on bone scintigraphy with diphosphonates has become a useful tool for the early detection of transthyretin cardiac amyloidosis (ATTR-CM), the prevalence of which remains unknown. Purpose To assess the prevalence of myocardial uptake in bone scintigraphy in patients without previous clinical suspicion of cardiac amyloidosis (CA). Methods Observational, retrospective, multicentre study in 21 hospitals across Spain, their reference population represented 24.38% of the total national population. All scans performed for non-cardiac reasons during the months of September, October and November 2019 were reviewed. Scans with positive cardiac uptake (Perugini scores 1-3) were evaluated by a central laboratory. Medical histories of the patients with positive uptake were reviewed. Results 9864 scans were reviewed. Cardiac uptake was observed in 71 patients (0.72%) over 18 years of age (85.90% male). According to the central laboratory assessment the distribution in the Perugini grading scale was, grade 1 (23.90%), grade 2 (29.60%) and grade 3 (46.50%). No relationship between sex and Perugini grade was observed. Heart/Contralateral ratio (H/CL) was available for 24 patients with a mean of 2.1 ± 1.1 (95% CI 1.7–2.6). A third of the patients (33.80%) also presented extracardiac uptake, being the most common: bone metastasis (7.04%) abdominal wall (5.60%) and lower limbs muscular mass (4.20%). A previous heart failure (HF) diagnosis was found in the 16.90% of the patients with positive uptake, being most of them 57.10% in NYHA class II. Patients ≤ 80 y.o. were diagnosed with heart failure earlier than patients > 80 y.o. (p = 0.02) and with atrial fibrillation earlier than patients > 80 y.o. (p = 0.05). Ten patients with cardiac uptake were subsequently diagnosed with ATTR amyloidosis (ATTR-Y) with a mean delay of 10.8 months (95% CI: 6.0–16.8). All ATTR-Y patients were > 70 y.o., 90.00% were male, had left ventricular hypertrophy (LVH) compared to 25.49% of patients in whom a diagnosis of ATTR (ATTR-N) was not confirmed (p = 0.00003). Patients in the ATTR-Y group presented some episode of orthostatic hypotension and involuntary weight loss in the clinical history (30.00% in both) compared to 3.77% (p = 0.025) and 5.88% (p = 0.05) of the ATTR-N group respectively. Conclusions This national study found a prevalence of 0.72% of incidental cardiac uptake in bone scintigraphies performed for non-cardiac reasons in adult patients. The results of this study bring light on the profile of the elderly patients with incidental cardiac uptake. The referral of these patients can facilitate the early diagnosis of CA with the consequent impact on the management and prognosis of patients.

