TTR Cardiac Amyloidosis Research Articles

Transthyretin Cardiac Amyloidosis: Insights into Wild-Type Variants and Familial Amyloid Cardiomyopathy

Transthyretin (TTR) cardiac amyloidosis is a progressive condition characterized by amyloid fibril deposition in the heart, leading to heart failure. This review focuses on insights into wild-type (ATTRwt) and familial (ATTRm) variants of TTR amyloidosis. The pathophysiology involves TTR tetramer destabilization, monomer misfolding, and amyloid fibril formation. Therapeutic advances, including TTR stabilizers like tafamidis and Diflunisal, and gene-silencing agents such as patisiran and inotersen, show promise in managing the disease. Despite these advancements, early diagnosis remains challenging, and side effects of current therapies necessitate the development of safer, more effective treatments. Future research should focus on novel therapies, improved diagnostic methods, and personalized treatment strategies to enhance patient outcomes. This review underscores the importance of continued innovation and collaboration in tackling TTR cardiac amyloidosis.

PERCUTANEOUS EDGE–TO–EDGE REPAIR OF MITRAL REGURGITATION IN CARDIAC AMYLOIDOSIS: DO IT BUT NOT TOO MUCH

Abstract We report the case of a 68 year old man with history of wild type TTR cardiac amyloidosis, treated with tafamidis since 1 year, symptomatic for advanced cardiac failure, already in optimal medical treatment, CRT–D, oral anticoagulation for permanent atrial fibrillation. The patient was hospitalised in our intensive care unit for refractory NYHA IV cardiac failure, anuria, very low ejection fraction combined with severe mitral regurgitation. He was treated with inotropes and diuretics then levosimendan however he remained in very critical state and we discussed the opportunity to reduce the mitral regurgitation by percutaneous edge to edge repair. In this setting of restrictive physiology literature is not unanimous and preload reduction secondary to mitral regurgitation treatment may sometimes be deleterious. We decided to offer our patient edge to edge repair by targeting a moderate reduction of mitral regurgitation and also considering some challenges linked to this pathology as atrial septal involvement with ovalis fossa relevant thickness. The procedure was successful with a reduction of mitral regurgitation grade from severe to mild–to moderate and this allowed the patient to re equilibrate his hemodynamic balance and he was able to be dismissed with a short term follow up program.

Patisiran is beneficial for the treatment of TTR cardiac amyloidosis.

Patisiran is beneficial for the treatment of TTR cardiac amyloidosis.

Hereditary transthyretin cardiac amyloidosis proven by endomyocardial biopsy: a single-centre retrospective study and literature review

Background This study aimed to report the genotypes and phenotypes of hereditary transthyretin cardiac amyloidosis (hATTR-CA) in a Western Chinese cohort and review the genetic profiles of this disorder in the Chinese population. Methods Transthyretin (TTR) gene sequencing of probands diagnosed with TTR cardiac amyloidosis and their relatives was performed at West China Hospital of Sichuan University from January 2018 to December 2021. All patients underwent endomyocardial biopsy for light and electron microscopy examinations. Clinical and essential examination materials were retrospectively collected and analysed. Results TTR gene alteration was demonstrated in five probands and their two relatives. Three TTR variants were identified, namely, Ser23Asn, Glu54Leu and Thr60Ala. This study is the first to report Glu54Leu as pathogenic mutations in Chinese hATTR-CA patients. The Ser23Asn mutation was the most common mutation in this cohort. Five probands, including two males and three females, were all ethnic Han-Chinese. The median age at diagnosis and delay in diagnosis (interval from onset to diagnosis) was 56 years (range, 54–69 years) and 8 years (range, from 1 to 30 years), respectively. Three cases showed a defined family history of amyloidosis. Endomyocardial biopsies and TTR immunohistochemistry showed positive results in all patients. Two probands died 17.0 months and 21.0 months after diagnosis. Conclusions We identified one novel TTR variants causing hATTR-CA in the West Han Chinese population. To avoid misdiagnosis or delayed diagnosis of hATTR-CA, TTR genotypic screening and endomyocardial biopsy should be performed as soon as possible in cases with heightened clinical suspicion.

