Amyloid Infiltration Research Articles

Clinical Phenotype and Prognosis of Asymptomatic Patients With Transthyretin Cardiac Amyloid Infiltration

Patients with transthyretin (ATTR) cardiac amyloid infiltration are increasingly diagnosed at earlier disease stages with no heart failure (HF) symptoms and a wide range of cardiac amyloid infiltration. To characterize the clinical phenotype and natural history of asymptomatic patients with ATTR cardiac amyloid infiltration. This cohort study analyzed data of all patients at 12 international centers for amyloidosis from January 1, 2008, through December 31, 2023. Inclusion criteria were asymptomatic ATTR cardiac amyloid infiltration, defined as an absence of HF history, HF signs and symptoms, diuretic therapy, and plasma cell dyscrasia with evidence of myocardial uptake on bone scintigraphy. If plasma cell dyscrasia was present, histologic confirmation of ATTR amyloid was required. Asymptomatic ATTR cardiac amyloid infiltration. The primary outcomes were all-cause and cardiovascular (CV) mortality. The secondary outcomes were unplanned HF hospitalization, unplanned CV-related hospitalization, and a composite outcome of CV mortality and HF hospitalization. The study comprised 485 patients with asymptomatic ATTR cardiac amyloid infiltration (mean [SD] age, 74.9 [9.9] years, 85.8% male, 112 [23.1%] with hereditary ATTR amyloidosis), with 369 (76.1%) having grade 2 or 3 and 116 (23.9%) having grade 1 cardiac uptake at baseline. Patients with grade 2 or 3 uptake exhibited significantly more cardiac functional and structural abnormalities vs patients with grade 1 uptake. At 3 years, compared with grade 1 uptake, patients with grade 2 or 3 uptake had greater development of HF (54.3% [95% CI, 47.7%-61.3%] vs 23.1% [95% CI, 14.8%-35.1%]), greater outpatient diuretic initiation and N-terminal pro-B-type natriuretic peptide progression (35.0% [95% CI, 28.0%-43.2%] vs 12.4% [95% CI, 6.3%-23.7%]), and greater HF hospitalization (8.7% [95% CI, 5.9%-12.9%] vs 0%) and unplanned CV hospitalization (20.0% [95% CI, 15.7%-25.3%] vs 4.3% [95% CI, 1.6%-11.3%]). Over a median follow-up of 37 months (IQR, 20-64 months), the all-cause death rate was similar between patients with grade 1 vs 2 and 3 uptake; however, those with grade 2 or 3 compared with grade 1 uptake had a significantly higher risk of CV mortality (unadjusted hazard ratio, 5.30; 95% CI, 1.92-14.65). This study shows that asymptomatic ATTR cardiac amyloid infiltration encompasses a wide spectrum of disease severity, with patients with grade 2 or 3 cardiac uptake experiencing an increased rate of CV events and CV mortality and patients with grade 1 uptake experiencing a lower CV event rate and predominantly non-CV mortality. These findings support the use of disease-modifying treatments in asymptomatic patients with grade 2 or 3 uptake and highlight the need of large-scale studies to assess their role in grade 1 uptake.

Abstract 4144567: Prevalence of Atrial Fibrillation in Amyloidosis and Their Association: A 5-Year Nationwide Analytical Cross-Sectional Study

Background: Atrial fibrillation (AF) is a common cardiac arrhythmia associated with significant morbidity and mortality. Amyloidosis (AM) is characterized by the accumulation of amyloid protein in various anatomical sites, including the heart, atria, and ventricles. This amyloid infiltration leads to adverse chamber remodeling, predisposing patients to tachyarrhythmias such as atrial fibrillation/flutter. This study aims to re-evaluate the association of AM with AF by using the large nationwide inpatient database over a total duration of 5 years. Methods: An analytical cross-sectional study was conducted utilizing the data from a survey-weighted national inpatient sample database covering admissions from Jan 2017 to Dec 2021. A total of 147,015,073 admissions of patients aged 18 years and above were included. Descriptive statistics and univariate logistic regression models were used to calculate prevalence rates and odds ratios (OR), respectively. The multivariate logistic regression model was then used to adjust various potential confounders, including age, gender, race, income, hypertension, diabetes, stage 3 or above chronic kidney disease (CKD), Charlson comorbidity index, and hospital-related factors. Results: The 5-year prevalence of AF was 36.73% and 15.42% in admissions with and without AM, respectively. Significant differences between the with AM and without AM groups were in mean ages (72.40 vs. 58.08), female (41.83% vs. 56.92%), race of Black (24.57% vs. 15.40%), and CKD stage 3+ (44.83% vs. 16.65%), respectively. The univariate logistic regression analysis showed an OR for AF of 3.18 (95%CI: 3.102 - 3.267, P<0.000) in admissions with AM compared to those without. After adjustment for the potential confounders, the OR for AF decreased to 1.64 (95%CI 1.597- 1.686; P<0.000) in patients with Amyloidosis compared to those without. Conclusion: This study confirms a significant association between amyloidosis and atrial fibrillation, demonstrating that patients with amyloidosis have a markedly higher prevalence of atrial fibrillation compared to those without. Univariate analysis showed an odds ratio of 3.18 for atrial fibrillation in amyloidosis patients, which remained significantly elevated at 1.64 after adjusting for confounders. These findings indicate the need for a comprehensive workup of suspected atrial fibrillation in amyloidosis patients. Further research should investigate the mechanisms behind this association and potential prevention.