Double Trouble: A Case Of Combined Amyloid And Ischemic Cardiomyopathy

Background The management of concurrent cardiac amyloidosis (CA) and ischemic cardiomyopathy (ICM) is not well established due to the rarity of this phenomenon. We present a case of mixed cardiomyopathy with challenging clinical decision-making. Case A 76-year-old African American woman with hypertension, diabetes, and longstanding carpal tunnel syndrome presented with progressive dyspnea and was found to have decompensated heart failure attributable to a new cardiomyopathy. Initial workup revealed left ventricular ejection fraction (LVEF) of 20% and severe triple vessel coronary artery disease. Echocardiogram also demonstrated an apical-sparing strain pattern (Figure 1A) prompted concern for coexisting CA given her demographic and carpal tunnel history. A cardiac magnetic resonance (CMR) raised further concern for CA given restrictive cardiomyopathy, pericardial effusion, and characteristic late gadolinium enhancement (Figure 1B and 1C). Ultimately, transthyretin CA (ATTR) was confirmed with a positive technetium-99m-Pyrophosphate Scintigraphy (PYP) scan (Figure 1D) paired with normal serum immunofixation electrophoresis. She was evaluated by cardiothoracic surgery but deemed a prohibitively high-risk candidate for CABG due to her advanced age, ATTR diagnosis, and significant systolic dysfunction. Instead, she was diuresed and started on guideline-directed medical therapy, which she tolerated unusually well despite her diagnosis of ATTR. Using Impella CP for temporary mechanical circulatory support, she underwent high-risk percutaneous coronary intervention to the distal left main artery extending into the proximal left circumflex. She was discharged on dual antiplatelet therapy. During outpatient follow-up in the Multidisciplinary CA Clinic, genetic testing revealed a pathogenic V122I mutation indicative of hereditary ATTR. She was started on tafamidis after nerve conduction studies did not demonstrate neuropathy. The combination of guideline-directed medical therapy, successful percutaneous revascularization, and ATTR-directed treatment resulted in remarkable improvement (NYHA Class II, LVEF 50% from NYHA IV, LVEF 20%). Conclusion Further investigation is needed to define optimal treatment strategies in patients with coexisting ischemic and amyloid cardiomyopathy. Until then, a multidisciplinary approach must be utilized to individualize the care of such patients. The management of concurrent cardiac amyloidosis (CA) and ischemic cardiomyopathy (ICM) is not well established due to the rarity of this phenomenon. We present a case of mixed cardiomyopathy with challenging clinical decision-making. A 76-year-old African American woman with hypertension, diabetes, and longstanding carpal tunnel syndrome presented with progressive dyspnea and was found to have decompensated heart failure attributable to a new cardiomyopathy. Initial workup revealed left ventricular ejection fraction (LVEF) of 20% and severe triple vessel coronary artery disease. Echocardiogram also demonstrated an apical-sparing strain pattern (Figure 1A) prompted concern for coexisting CA given her demographic and carpal tunnel history. A cardiac magnetic resonance (CMR) raised further concern for CA given restrictive cardiomyopathy, pericardial effusion, and characteristic late gadolinium enhancement (Figure 1B and 1C). Ultimately, transthyretin CA (ATTR) was confirmed with a positive technetium-99m-Pyrophosphate Scintigraphy (PYP) scan (Figure 1D) paired with normal serum immunofixation electrophoresis. She was evaluated by cardiothoracic surgery but deemed a prohibitively high-risk candidate for CABG due to her advanced age, ATTR diagnosis, and significant systolic dysfunction. Instead, she was diuresed and started on guideline-directed medical therapy, which she tolerated unusually well despite her diagnosis of ATTR. Using Impella CP for temporary mechanical circulatory support, she underwent high-risk percutaneous coronary intervention to the distal left main artery extending into the proximal left circumflex. She was discharged on dual antiplatelet therapy. During outpatient follow-up in the Multidisciplinary CA Clinic, genetic testing revealed a pathogenic V122I mutation indicative of hereditary ATTR. She was started on tafamidis after nerve conduction studies did not demonstrate neuropathy. The combination of guideline-directed medical therapy, successful percutaneous revascularization, and ATTR-directed treatment resulted in remarkable improvement (NYHA Class II, LVEF 50% from NYHA IV, LVEF 20%). Further investigation is needed to define optimal treatment strategies in patients with coexisting ischemic and amyloid cardiomyopathy. Until then, a multidisciplinary approach must be utilized to individualize the care of such patients.

Inter-observer reproducibility and intra-observer repeatability in 99mTc-pyrophosphate scan interpretation for diagnosis of transthyretin cardiac amyloidosis