P203 PLASMA TRANSTHYRETIN FORMS IN PATIENTS WITH WILD–TYPE TRANSTHYRETIN CARDIAC AMYLOIDOSIS: INFLUENCED OF TAFAMIDIS TREATMENT

Abstract Introduction Transthyretin (TTR) is a plasma protein that transports thyroxin and retinol complexed to retinol–binding protein (RBP). TTR misfolding and aggregation can lead to the extracellular deposition of amyloid in the myocardium, causing TTR cardiac amyloidosis (ATTR–CA). Aim of this study is to develop a native electrophoretic method to characterize circulating TTR forms in plasma samples of ATTR–CA patients, before and after administration of tafamidis, a TTR stabilizer. Material & Methods Plasma samples from patients affected by wild–type ATTR amyloidosis (ATTRwt, n=10) were collected before (T0) and during tafamidis treatment at 14, 30 and 90 days. Plasma samples of sex– and age–matched healthy controls (n=6) were also collected. All samples were separated on a native 4–20% Tris–Gly polyacrylamide gel. Western blot analysis was performed with anti–TTR or anti–RBP antibodies. Proteins were detected by Clarity ECL substrate. ImageLab software was used for image acquisition and densitometric analysis of the blots. Total TTR (mg/dl) and RBP (mg/dl) were quantified by nephelometry. Results In both groups, the most represented forms were: TTR dimers or trimers (37–50kDa), TTR tetramers complexed with RBP protein in 1:1 (75kDa,) or 1:2 ratio (100kDa), and high molecular weight aggregates (>150kDa). RBP protein was detectable in association with TTR tetramers and some of the TTR aggregates (250kDa, 480kDa). Based on TTR electrophoretic pattern at T0, patients could be divided in 2 groups: ATTR–1, characterised by the presence of TTR tetramers (55kDa), and ATTR–2, characterised by its absence. The ATTR–1 group showed also higher levels of total TTR in comparison with ATTR–2 (mean±SD 25.5±3.8, 16.6±4.2 respectively, p=0.004), while plasma RBP levels were similar (5.1±0.7, 5.1±1.4 respectively). The electrophoretic patterns of ATTR–1 at T0, as well as TTR and RBP levels were comparable to those of controls (TTR 22.6±3.8, RBP 4.4±0.9). Tafamidis treatment was associated with a progressive increase of total TTR levels both in ATTR–1 and –2 (T90 31.4±5.8, 28.7±6.8) but the 2 groups continued to be distinguishable by the electrophoretic pattern. Conclusions The native electrophoresis allowed us to detect diverse circulating TTR forms and to classify patients in 2 groups according to their electrophoretic pattern. TTR quali/quantitative evaluation by electrophoresis could represent a valid tool to assess the individual pharmacological response to tafamidis.

Cellular environment of TTR deposits in an animal model of ATTR-Cardiomyopathy.

Introduction: Cardiac amyloidoses are the most fatal manifestation of systemic amyloidoses. It is believed the number of cases to be greatly underestimated mostly due to misdiagnosis. Particularly, the involvement of TTR V30M in the heart of ATTRV30M amyloidosis has not been completely understood specifically in terms of implicated cellular pathways, heart function and cardiac physiology. In the present work we proposed to characterize TTR V30M cardiac involvement particularly at the tissue cellular level in a mouse model. Methods: HSF ± hTTR V30M mice, a model that expresses human TTRV30M in a Ttr null background, widely used for the characterization and modulation of neurological features of ATTRV30M amyloidosis was used. SDS-PAGE of cardiac homogenates followed by Western blot was performed. Immunohistochemistry and double immunofluorescence analyses were carried out to determine TTR deposition pattern and sub-localization. Results: Western blots were able to detect TTR in its monomeric state at ∼14kDa. Immunofluorescent images showed TTR was found mostly in the intercellular spaces. Blood contamination was excluded by CD31 staining. Tissues were Congo Red negative. Upon TTR and macrophages (CD68) staining in the cardiac tissue a clear tendency of macrophage convergence to the tissue regions where TTR was more abundant was observed. Moreover, in some instances it was possible to detect co-localization of both fluorophores. Cardiac fibroblasts were stained with PDGFr-alpha, and here the co-localization was not so evident although there was some degree of co-occurrence. The hearts of transgenic mice revealed higher content of Galectin-3. Conclusion: This animal model and associated features observed as result of cardiac TTR deposition provide a promising and invaluable research tool for a better understanding of the implicated pathways that lead to the lethality associated to TTR cardiac amyloidosis. New therapeutic strategies can be tested and ultimately this will lead to improved treatment alternatives capable of increasing patient's quality of life and life expectancy and, hopefully to eradicate a condition that is silently spreading worldwide.