Effect of tafamidis on left atrial function in patients with transthyretin amyloid cardiomyopathy

Abstract Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is characterized by the functional and structural consequences of amyloid infiltration predominantly within the ventricles, causing biventricular wall thickening. Amyloid infiltration can be observed in left atrium in ATTR-CM, however, the association of left atrial (LA) myocardial function with cardiovascular events and changes in LA myocardial function with tafamidis administration have not been elucidated. Purpose The aim of this study was to identify the association between baseline LA reservoir function evaluated by left atrial reservoir strain and cardiovascular events. Furthermore, monitoring the LA reservoir function before and after tafamidis administration, we also investigated the baseline factors associated with changes in LA reservoir function in patients with ATTR-CM. Methods We studied 55 patients with biopsy-proven ATTR-CM who were started on tafamidis in our institution between July 2019 and December 2022 (age: 76 ± 2 years, male: 93%). The primary endpoint was defined as hospitalization for heart failure or cardiovascular death during a median follow-up period of 28 ± 4 months after tafamidis administration. Furthermore, we assessed the factors associated with changes in LA function before and 25 ± 3 months after tafamidis administration for 49 patients who underwent sufficient follow-up echocardiography. Results During the follow-up period, 8 patients had cardiovascular death or cardiovascular hospitalization. The Kaplan-Meier curve indicated that the occurrence of cardiovascular events for patients with LA strain ≥ the median 8.6% was significantly lower than for those with LA strain < 8.6% (log-rank P =0.002; Figure A). Furthermore, comparing LA strain before and after tafamidis administration, the group with worsening LA strain tended to be older (79.0 ± 2.0 years vs. 73.6 ± 3.3 years, P=0.004), have higher brain natriuretic peptide (350 ± 83 pg/mL vs. 199 ± 47 pg/mL, P=0.003), have lower global longitudinal strain (GLS) (9.8 ± 1.4 % vs. 12.6 ± 1.6 pg/mL, P=0.008), and higher relative apical longitudinal strain index (1.63 ± 0.4 % vs. 1.14 ± 0.2 %, P=0.021). The multivariate logistic regression analysis was that age, GLS and relative apical longitudinal strain index were the independent determinants for deterioration of LA strain after tafamidis administration (Figure B). Conclusion In our study, baseline LA reservoir function was found to be closely associated with cardiovascular events after tafamidis administration, while age, GLS and relative apical longitudinal strain index were associated with worsening LA strain after tafamidis administration. Our findings could represent an additional parameter for the effective management of patients with ATTR-CM.Figure AFigure B

Microvascular obstruction in cardiac amyloidosis.

Cardiac amyloidosis (CA) is characterized by deposition of amyloid fibrils within the extracellular space, causing disarray of the myocardial structure and capillary architecture. This study aims to characterize the prevalence of microvascular obstruction (MVO) in patients with CA and to assess the association between MVO and prognosis. The study population comprised 800 patients, of which 400 had light-chain CA (AL-CA) and 400 had transthyretin CA (ATTR-CA). MVO was present in 221 (27.6%) patients, and more common in ATTR-CA than AL-CA (124 [56.1%] vs. 97 [43.9%], p = 0.033). Patients with MVO had a more severe cardiac phenotype evidenced by higher N-terminal pro-brain natriuretic peptide (3516 ng/L [1944-6247] vs. 2508 ng/L [1203-5752], p < 0.001), worse global longitudinal strain (-10.5% [-12.6; -7.9] vs. -12.0% [-16.0; -8.9], p < 0.001), and higher extracellular volume (56% [51-61] vs. 50% [45-57], p < 0.001). Patients with AL-CA and MVO had a higher serum troponin (86 ng/L [47-148] vs. 59 ng/L [44-78], p < 0.001), and higher T2 (53 ms [50-56] vs. 50 ms [48-52], p < 0.001), but lower extracellular volume (55% [50-60] vs. 58% [53-61], p = 0.008) and lower indexed myocyte cell volume (48.6 g/m2 [41.1-59.8] vs. 55.7 g/m2 [47.5-68.4], p < 0.001) than patients with ATTR-CA and MVO. MVO was associated with an increased risk of mortality in the overall population (hazard ratio [HR] 1.28, 95% confidence interval [CI] 1.03-1.59, p = 0.025), and the subgroup with AL-CA (HR 1.59, 95% CI 1.17-2.17, p = 0.003) but not ATTR-CA (HR 1.04, 95% CI 0.77-1.40, p = 0.814). Microvascular obstruction is common in CA and is related to markers of amyloid infiltration. MVO is associated with an increased risk of mortality in AL-CA, but not in ATTR-CA. This reflects the intrinsic differences in disease biology between these two forms of CA, with MVO likely related to multiple myocardial processes, amyloid infiltration, oedema and myocyte death.