AimThe purpose of this study was to determine the inter- and intra-observer variability in 99mtechnetium-pyrophosphate (99mTc-PYP) scan interpretation for diagnosis of transthyretin cardiac amyloidosis (ATTR). Methods and ResultsOur study cohort comprised 100 consecutive subjects referred for 99mTc-PYP imaging based on clinical suspicion of ATTR cardiac amyloidosis. Myocardial 99mTc-PYP uptake was assessed by both visual (comparison of myocardial to rib uptake) and semi-quantitative (heart-to-contralateral lung uptake ratio, H:CL) methods. Twenty scans were analyzed twice, at least 48 hours apart, by each of two independent observers. Patients with visual scores of ≥ 2 on planar imaging as well as myocardial uptake on SPECT/CT were classified as ATTR positive. Diagnosis of ATTR by visual 99mTc-PYP grade was perfectly reproducible [concordance: positive and negative scans 100% (53/53 and 47/47, respectively). Both inter- and intra-observer correlations for H:CL ratio (r2 = 0.90, 0.99 (Observer 1) and 0.98 (Observer 2), respectively) and repeatability values on Bland–Altman plots were excellent. The coefficient of variation (%) for Observers 1 and 2 was 3.21 (2.14 to 4.29) and 7.49 (4.95 to 10.09), respectively. In addition, there was 100% concordance in positive and negative scan interpretation by visual grading between novice CV imagers (< 3 years’ experience) and an experienced CV imager (10 years’ experience). ConclusionsThis study showed excellent inter-observer reproducibility and intra-observer repeatability of 99mTc-PYP visual scan interpretation and H:CL ratio for diagnosis of cardiac ATTR amyloidosis. Cardiac ATTR amyloidosis can be diagnosed reliably using 99mTc-PYP SPECT/CT by novice and experienced CV imagers.

Are there predictor variables for the diagnosis of transthyretin cardiac amyloidosis?

Abstract Introduction Transthyretin cardiac amyloidosis (ATTR) can be reliably diagnosed in the absence of histology if grade 2 or 3 cardiac uptake is demonstrated on 99mTc-DPD scan (DPD) in the absence of a detectable monoclonal component. Diagnosis requires a high degree of clinical suspicion in the presence of often non-specific findings and that it may be one of the reasons to under-diagnose ATTR. The aim of the study is to identify clinical, analytical and ECG variables that best predict a positive DPD result. Methods This is a multicentre retrospective study including all patients undergoing consecutive 99mTc-DPD scintigraphy in a reference area of 750,000 inhabitants between January 2016 and January 2021 for suspected ATTR. AL amyloidosis patients were excluded. Clinical, analytical, ECG and echocardiographic data were analyzed. We identified variables that independently predicted a positive DPD study using a multivariable logistic regression analysis. Receiver Operating Curve (ROC) analysis and the Area under the Curve (AUC) were calculated to assess the discrimination capacity of the model to predict a positive DPD study. Results DPD scans from a total of 181 patients were analyzed. Mean age of the sample: 78 years (42–96), 100% caucasians, 77% male. 54.7% (N=99) had a positive DPD study (defined as grade 2 or 3 Perugini uptake) and 45.3% (N=82) were negative. Independent predictors of a positive study were age, male gender, left ventricular septum thickness, any grade of atrioventricular block, low QRS voltage, Carpal tunnel syndrome, history of hypotension or need to lower antihypertensive drugs and a NT-proBNP value above 1800 pg/ml (See Table 1). The diagnostic accuracy of the model was excellent, with an AUC of 0.92 (IC 95% 0.87–0.96) (see Figure 1). Conclusions There are clinical-analytical factors and ECG and echocardiogram findings accessible in daily clinical practice that are able to predict a positive result on cardiac scintigraphy requested for suspected ATTR. Identifying these factors may improve the non-invasive diagnosis of ATTR. Funding Acknowledgement Type of funding sources: None. Table 1. Multivariable logistic regression analysFigure 1. ROC curve

P825 Multi-modality imaging for noninvasive diagnosis of transthyretin amyloid cardiomyopathy-single centre experience