396 ARE BLOOD LEVELS OF RETINOL BINDING PROTEIN USEFUL IN DIAGNOSING ATTR-CA? A NEGATIVE STUDY, SO FAR

Abstract Introduction Retinol binding protein (RBP) is a protein synthesized in the liver which forms, along with transthyretin (TTR) the retinol-transport-complex. This complex ligates retinol and thyroxine and transports them in the human plasma. TTR is a protein longer and heavier than RBP. It ligates RBP preventing its renal filtration. Our hypothesis is that the relationship between RBP and TTR is dual: TTR avoids renal filtration of RBP, but also RBP itself, functioning as an endogenous ligand, has an action on TTR by stabilizing and avoiding TTR misfolding. Misfolded TTR proteins form amyloid fibrils rich in beta-cross-sheets that can infiltrate healthy tissues altering their physiology. The infiltration of these fibrils in the cardiac tissue leads to the well-known condition of TTR cardiac amyloidosis (ATTR CA). Our hypothesis is that the lack of TTR stabilization that can happen with low blood levels of RBP is a risk factor for developing ATTR CA. The main goal of our study is to understand if high or normal values of RBP can help exclude any pathological condition linked to the accumulation of misfolded TTR proteins. Methods All patients referred to our Cardiomyopathy Clinic with a clinical and echographic suspicion of CA were consecutively enrolled. All patients underwent a complete diagnostic workup in order to confirm or exclude CA, comprehending lab tests (including RBP4), SPECT, cardiac MR, genetic testing and cardiac biopsy as recommended by current recommendations. At the end of the diagnostic process, patients with ATTR-wt CA were enrolled as cases, and patients with no CA were considered as controls. Patients with ATTR-mutated CA or AL CA were excluded from the present analysis. Results Fifty-nine consecutive patients (42 males, age 77+/-13 years) were enrolled. Of those, 27 had a definitive diagnosis of ATTR-wt CA, while 32 had another diagnosis. Mean levels of RBP4 were not different between patients with and without CA (5.4+/-1.9 vs. 5.0+/-1.8 mg/dl; p=ns) as were Troponin I, BNP and NT-proBNP levels (all p=ns). Among patients with a definitive diagnosis of ATTR-wt CA and a positive SPECT, RBP4 levels were similar between Perugini 2 and 3 scores (5.4+/-2.1 vs. 5.6+/-2.0 mg/dl; p=ns). Discussion From our findings, it seems that there is no significant correlation between low levels of RBP and the presence of ATTR CA as we found no difference in the distribution of RBP levels between cases and controls. It also did not seem to be a useful marker to stratify the levels of myocardial infiltration as long as there is no difference in RBP between Perugini score 2 and 3.

Abstract 14185: Higher Rates of Heart Failure Hospitalizations for V142I ATTR-CM Patients With Atrial Arrhythmias and Conduction Disease

Introduction: TTR cardiac amyloidosis (ATTR-CM) is a progressive, infiltrative cardiomyopathy that is characterized by the deposition of amyloid fibril extracellularly in the myocardium. Patients with ATTR-CM are known to be at higher risk for arrhythmias and conduction disease, likely due to changes in the cardiac anatomy and disruption of the conduction system by amyloid fibrils. Our study aims to determine whether presence of an arrhythmia or conduction disease is associated with mortality and heart failure hospitalizations in patients with ATTR-CM and V142I mutation. Hypothesis: Patients with arrhythmia or conduction disease will have higher rates of heart failure hospitalizations (HFH) and mortality than those without it. Methods: We conducted a retrospective chart review of patients diagnosed with ATTR-CM with V142I mutations enrolled in Emory University's Cardiac Amyloidosis Clinic between January 2014 and April 2022. Kaplan-Meier (KM) curves stratified by presence of atrial arrhythmia, ventricular arrhythmia, or conduction disease were generated for mortality and first HFH within 2 years of initial diagnosis. Log-rank test was used to compare KM curves. A p-value < 0.05 was considered significant. Results: 111 patients were identified to have ATTR-CM with V142I mutation. 51.4% (57) of the patients had an atrial arrhythmia (fibrillation or flutter), 46.8% (52) had conduction abnormalities (defined as second or third degree heart block). 44.1% (49) had ventricular arrhythmias (including NSVT, sustained VT, and/or VF). Patients who had atrial arrhythmia and conduction disease were more likely to have HFH within 2 years compared to those who did not (p = 0.0011, p = 0.044 respectively). Patients with atrial arrhythmia, ventricular arrhythmia, or conduction disease were not at higher risk of mortality within 2 years (p=0.21, p=0.71, p=0.66 respectively). Conclusions: For patients with ATTR-CM with V142I mutation, atrial arrhythmia and conduction disease were risk factors for HFH within 2 years. Atrial and ventricular arrhythmia and conduction disease were not associated with higher mortality within 2 years.