Effect of tafamidis on left atrial function of patients with transthyretin amyloid cardiomyopathy.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is characterized by the functional and structural effects of amyloid infiltration, predominantly within the ventricles, causing biventricular wall thickening. Amyloid infiltration can be observed in the left atrium in ATTR-CM patients, but the association of left atrial (LA) myocardial function with cardiovascular events and of changes in LA myocardial function with tafamidis administration have not yet been clarified. Our aim was, therefore, to use speckle-tracking strain for investigating LA myocardial function in patients with ATTR-CM treated with tafamidis. We studied 55 patients with biopsy-proven ATTR-CM who had been treated with tafamidis (age: 76 ± 2years, male: 93%). For speckle-tracking analysis of LA myocardial function, the systolic LA strain (LA reservoir function) was defined for this study as LA myocardial function from the apical 4-chamber view. The primary endpoint was defined as a composite comprising cardiovascular death and/or heart failure hospitalization after tafamidis administration over a median follow-up period of 28 ± 4months. Patients with baseline LA strain < 8.6% (median value) experienced significantly more cardiovascular events than those without (log-rank P = 0.002). Moreover, LA strain in 26 patients worsened after tafamidis administration, and multivariate logistic regression analysis showed age, global longitudinal strain and relative apical longitudinal strain index were identified as independent determinants of deterioration of LA strain after tafamidis administration. In conclusion, baseline LA reservoir function is closely associated with cardiovascular events after tafamidis administration, and could be an additional parameter for the management of patients with ATTR-CM.

Basal inferoseptal segment is highly susceptible to deformation in the clinical spectrum of transthyretin-derived amyloid cardiomyopathy.

While the prevalence of transthyretin-derived amyloid cardiomyopathy (ATTR-CM) is on the rise, detailed understanding of its morphological and functional characteristics within the left ventricle (LV) across heart failure (HF) remains limited. Utilizing two-dimensional (2D) speckle-tracking echocardiography, we assessed longitudinal strain (LS) in 63 histology-confirmed ATTR-CM patients. Additionally, cardiac magnetic resonance (CMR) images measured native T1 and extracellular volume (ECV), compared with LS across 18 LV segments. Patients were categorized into three groups based on HF status: Group 1 (no HF symptoms), Group 2 (HF with preserved LV ejection fraction), and Group 3 (HF with reduced LV ejection fraction). LS analysis unveiled susceptibility to deformation in the basal inferoseptal segment, persisting even in asymptomatic cases. CMR demonstrated increasing native T1 deviation, particularly evident in segments distant from the inferoseptal region. Contrastingly, maximal ECV was consistently observed in the basal and mid-ventricular inferior-septum, even in asymptomatic individuals. Segmental LS decline correlated with ECV expansion but not with native T1 values. Our findings suggest that the inferoseptal segment is highly susceptible to amyloid infiltration, and 2D speckle-tracking echocardiography and CMR may serve as a valuable tool for its early detection.

Redefining Cardiac Involvement and Targets of Treatment in Systemic Immunoglobulin AL Amyloidosis

Cardiac amyloid infiltration is the key determinant of survival in systemic light-chain (AL) amyloidosis. Current guidelines recommend early switching therapy in patients with a nonoptimal or suboptimal response regardless of the extent of cardiac amyloid infiltration. To assess the differences between serum biomarkers, echocardiography, and cardiovascular magnetic resonance (CMR) with extracellular volume (ECV) mapping in characterizing cardiac amyloid, the independent prognostic role of these approaches, and the role of ECV mapping to guide treatment strategies. Consecutive patients newly diagnosed with systemic AL amyloidosis (2015-2021) underwent echocardiography, cardiac biomarkers, and CMR with ECV mapping at diagnosis. Data were analyzed from January to June 2024. The primary outcomes of the study were all-cause mortality and hematological response as defined according to validated criteria: no response (NR), partial response (PR), very good partial response (VGPR), and complete response (CR). Secondary outcomes were the depth and speed of hematological response and overall survival according to ECV. Of 560 patients with AL amyloidosis, the median (IQR) age was 68 years (59-74 years); 346 patients were male (61.8%) and 214 female (38.2%). Over a median (IQR) 40.5 months 9-58 months), ECV was independently associated with mortality. In the landmark analysis at 1 month, long-term survival was independent of the achieved hematological response in ECV less than 0.30% and ECV of 0.31% to 0.40%, while it was dependent on the depth of the hematological response in ECV greater than 0.40%. In the landmark analysis at 6 months, survival was independent of the achieved hematological response in ECV less than 0.30% and dependent on achieving at least PR in ECV of 0.31% to 0.40%. Survival was dependent on achieving CR in ECV of 0.41% to 0.50% and ECV greater than 0.50%. Achieving a deep hematological response at 1 month was associated with better survival compared with 6 months in patients with ECV greater than 0.40% but not with ECV less than 0.40%. This study found that ECV mapping, in systemic AL amyloidosis, is an independent predictor of prognosis, can help define the hematological response associated with better long-term outcomes for each patient and potentially inform treatment strategies.