Abstract Background Thransthyretin amyloidosis (ATTR) is a rare progressive disease that may present as heart failure with preserved ejection fraction, severe aortic stenosis, hypertrophic cardiomyopathy (HCM) or resctrictive cardiomyopathy. There are two types of ATTR: hereditary ATTR (hATTR) caused by mutations in the TTR gene and wild-type ATTR (wtATTR) resulting from deposition of wild-type TTR protein. Purpose We describe the clinical heterogeneity of ATTR patients from our centre diagnosed noninvasively in 2018-2019. Methods All patients presented intensive cardiac uptake at 99mTc-DPD scintigraphy. Light chain amyloidosis was excluded. Results 8 patients were diagnosed with ATTR (Table 1). Three unrelated male patients were diagnosed with hATTR due to rare mutations: 2 of them had Phe33Leu, 1 patient had Glu89Lys mutation. Five patients (males) were diagnosed with wtATTR. Age of onset differed among the patients. Characteristic clinical features included cardiomyopathy with increased left and right ventricular wall thickness. Only 2 patients had restrictive filling pattern, 3 patients had atrial fibrillation. Laboratory examination showed increased level of troponin T and NT-proBNP. Three patients had bilateral carpal tunnel syndrome. Thanks to DPD-scintygraphy we excluded ATTR in two patients with false-positive results of histological exam for TTR-related amyloid deposits. Conclusions Although ATTR is known for its broad clinical spectrum, patients from our center presented mostly as HCM phenocopies but in different stages of heart failure. Appropriate diagnosis of ATTR is crucial and have direct therapeutic impact. Echocardiography raise the suspicion of amyloid cardiomyopathy, while other imaging technique (DPD-scintigraphy) confirm it or exclude it in noninvasive way. Patient 1 2 3 4 5 6 7 8 Mutation Glu89Lys Phe33Leu Phe33Leu wild type wild type wild type wild type wild type Sex male male male male male male male male Age of onset 57 56 55 77 78 80 77 76 Electrocardiogram AF low QRS voltage low QRS voltage AF, RBBB LVH LVH pseudoinfarct pattern, low QRS voltage AF, LVH Maximal wall thickness [mm] 23 20 18 28 22 23 18 20 LVEF% 45 40 40 60 65 60 45 55 Asymmetric hypertrophy pattern + - - - + + - + NYHA III II II II III II II II NT-proBNP pg/ml 2122 1200 1500 2755 222 2630 2426 hs-Troponin T ng/l 50 98 42 65 35 63 64 Abstract P825 Figure 1

Application of nuclear medical imaging in the diagnosis of myocardial amyloidosis

Amyloidosis is a disease caused by abnormal deposition of amyloid protein, and the main types of amyloidosis involving myocardium are light chain amyloidosis (AL) and transthyretin-related amyloidosis (ATTR). Different types of myocardial amyloidosis have different prognosis and treatment methods. Therefore, early diagnosis and classification are particularly important. Nuclear medical imaging can diagnose and classify myocardial amyloidosis noninvasively. Radiotracers for bone scintigraphy has high sensitivity and specificity for the diagnosis of ATTR, and have certain value for prognosis. Sympathetic innervation imaging tracers can detect cardiac sympathetic innervation, which may show myocardial involvement of amyloidosis earlier than bone scintigraphy. Amyloid protein specific imaging agent, which was first used in the diagnosis of amyloidosis in nervous system, has also yielded good results from preliminary studies in myocardial amyloidosis, and the diagnostic specificity in AL is slightly better than that in ATTR. This review introduces the application of nuclear medical imaging in myocardial amyloidosis. Key words: Amyloidosis; Myocardium; Radionuclide imaging; Positron-emission tomography; 3-idobenzylguanidine; Amyloid; Trends

Indications and diagnostic yield of endomyocardial biopsies for unexplained cardiomyopathy, a single center experience

Background: Endomyocardial biopsies (EMBs) remain the golden standard to diagnose underlying pathophysiologic process in heart failure (HF), when potential therapeutic decisions cannot be made by non-invasive techniques. However, changes in the field of non-invasive diagnostic testing might have an impact on the need for performing an EMB in certain scenarios.Methods: We performed a retrospective analysis of consecutive EMBs performed in a single, non-academic, tertiary-care centre. EMBs were performed between February 2009 and March 2018. Baseline characteristics including non-invasive imaging and hemodynamic profile were assessed. Indications of EMBs were analysed in accordance with the 2007-AHA/ACC/ESC-scientific statement on EMBs.Results: A total of 57 patients (74% male) were included. The overall diagnostic yield was 58%, with a trend towards a higher yield in left-side (64%) versus right-side EMBs (45%; p = .346). The majority of patients (88%) underwent EMBs for a class IIa-recommendation, 9% for a class-I recommendation and the remaining patients for a class IIb-indication. Of the EMBs for a class IIa indication, 82% (n = 47) was for an unexplained restrictive cardiomyopathy, in which 53% (n = 25) revealed a diagnosis (of whom n = 23 patients had amyloidosis). Subtyping of the EMBs with a pathologic diagnosis of amyloidosis revealed that 52% (n = 12) had transthyretin amyloidosis (ATTR) and 43% (n = 10) had light-chain amyloidosis (AL). Overall one major (1.7%) and one minor (1.7%) complication occurred following the EMB-procedure.Conclusions: When following the AHA/ACC/ESC-scientific statement on EMBs, the performance of EMBs had a high diagnostic yield, with acceptable complication rates. However, in patients presenting with an unexplained restricted cardiomyopathy, technetium-labelled bone scanning could offer a non-invasive approach to establishing the diagnosis of ATTR, mitigating the need for EMBs in a subset of patients.