Global and regional left ventricular deformation evaluation with feature tracking in transthyretin cardiac amyloidosis. Comparison with echocardiographic findings

Abstract Background Diagnosis of cardiac amyloidosis (CA) is basically based on imaging techniques. Transthoracic echocardiography (TTE) is crucial to raise suspicion of this disease through detection of the classical features. An specific left ventricular (LV) deformation pattern with apical sparing (“cherry on top”) has been described on speckle tracking (ST) TTE. However, there is no data regarding the role of the LV global and regional analysis with the new tool feature tracking (FT) of cardiac magnetic resonance (CMR) in CA. Purpose Our aim is to analyze the concordance of LV deformation between ST-TTE and FT-CMR. Methods Consecutive patients with definitive diagnosis of transthyretin (TTR) CA, based on DPD scintigraphy, and imaging evaluation with TTE and CMR were retrospectively included. LV volumes and ejection were calculated from both TTE and CMR following the ongoing recommendations. Global and segmental longitudinal strain values were obtained from apical 2-, 3- and 4-chambers projections on TTE, while the same parameters were calculated on the same cine views of CMR using a dedicated software of FT analysis. Student t-test was used to compared mean measurements derived from both imaging techniques. Apical index was calculated as the ratio between apical and basal-mid longitudinal values. Moreover, agreement was established using Passing-Bablok regression analysis. Results 27 patients (80 years-old, 88% men) with definitive diagnosis of TTR CA from our tertiary hospital were included. Regarding echocardiographic findings, 80% showed concentric LV hypertrophy with low normal ejection fraction in the majority (52±10%). When longitudinal LV strain parameters were compared (Table 1), no differences were noted in global and apical values whereas basal and mid measurements were higher from CRM resulting in different apical indexes. Although 42% showed a typical “cherry on top” pattern in ST analysis, in only 18% of the FT apical sparing was detected. Consistently, decremental pattern was observed in 60% of TTE and in 20% of CMR. Concordance analysis with Passing-Bablok showed no constant or proportional differences, meaning both techniques were comparable. Conclusions Among patients with TTR CA there were no differences in global longitudinal LV strain analysis between ST-TTE and FT-CMR. Nevertheless, discordance in regional parameters resulted in a less frequent detection of apical sparing in CMR. Funding Acknowledgement Type of funding sources: None.

Analysis of myocardial function by deformation imaging in patients with transthyretin gene mutation

Abstract Introduction Hereditary transthyretin (TTR) amyloidosis is a rare disease that can affect various organs. The early identification of cardiac involvement through echocardiography allows to corroborate the diagnosis and to start therapy at an early stage. Purpose The aim of our study was to detect early signs of cardiac involvement in patients with TTR gene mutation and neurological phenotype or absence of any organ disease (carriers) compared to patients with TTR gene mutation and cardiac amyloidosis (CA). Material and methods An observational study was conducted on a sample of 31 patients with TTR gene mutation. Patients were divided into 3 groups (23% CA, 42% amyloid neuropathy and 35% carriers). All patients underwent echocardiography with evaluation of left ventricular myocardial deformation indices (apical/basal strain ratio and relative apical sparing). Results Carriers and patients with amyloid neuropathy had normal left ventricular systolic and diastolic function. Analyzing left ventricular longitudinal global strain (GLS) we didn't find significant differences between carriers and neuropathy, but we found a significant difference about apical/basal strain ratio and relative apical sparing (respectively 1.33±0.20 vs 1.58±0.25, p value 0.001 and 0.62±0.07 vs 0.72±0.08, p value 0.039). Conclusion Relative apical sparing is specific to identify CA; the apical/basal ratio seems to gradually increase from carriers to patients with cardiac amyloidosis and it could be used to monitor patients with TTR mutation, before developing CA. Funding Acknowledgement Type of funding sources: None.