Assessing left atrial dysfunction in cardiac amyloidosis using LA-LV strain slope.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is an infiltrative disease of the myocardium in which extracellular deposits of amyloid cause progressive cardiac impairment. We aimed to evaluate left atrial (LA) deformation and its association with left ventricular (LV) deformation using LA-LV strain loops in patients with ATTR-CM and patients with LV hypertrophy (LVH). We hypothesized that LA strain in ATTR-CM patients is abnormal and more independent of LV strain, compared to LVH patients. Retrospective study based on echocardiographic data including 30 patients diagnosed with ATTR-CM based on an end-diastolic interventricular septal (IVSd) thickness of ≥14 mm, and 29 patients with LVH (IVSd ≥ 14 mm and no ATTR-CM diagnosis) together with 30 controls. LV global longitudinal strain (LV-GLS) and LA strain, assessed as peak atrial longitudinal strain (PALS), were acquired and plotted to construct LA-LV strain loops and used regression line to determine a LA-LV strain slope. Significantly lower PALS and LA-LV strain slope values were detected in ATTR-CM patients compared to LVH patients (P = 0.004 and P = 0.014, respectively). A receiver operating characteristic (ROC) curve demonstrated similar area under the curve (AUC) using PALS (AUC 0.72) and LA-LV slope (AUC 0.71), with both resulting in higher values than recorded for LV-GLS (AUC 0.62). LA deformation demonstrates an independent ability to differentiate ATTR-CM from LVH. Combining LV strain and LA deformation analysis displays the mechanical LA-LV dissociation in ATTR cardiac amyloidosis and potentially unmasks LA amyloid infiltration; this could potentially enable quicker diagnosis and initiation of treatment for ATTR-CM.

Prognostic Value of Serum Galectin-3 for Survival in Patients with Cardiac Light-Chain Amyloidosis.

Amyloid light-chain (AL) amyloidosis is a multisystem disorder, with cardiac amyloid infiltration being a prevalent manifestation. This study aimed to explore the prognostic value of galectin-3 (Gal-3), a soluble marker associated with fibrosis, inflammation, heart failure, and kidney injury, in patients with cardiac AL amyloidosis. A total of 60 patients who were diagnosed with cardiac AL amyloidosis from January 2015 to May 2018 were enrolled. The prognostic value of Gal-3 was assessed. Receiver operating characteristic (ROC) curves were used to evaluate the predictive accuracy of Gal-3. A Gal-3 cut-off value was identified to predict survival rates. The ROC curves demonstrated a moderate predictive accuracy of Gal-3 for 0.5- and 5-year survival, with area under the curve (AUC) values of 0.722 and 0.788, respectively. A Gal-3 cut-off value of 15.154 ng/mL was found to predict survival. Kaplan-Meier survival analysis revealed a significant difference in mean overall survival between patients with Gal-3 levels below and above the established cut-off (69.2 months versus 42.1 months, respectively; p = 0.036). Multivariate analysis confirmed that Gal-3 > 15.154 ng/mL remained an independent predictor of survival (HR 2.451, 95% CI 1.017-5.910, p = 0.046). This study suggests that Gal-3 holds independent prognostic value for survival in patients with cardiac AL amyloidosis. Gal-3 could potentially enhance the prognostic capabilities of the current soluble markers, thereby improving the management of cardiac AL amyloidosis. However, further validation in larger prospective studies is warranted.

Regional Distribution of Extracellular Volume Quantified by Cardiac CT in Aortic Stenosis: Insights Into Disease Mechanisms and Impact on Outcomes.