CLINICAL MASKS OF AMYLOIDOSIS WITH THE HEART INVOLVEMENT: MODERN DIAGNOSTIC ISSUES

In amyloidosis AL-type the heart involvement is most common; this type is specific with predecessor proteins of light immunoglobulin chains, transthyretin (TTR), mutant and wild (senile) types. Most common clinical form is restriction cardiomyopathy. Aim. To assess the recent specifics of diagnostics, due to broader abilities of novel methods. Material and methods. Five 40-79-year old patients with various morpho￾functional variants of heart involvement and typical ECG signs (low QRS voltage, QS, non-sufficient R increase, absence of left ventricle (LV) hypertrophy signs) to verify the suspected amyloidosis, underwent EchoCG, immunohistochemistry of blood and urine for light chains of immunoglobulines, biopsy of subcutaneous fat and mucose of the gum/gut; MDCT of the heart (n=3), MRI (n=1), scintigraphy with 99Tc-pyrophosphate with assessment in 1 hour after indicator injection (n=1), endomyocardial biopsy (n=2), titer of anticardial antibodies assessment (n=2), DNA-diagnostics (n=1). Results. The diagnosis of amyloidosis was confirmed in all cases. Its morpho-functional types were RSMP with LV hypertrophy, hypertrophic cardiomyopathy (HCMP) with no restriction but progressing fall of ejection fraction (EF), dilation cardiomyopathy (DCMP), severe hypertrophy with low EF, minimal hypertrophy with no restriction and systolic dysfunction. There was AL-type diagnosed (n=2, one case with myopathy mimicking “dermatomyositis”), mutant TTR (n=1, novel mutation Thr40Asn) and wild TTR (n=2) types. The leading clinical signs were biventricular heart failure and atrial rhythm disorders: sustained atrial fibrillation in 3 patients (in one, before amyloidosis verification, the RF-modification was done as “labyrinth” surgery, isthmus block with no established efficacy) and frequent supraventricular extrasystoly in one another. To the patient with mutant ATTR the ICD was implanted with further replacement by CRT-D, and increase of EF from 24% to 31% was achieved (patient is followed-up for 8 years). As the morphological equivalent of severe systolic dysfunction in this patient the amyloid deposition in myocardial arteries could be suspected. MDCT revealed typical subendocardial delayed deposition in 2 from 3 patients, in one case there was also diffuse deposition of 99Tc-pyrophosphate in myocardium. Antibodies to the nuclei of cardiomyocytes (specific ANF) was found in a female patient with AL-type and DCMP, which made not to rule out myocarditis. Conclusion. Cardiac amyloidosis might present as any structural and functional variant of cardiomyopathy, including DCMP. The most specific is diffuse hypertrophy with restriction and EF decrease, but with no LV dilation. Early fall of contractility, ischemia symptoms and LV dilation might be the result of amyloid lesion of small arteries. In the presence of any systemic presentations together with “HCMP”, “RCMP”, “DCMP” there must be amyloidosis ruled out. Myocardial scintigraphy with 99Tc-pyrophosphate is a method of use for the diagnosis of ATTR; MDCT of the heart — for any type of amyloidosis. Cardiac amyloidosis might be followed by significant type of the titer of specific ANF (secondary reaction or concomitance with myocarditis?).