EFFECT OF TAFAMIDIS ON GLOBAL LONGITUDINAL STRAIN USING A CORRECTION METHOD IN TRANSTHYRETIN CARDIAC AMYLOIDOSIS

Various pharmacological options have been developed for TTR cardiac amyloidosis (TTR-CA), targeting different phases of the disease process. Tafamidis is a stabilizer of the TTR molecule that reduces CV mortality and CV-related hospitalization in patients with either wild-type or hereditary TTR CM. Echocardiography is an important tool in the diagnosis and follow-up of patients with TTR-CA, however, no echocardiographic markers of response to treatment with Tafamidis have been identified to date.

Analysis of lumbar spine stenosis specimens for identification of amyloid.

Lumbar spinal stenosis (LSS) is a common reason for spine surgery in which ligamentum flavum is resected. Transthyretin (TTR) amyloid is an often unrecognized and potentially modifiable mechanism for LSS that can also cause TTR cardiac amyloidosis. Accordingly, older adult patients undergoing lumbar spine (LS) surgery were evaluated for amyloid and if present, the precursor protein, as well as comprehensive characterization of the clinical phenotype. A prospective, cohort study in 2 academic medical centers enrolled 47 subjects (age 69 ± 7 years, 53% male) undergoing clinically indicated LS decompression. The presence of amyloid was evaluated by Congo Red staining and in those with amyloid, precursor protein was determined by laser capture microdissection coupled to mass spectrometry (LCM-MS). The phenotype was assessed by disease-specific questionnaires (Swiss Spinal Stenosis Questionnaire and Kansas City Cardiomyopathy Questionnaire) and the 36-question short-form health survey, as well as biochemical measures (TTR, retinol-binding protein, and TTR stability). Cardiac testing included technetium-99m-pyrophosphate scintigraphy, electrocardiograms, echocardiograms, and cardiac biomarkers as well as measures of functional capacity. Amyloid was detected in 16 samples (34% of participants) and was more common in those aged ≥ 75 years of age (66.7%) compared with those <75 years (22.3%, p < 0.05). LCM-MS demonstrated TTR as the precursor protein in 62.5% of participants with amyloid while 37.5% had an indeterminant type of amyloid. Demographic, clinical, quality-of-life measures, electrocardiographic, echocardiographic, and biochemical measures did not differ between those with and without amyloid. Among those with TTR amyloid (n=10), one subject had cardiac involvement by scintigraphy. Amyloid is detected in more than a third of older adults undergoing LSS. Amyloid is more common with advancing age and is particularly common in those >75 years old. No demographic, clinical, biochemical, or cardiac parameter distinguished those with and without amyloid. In more than half of subjects with LS amyloid, the precursor protein was TTR indicating the importance of pathological assessment.

Census of Cardiac Uptake on Routine Bone Scintigraphy, a Methodology to Assess the Prevalence of the TTR Amyloidosis

Objective: Transthyretin cardiac amyloidosis is a rapidly progressive disease, remains underdiagnosed, and has long been considered a rare disease. Diagnosis decision making cannot be based on echography and MRI findings alone because they lack accuracy. However, it requires invasive test of myocardial or fat pad biopsies. Thus, the diagnosis is challenging, and the non-invasive scintigraphic technique using bone-seeking radiopharmaceuticals has become a cornerstone in the workup revealing a myocardial uptake. Our work consists of a single institution retrospective study aiming to estimate the bone scintigraphies, and the prevalence of the transthyretin cardiac amyloidosis in our population. Methods: We have carried out a census of the incidental cardiac uptake on routine bone scintigraphy in 2211 consecutive patients enrolled between 2009 and 2020, mostly performed for oncologic purposes. The visual analysis of the scintigraphic images classifies the cardiac uptake into 3 levels of gradation and evokes the diagnosis of the TTR cardiac amyloidosis in grades 2 and 3. Results: Different grades of myocardial uptake were observed in 1.37 % of all patients. Prevalence of uptake was 0.37% in the 50th, increased dramatically at the 60th (2.49%), and reached 4% above the age of 80. The diagnostic grades 2 and 3 cardiac uptakes were identified in 5 patients (0.23% of overall patients) ranging between 56- and 91-y-old. Our results concord with the trend of disease increases with age. Conclusion: The careful analysis of the bone scintigraphy of all incoming adult patients should allow to make the diagnosis of the TTR cardiac amyloidosis at a preclinical stage and establish new effective treatments. Our results provide an estimate of the number of patients that could be diagnosed and improve the awareness of the corresponding prevalence in our population. In this way, multicentric studies should be implemented by enrolling large cohorts of bone scintigraphy cases.