Extracellular volume fraction (ECV) is a marker for myocardial fibrosis and infiltration, can be quantified using cardiac computed tomography (ECVCT), and has prognostic utility in several diseases. This study aims to map out regional differences in ECVCT to obtain greater insights into the pathophysiological mechanisms of ECV expansion and its clinical implications. Three prospective cohorts were included: patients with aortic stenosis (AS) and coexisting AS and transthyretin cardiac amyloidosis were referred for a transcatheter aortic valve replacement and had ECG-gated CT angiography and Technetium-99m-labelled 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy to differentiate between the 2 cohorts. Controls had CT angiography and cardiac magnetic resonance demonstrating no significant coronary artery disease or infarction. Global and regional ECVCT was analyzed, and its association with mortality was assessed for patients with AS. In 199 patients, controls (n=65; 66% male), AS (n=115), and coexisting AS and transthyretin cardiac amyloidosis (n=19) had a global ECVCT of 26.1 (25.0-27.8%) versus 29.1 (27.5-31.1%) versus 37.4 (32.5-46.6%), respectively; P<0.001. Across cohorts, ECVCT was higher at the base (versus apex), the inferoseptum (versus anterolateral wall), and the subendocardium (versus subepicardium); P<0.05 for all. Among patients with AS, epicardial ECVCT, rather than any other regional value or global ECVCT, was the strongest predictor of mortality at a median of 3.9 (max 6.3) years (adjusted hazard ratio, 1.21 [95% CI, 1.08-1.36]; P=0.002). Regional differences in ECVCT suggest a predilection for fibrosis and amyloid infiltration at the base, subendocardium, inferior wall, and septum more than the anterior and lateral myocardium. ECVCT can predict long-term mortality with the subepicardium demonstrating the strongest discriminatory power. URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03029026 and NCT03094143.

Cardiopulmonary Exercise Testing in Evaluating Transthyretin Amyloidosis.

Cardiopulmonary exercise testing (CPET) has an established role in the assessment of patients with heart failure. However, data are lacking in patients with transthyretin (ATTR) amyloidosis. To use CPET to characterize the spectrum of functional phenotypes in patients with ATTR amyloidosis and assess their association with the cardiac amyloid burden as well as the association between CPET parameters and prognosis. This single-center study evaluated patients diagnosed with ATTR amyloidosis from May 2019 to September 2022 who underwent CPET at the National Amyloidosis Centre. Of 1045 patients approached, 506 were included and completed the study. Patients were excluded if they had an absolute contraindication to CPET or declined participation. The mean (SD) follow-up period was 22.4 (11.6) months. Comparison of CPET parameters across disease phenotypes (ATTR with cardiomyopathy [ATTR-CM], polyneuropathy, or both [ATTR-mixed]), differences in CPET parameters based on degree of amyloid infiltration (as measured by cardiovascular magnetic resonance [CMR] with extracellular volume mapping), and association between CPET parameters and prognosis. Among the 506 patients with ATTR amyloidosis included in this study, the mean (SD) age was 73.5 (10.2) years, and 457 participants (90.3%) were male. Impairment in functional capacity was highly prevalent. Functional impairment in ATTR-CM and ATTR-mixed phenotypes (peak mean [SD] oxygen consumption [VO2], 14.5 [4.3] mL/kg/min and 15.7 [6.2] mL/kg/min, respectively) was observed alongside impairment in the oxygen pulse, with ventilatory efficiency highest in ATTR-CM (mean [SD] ventilatory efficiency/volume of carbon dioxide expired slope, 38.1 [8.6]). Chronotropic incompetence and exercise oscillatory ventilation (EOV) were highly prevalent across all phenotypes, with both the prevalence and severity being higher than in heart failure from different etiologies. Worsening of amyloid burden on CMR was associated with decline in multiple CPET parameters, although chronotropic response and EOV remained abnormal irrespective of amyloid burden. On multivariable Cox regression analysis, peak VO2 and peak systolic blood pressure (SBP) were independently associated with prognosis (peak VO2: hazard ratio, 0.89 [95% CI, 0.81-0.99; P = .03]; peak SBP: hazard ratio, 0.98 [95% CI, 0.97-0.99; P < .001]). In this study, ATTR amyloidosis was characterized by distinct patterns of functional impairment between all disease phenotypes. A high prevalence of chronotropic incompetence, EOV, and ventilatory inefficiency were characteristic of this population. CPET parameters were associated with amyloid burden by CMR and with peak VO2, and SBP, which have been shown to be independent predictors of mortality. These findings suggest that CPET may be useful in characterizing distinct patterns of functional impairment across the spectrum of amyloid infiltration and predicting outcomes, and potentially offers a more comprehensive method of evaluating functional capacity for future prospective studies.

Myocardial perfusion in cardiac amyloidosis.

Cardiac involvement is the main driver of clinical outcomes in systemic amyloidosis and preliminary studies support the hypothesis that myocardial ischaemia contributes to cellular damage. The aims of this study were to assess the presence and mechanisms of myocardial ischaemia using cardiovascular magnetic resonance (CMR) with multiparametric mapping and histopathological assessment. Ninety-three patients with cardiac amyloidosis (CA) (light-chain amyloidosis n = 42, transthyretin amyloidosis n = 51) and 97 without CA (three-vessel coronary disease [3VD] n = 47, unobstructed coronary arteries n = 26, healthy volunteers [HV] n = 24) underwent quantitative stress perfusion CMR with myocardial blood flow (MBF) mapping. Twenty-four myocardial biopsies and three explanted hearts with CA were analysed histopathologically. Stress MBF was severely reduced in patients with CA with lower values than patients with 3VD, unobstructed coronary arteries and HV (CA: 1.04 ± 0.51 ml/min/g, 3VD: 1.35 ± 0.50 ml/min/g, unobstructed coronary arteries: 2.92 ± 0.52 ml/min/g, HV: 2.91 ± 0.73 ml/min/g; CA vs. 3VD p = 0.011, CA vs. unobstructed coronary arteries p < 0.001, CA vs. HV p < 0.001). Myocardial perfusion abnormalities correlated with amyloid burden, systolic and diastolic function, structural parameters and blood biomarkers (p < 0.05). Biopsies demonstrated abnormal vascular endothelial growth factor staining in cardiomyocytes and endothelial cells, which may be related to hypoxia conditions. Amyloid infiltration in intramural arteries was associated with severe lumen reduction and severe reduction in capillary density. Cardiac amyloidosis is associated with severe inducible myocardial ischaemia demonstrable by histology and CMR stress perfusion mapping. Histological evaluation indicates a complex pathophysiology, where in addition to systolic and diastolic dysfunction, amyloid infiltration of the epicardial arteries and disruption and rarefaction of the capillaries play a role in contributing to myocardial ischaemia.

The Most Predictive Red Flags for Suspecting Cardiac Amyloidosis in Patients with Heart Failure with Preserved Ejection Fraction.

Cardiac amyloidosis (CA) is a cardiomyopathy characterized by amyloid infiltration in the myocardium. Transthyretin cardiac amyloidosis (TTR-CA), commonly presenting as heart failure with preserved ejection fraction (HFpEF), was the focus of our study, which aimed to identify red flags that heighten suspicion of CA in HFpEF patients. We prospectively included patients diagnosed with HFpEF. All patients were assessed for TTR-CA red flag features, cardiac and extra-cardiac, as outlined in the 'Diagnosis and Treatment of Cardiac Amyloidosis: A Position Statement of the European Society of Cardiology.' Technetium-99m pyrophosphate (99mTc-PYP) cardiac scintigraphy was performed in 167 HFpEF patients suspected of having TTR-CA. Patients testing positive and negative for TTR-CA were compared based on these red flag features. Out of 167 HFpEF patients, 19 (11.3%) were diagnosed with TTR-CA. In the TTR-CA group, 17 (89.5%) patients were 65 years or older. The presence of three or more red flags differentiated the TTR-CA positive and negative groups (P = 0.040). Features such as low voltage and pseudo infarct patterns were more prevalent in the TTR-CA group (P < 0.001 and P < 0.048, respectively). Left ventricular global longitudinal strain (LV-GLS) was lower in the TTR-CA positive group (P < 0.001). Multivariate analysis identified four variables-older age, pseudo infarct pattern, low/decreased QRS voltage, and LV-GLS-as strong, independent predictors of TTR-CA, with significant odds ratios (ORs) of 7.8, 6.8, 16.9, and 1.2, respectively. In this study, TTR-CA etiology occurs in approximately one in every ten HFpEF patients. The presence of three or more red flags increases the likelihood of TTR-CA. Older age, pseudo infarct pattern, low/decreased QRS voltage, and reduced LV-GLS are the most significant red flags indicating TTR-CA in HFpEF patients.

Cardiac Amyloidosis: Mutimodality Imaging for Diagnosis and Prognosis

Abstract Cardiac amyloid cardiomyopathy (CM) is a rapidly progressive disease that is frequently underrecognized and frequently diagnosed late in a significant number of individuals suffering from heart failure. Cardiac amyloid infiltration resulting in myocardial hypertrophy and restrictive CM is primarily caused by the misfolding of precursor proteins such as transthyretin, light chain immunoglobulin, and apolipoprotein AI-IV. The utilization of echocardiography, cardiac magnetic resonance, and bone avid radiotracer scintigraphy are essential in establishing a reliable diagnosis and prognosis of cardiac amyloidosis in the majority of patients. However, in certain clinical scenarios, the use of cardiac or extracardiac biopsy is necessary. There are significant developments in the understanding of the pathobiology of amyloid formation, which has paved the way for the development of new-targeted therapies, specifically for transthyretin cardiac amyloidosis. Imaging techniques are developing to monitor quantitatively the progression and regression of cardiac and systemic amyloid infiltration.