Racial Differences in Val122Ile-Associated Transthyretin Cardiac Amyloidosis

The valine-to-isoleucine substitution (Val122Ile) is the most common variant of transthyretin (TTR) amyloidosis in the United States, affecting primarily individuals of African descent. This variant has been identified recently in a cluster of white individuals in Italy. Clinical phenotype and chamber performance of Black and white individuals with Val122Ile TTR cardiac amyloidosis (ATTR-CA) were compared. Compared to white patients (n = 17), Black individuals (n = 53) had lower systolic blood pressures (110 vs 131 mmHg, <0.001), reduced pulse pressures (41 vs 58 mmHg; P < 0.001), and impaired renal function (eGFR 46 vs 67 mL/min/1.73m2; P < 0.001) at presentation. Systolic properties and arterial elastance were similar. Black patients had end-diastolic pressure-volume relationships that were shifted upward and leftward relative to those of white patients, indicating reduced left ventricular chamber capacitance. Pressure-volume area at a left ventricular end-diastolic pressure of 30 mmHg was lower in Black than in white individuals (8055 mmHg/mL vs 11,538 mmHg/mL; P = 0.008). Despite presenting at ages similar to those of white patients, Black individuals with Val122Ile-associated ATTR-CA had a greater degree of cardiac chamber dysfunction at the time of diagnosis due to impaired ventricular capacitance. Whether these differences are attributable to amyloidosis or other cardiovascular disease requires further study.

Registry of Transthyretin Amyloidosis in the State of São Paulo (REACT-SP)

Background Amyloidosis is a systemic disease that involves multiple organs, characterized by the deposition of amyloid fibrils. Knowledge regarding the epidemiological, clinical, and genetic profile of the population affected by amyloidosis throughout the country is of fundamental importance for establishing diagnostic and therapeutic strategies. Objective To evaluate the epidemiological, clinical, laboratory, imaging, and treatment variables of patients with TTR cardiac amyloidosis. Methods A multicenter, retrospective, prospective, and observational study based on collection of data on the natural history of [...]

373 Utility of the early phase of DPD scintigraphy in the diagnosis of correlated TT-R cardiac amyloidosis

Abstract Aims The importance of cardiac scan with phosphonate-based radiotracers in the diagnosis of cardiac amyloidosis is now well established. Standard imaging is performed 3 h after tracer injection with a planar view on the cardiac region. This study sought to evaluate the predictive role of early-phase myocardial uptake (10 min after injection) of 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) compared compared with standard late acquisition, in patients with suspected hereditary transthyretin-related cardiac amyloidosis (TTR-CA). Methods and results Fifty five patients with suspected of TTR-CA with typical aspects of the relative apical sparing at two-dimensional speckle-tracking echocardiography, reported as a specific pattern for cardiac amyloidosis, were enrolled after having signed informed written consent. They have been subjected to a 99mTc-DPD cardiac scintigraphy with planar acquisition at 10 min and 3 h after tracer injection (13 Mbq/Kg). Patients with cardiac uptake on the planar images concluded the examination with a SPECT-CT (cardiac protocol) to assess the affected myocardial segments. On planar images the heart-to-mediastinum-ratio was measured. Subsequently, the diagnosis of amyloidosis has to be confirmed with morphologic examinations such as biopsy and genetic tests. Of the enrolled patients with clinical and echocardiographic aspect of TTR-CA, 22 were positive for cardiac amyloidosis. All of them showed tracer uptake in both early and late images. In patients with positive results, the early-phase showed a Heart-to-mediastinum-ratio &amp;gt;1.2. SPECT/CT showed involvement of almost two myocardial segments: in all patients the ventricular septum showed significant tracer uptake. Conclusions Our small group of patients showed that 99mTc-DPD myocardial uptake intensity on early-phase scintigraphy can be used to anticipate the results of late images in diagnosis of TTR cardiac amyloidosis.