Cardiac Amyloidosis and Valvular Heart Disease.

Growing interest has accrued in the co-existence of cardiac amyloidosis and valvular heart disease. Amyloid infiltration from either transthyretin (ATTR) or of light chain (AL) origin may affect any structure of the heart, including the valves. The recent literature has mainly focused on aortic stenosis and cardiac amyloidosis, improving our understanding of the epidemiology, diagnosis, treatment and prognosis of this dual pathology. Despite being of high clinical relevance, data on mitral/tricuspid regurgitation and cardiac amyloidosis are rather scarce and mostly limited to case reports and small cases series. It is the aim of this review article to summarize the current evidence of concomitant valvular heart disease and cardiac amyloidosis by including studies on epidemiology, diagnostic approaches, screening possibilities, therapeutic management, and prognostic implications.

Recurrent Massive Gastrointestinal Bleeding as a first presentation of AL Amyloidosis in a 76-Year-Old Patient

Background: Light chain or AL amyloidosis is a systemic disease that occasionally involves the gastrointestinal tract, but very rarely presents as gastrointestinal bleeding without evidence of systemic involvement. In such cases recognition of amyloidosis as the cause of bleeding is essential in order to rapidly initiate effective treatment to stop the bleeding. Case presentation: We describe a 76-year-old patient who presented with recurrent massive gastrointestinal bleeding as the initial manifestation of AL amyloidosis. One episode necessitated emergency right colectomy, and histopathological analysis of the resected bowel revealed diffuse amyloid infiltration. This finding prompted further investigations, which demonstrated elevated plasma lambda light chain levels, and 10% monoclonal plasma cells in the bone marrow. Treatment with bortezomib, dexamethasone, and daratumumab was initiated and no further gastrointestinal bleeding occurred. Conclusion: The diagnosis of amyloidosis involving the gastrointestinal tract should be considered in adult patients with unexplained recurrent gastrointestinal bleeding.

Intranasal administration of induced pluripotent stem cell-derived cortical neural stem cell-secretome as a treatment option for Alzheimer’s disease

BackgroundAlzheimer’s disease (AD) is the most common neurodegenerative disorder in the elderly, resulting in gradual destruction of cognitive abilities. Research on the development of various AD treatments is underway; however, no definitive treatment has been developed yet. Herein, we present induced pluripotent stem cell (iPSC)-derived cortical neural stem cell secretome (CNSC-SE) as a new treatment candidate for AD and explore its efficacy.MethodsWe first assessed the effects of CNSC-SE treatment on neural maturation and electromagnetic signal during cortical nerve cell differentiation. Then to confirm the efficacy in vivo, CNSC-SE was administered to the 5×FAD mouse model through the nasal cavity (5 μg/g, once a week, 4 weeks). The cell-mediated effects on nerve recovery, amyloid beta (Aβ) plaque aggregation, microglial and astrocyte detection in the brain, and neuroinflammatory responses were investigated. Metabolomics analysis of iPSC-derived CNSC-SE revealed that it contained components that could exert neuro-protective effects or amplify cognitive restorative effects.ResultsHuman iPSC-derived CNSC-SE increased neuronal proliferation and dendritic structure formation in vitro. Furthermore, CNSC-SE-treated iPSC-derived cortical neurons acquired electrical network activity and action potential bursts. The 5×FAD mice treated with CNSC-SE showed memory restoration and reduced Aβ plaque accumulation.ConclusionsOur findings suggest that the iPSC-derived CNSC-SE may serve as a potential, non-invasive therapeutic option for AD in reducing amyloid infiltration and restoring memory.