158 Racial differences in val122Ile associated transthyretin cardiac amyloidosis

Abstract Aims The valine-to-isoleucine substitution (Val122Ile) is the most common variant of transthyretin (TTR) amyloidosis in the USA, primarily affecting individuals of African descent and leading to a restrictive cardiomyopathy. This variant has recently been identified in a cluster of White individuals in Italy. In this study we aimed to investigate differences in the clinical phenotype of Val122Ile associated TTR cardiac amyloidosis (ATTR-CA) between Black and White individuals. Methods and results In this retrospective study of 70 patients (mean age 72 years) with Val122Ile associated TTR ATTR-CA, cardiac chamber performance was compared using noninvasive pressure-volume analysis. Compared to White patients (n = 17), Black individuals (n = 53) had lower systolic blood pressures (110 vs. 131 mmHg, P &amp;lt; 0.001), reduced pulse pressures (41 vs. 58 mmHg, P &amp;lt; 0.001), and impaired renal function (eGFR 46 vs. 67 mL/min/1.73 m2, P &amp;lt; 0.001) at presentation. Systolic properties and arterial elastance were similar. Black patients had an end-diastolic pressure-volume relationship shifted upward and leftward relative to White patients, indicating reduced left ventricular chamber capacitance. Pressure-volume area at a left ventricular end-diastolic pressure of 30 mmHg was lower in Black compared to White individuals (8055 mmHg*ml vs. 11 538 mmHg*ml, P = 0.008). Conclusions Despite presenting at a similar age to White patients, Black individuals with Val122Ile associated ATTR-CA have a greater degree of cardiac chamber dysfunction at the time of diagnosis due to impaired ventricular capacitance. Whether these differences are attributable to amyloidosis or other cardiovascular disease requires further study.

Concordance between quantitative and semi-quantitative analysis of Tc-99m-pyrophosphate scintigraphy for the diagnosis of transthyretin cardiac amyloidosis in patients with HFpEF

Abstract Background Transthyretin (TTR) cardiac amyloidosis (CA) is an underdiagnosed cause of heart failure with preserved ejection fraction (HFpEF). Cardiac scintigraphy with 99mTechnetium-pyrophosphate (99mTc-PYP) is referred as a simple, non-invasive and reliable method in the diagnosis of TTR-CA. American Society of Nuclear Cardiology Practice Points recommends two interpretative approaches: the quantitative heart-to-contralateral lung ratio (H/CL) at 1 hour or the semi-quantitative visual assessment at 3 hours after radiotracer injection. Purpose In this study, we evaluated the concordance between semi-quantitative and quantitative approaches in the diagnosis of TTR CA in patients with HFpEF. Methods This single-center, prospective study included 78 patients who had a diagnosis of HFpEF according to 2016 ESC HF guidelines. 99mTc-PYP cardiac scintigraphy was performed in 43 patients who have ≥2 red flags for TTR-CA including left ventricular hypertrophy (LVH) (wall thickness ≥12 mm), biventricular hypertrophy, sparkling pattern, reduction in longitudinal strain with apical sparing, thickening of the interatrial septum (&amp;gt;6mm), low-voltage, pseudo infarct pattern or atrioventricular block on ECG. In the absence of monoclonal protein in the serum and urine, Grade 2 to 3 myocardial uptake in semi-quantitative analysis at 3 hours or a H/CL ratio of ≥1.5 in quantitative analysis at 1 hour post injection of 99mTc-PYP is considered positive for TTR-CA. Grade 2–3 uptake with a H/CL ratio ≥1.5 or Grade 0–1 uptake with a H/CL ratio &amp;lt;1.5 were considered as concordant results. Grade 2–3 uptake with a H/CL ratio &amp;lt;1.5 or Grade 0–1 uptake with a H/CL ratio ≥1.5 were considered as discordant results. Results Mean age of study population was 68.26±9.97 years. 17 (39.5%) of 43 patients who underwent 99mTc-PYP cardiac scintigraphy showed a Grade 2 or 3 cardiac uptake and in these patients with Grade 2–3 uptake, 11 patients (65%) had a H/CL ratio ≥1.5 (concordant results) and 6 patients (35%) had a H/CL ratio &amp;lt;1.5 (discordant results). 26 (60.5%) of 43 patients showed Grade 0–1 cardiac uptake. All patients (100%) with Grade 0–1 uptake had a H/CL ratio &amp;lt;1.5 and therefore, showed concordant results. Overall, 37 (86%) patients had concordant and 6 (14%) patients had discordant results (Table 1). Conclusion The results of this study showed that although there was a high agreement between semi-quantitative and quantitative analysis of 99mTc-PYP cardiac scintigraphy, 14% of patients have discordant results and need further workup to confirm TTR-CA in patients with HFpEF. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Pfizer independent grant.

18F-sodium fluoride PET/MRI myocardial imaging in patients with suspected cardiac amyloidosis

BackgroundWe evaluated the diagnostic performance of 18F-NaF PET/MRI in patients with suspected cardiac amyloidosis (CA). MethodsTwenty-seven consecutive patients underwent myocardial PET 1 hour after injection of 4 MBq/kg 18F-NaF with simultaneous MRI including cine-MRI, T1 and T2 mapping, first-pass and late gadolinium enhancement (LGE). 18F-NaF uptake was measured visually and semi-quantitatively by calculating myocardium-to-blood pool (M/B) ratios. CA was confirmed histologically. ResultsTransthyretin (TTR)-CA was diagnosed in 16 patients, light-chain (AL)-CA in 7, and no-CA in 4. Visual interpretation of 18F-NaF images revealed a relative increase in myocardial uptake in only 3 patients, all with TTR CA, and a relative decrease in 13, including 7 AL CA, 3 no-CA, and 3 TTR CA. M/B ratios were significantly higher in TTR CA (1.00 ± 0.12) than in AL CA (0.81 ± 0.06, P = 0.001) or in no-CA (0.73 ± 0.16, P = 0.006). The optimal M/B cut-off to distinguish TTR CA from AL CA was ≥ 0.90 (Fischer, P = 0.0005). By comparison, classification of patients using 99mTc-HMDP heart-to-mediastinum ratios with the previously published cut-off ≥ 1.21 reached higher significance (P < 0.0001). Among MRI parameters, myocardial T1, LGE score, and extracellular volume were higher in CA than in no-CA patients, 1409 ± 76 vs 1278 ± 35 ms (P = 0.004), 10.35 ± 5.30 vs 3.50 ± 3.42 (P = 0.03), and 46 ± 10 vs 33 ± 8 % (P = 0.01), respectively. Conclusion18F-NaF PET/MRI shows good diagnostic performance when semi-quantification is used. However, contrast is low and visual interpretation may be challenging in routine. PET/MRI could constitute a one-stop-shop evaluation of amyloid load and cardiac function in patients needing rapid work-up.

Use of Patisiran Following Heart Transplant in a Patient with Hereditary Transthyretin Cardiac Amyloidosis and Polyneuropathy

Introduction For patients with end-stage hereditary transthyretin (TTR) cardiac amyloidosis, heart or heart-liver transplant can be considered. Due to advances in treatment, liver transplant may no longer be necessary, even if concomitant polyneuropathy is present as there are novel therapies that may halt, and in some cases reverse the burden of disease. We present a case of mixed phenotype TTR amyloidosis (cardiac involvement and polyneuropathy) successfully treated with orthotopic heart transplant (OHT) and patisiran therapy. Case Report A 73-year-old previously healthy African American male was referred for evaluation due to new-onset dyspnea. Electrocardiogram revealed atrial flutter with a controlled ventricular response. Echocardiogram was notable for severe biventricular hypertrophy, severe biatrial enlargement, severely depressed ejection fraction, and a pericardial effusion. An endomyocardial biopsy confirmed amyloid deposits. Mass spectrometry and genetic testing confirmed the presence of a pathogenic mutation in the TTR gene. During that same time period, the patient reported neuropathy. Nerve conduction studies revealed decrement in conduction consistent with an amyloid polyneuropathy. Despite initiation of tafamidis, the patient's clinical picture deteriorated, and he eventually required initiation of inotropes as a bridge to OHT. He successfully underwent OHT and was discharged home soon after. His immediate and long-term post-operative course was uneventful up until 10 months post-transplant, when the patient began to report worsening symptoms of neuropathy. Neurologic evaluation confirmed the clinical presence of an amyloid polyneuropathy, previously supported by nerve conduction studies. The patient was initiated on patisiran, an anti-transthyretin RNA interference agent, approximately one-year following transplant. At 18 months, the patient reports stability of his polyneuropathy symptoms and has not had any complications from patisiran infusions. Summary In patients undergoing OHT for hereditary TTR cardiac amyloidosis with concomitant polyneuropathy, post-transplant treatment with patisiran can be considered to halt progression of polyneuropathy. Effects on other organs including the transplanted heart may also be favorable, although this area is absent supporting data.