Human in vitro disease modeling of ATTR cardiac amyloidosis

Abstract Background Amyloidosis is a systemic protein-folding disorder characterized by extracellular misfolded fibrillar protein aggregates that are insoluble and resistant to proteolysis, leading to progressive and vital organ damage [1]. Transthyretin amyloidosis (ATTR) is one of the primary amyloidosis types that affect the heart. Based on the TTR gene sequence, ATTR is further classified into wild-type ATTR (ATTRwt) and hereditary ATTR (ATTRv). Advanced stage TTR amyloid infiltration of the myocardium results in progressive thickening and stiffening of the ventricle wall, and symptoms of restrictive cardiomyopathy and congestive heart failure. Due to the lack of specificity of cardiac amyloidosis symptoms, misdiagnosis and delays in diagnosis are common, resulting in worsening symptoms, organ damage, and increased mortality [2]. Despite the development of several disease-modifying agents [3], current experimental cell and animal models do not adequately represent the human situation, thereby limiting disease understanding and therapeutic discovery. Purpose This project aims to develop an in vitro ATTR disease model, which is critical to define early disease stages and disease progression, map human disease-specific pathways, and screen for novel drugs or validating cutting-edge therapeutic strategies. Methods Recombinant WT-TTR and V122I mutated TTR (V122I) were prepared using E.coli protein production system. TTR purification and acid-mediated TTR-fibril were characterized by SDS-PAGE, Thioflavin T fluorescence measurement, and transmission electron microscope (EM). iPSC-derived cardiomyocytes (iPS-CMs) were differentiated using GiWi protocol as described [4,5]. iPS-CMs or HUVECs were seeded on TTR or TTR-fibril, and we measured beating rate, cell viability (AlamarBlue and LiveDead), and cell/fibril morphology using immunofluorescence. Results Purified recombinant WT and V122I TTR was successfully generated (Figure 1A). Fluorescence increase (Thioflavin T) and EM revealed the presence of TTR-fibril (Figure 1B). iPS-CMs seeded on TTR-fibril resulted in a dose- and time-dependent increase in cell death. Confocal microscopy revealed the attachment of TTR-fibril on iPS-CMs, leading to sarcomere disarray, loss of cell-to-cell coupling, resulting in irregular beating (Figure 2A). Additionally, we found drastically affected viability of HUVECs upon TTR-fibril exposure (Figure 2B). Conclusion Here, we demonstrate an established method to generate purified TTR and TTR-fibril. TTR-fibril attached to the surface of iPS-CMs decreased cell viability and functionality. Similar reduction in HUVEC viability were observed as well. These findings reflect the cytotoxicity of TTR-fibril in a human in vitro model.TTR and TTR-fibril characterizationCell viability up TTR-fibril exposure

Abstract 14418: Prevalence, Characteristics, and Factors Associated With Atrial Fibrillation and Flutter in Patients With Transthyretin Cardiac Amyloidosis

Introduction: Transthyretin cardiac amyloidosis (ATTR-CA) is an increasingly recognized form of restrictive cardiomyopathy in older adults. Adverse chamber remodeling from amyloid infiltration predisposes these patients to tachyarrhythmias such as atrial fibrillation/flutter (AF), which increase the risk of thromboembolic events. The goal of our study was to explore the prevalence, phenotypic characteristics, and factors associated with AF in ATTR-CA patients. Methods: This is a retrospective cohort study of 419 patients diagnosed with ATTR-CA comparing demographics and clinical characteristics between patients with and without AF at baseline. AF was ascertained based on review of prior electrocardiogram, long term monitors when performed, pacemaker interrogations if applicable, and charted history. Binary logistic regression was then performed to determine factors associated with prevalence of AF. Results: AF was prevalent in 58% (n=244) of ATTR-CA patients on initial presentation. Compared to those without AF, individuals with AF were older, of white race, exhibited NYHA class III-IV symptoms, and less frequently had variant disease (ATTRv-CA). They also had more prior stroke/TIA, chronic kidney disease, implanted pacemakers, and need for loop diuretics at baseline (Table 1). AF patients more consistently had Columbia stage II-III disease as per established biomarker cutoffs and greater left atrial volume index on echocardiogram (LAVI). On multivariable logistic regression, per point increase in Columbia score (OR 1.48, 95% CI 1.25-1.75) and per mL/m 2 increase in LAVI (OR 1.05, 95% CI 1.02-1.08) were predictive of prevalent AF, while ATTRv-CA (OR 0.19, 95% CI 0.07-0.55) was protective, all p&lt;0.05. Conclusions: More than half of ATTR-CA patients have preexisting AF. Wild-type ATTR-CA, greater Columbia staging, and a dilated LA are the main clinical factors associated with prevalent AF.

SAT473 First Case Of Diffuse Thyroid Lipomatosis With Amyloid Deposits Presenting With Hyperthyroidism

Abstract Disclosure: A.M. Gonzalez Gil: None. M.A. Ruiz Santillan: None. H. Quadri: None. B.K. Force: None. R. Gaba: None. Background: Diffuse thyroid lipomatosis (DTL) is an exceedingly rare entity of unknown etiology which can be associated with amyloidosis. It generally presents with euthyroidism but very few cases with hyperthyroidism have been reported. Clinical Case: A 64-year-old woman from Pakistan with a several-year history of a non-tender goiter presented to the emergency department with an upper respiratory and gastrointestinal viral syndrome in the context of several weeks of progressively worsening fatigue. She also reported unintentional weight loss over several years. She denied other hyperthyroid or compressive symptoms. Her exam was notable for resting sinus tachycardia and an approximately 100 gm painless goiter. Laboratory evaluation was notable for a markedly elevated creatinine with nephrotic range proteinuria. She was declared to have end stage renal disease (ESRD) and hemodialysis was initiated. She was also found to have a suppressed TSH (&amp;lt;0.01 uIU/mL, NR=0.45-5.33) and elevated FT4 (2.17 ng/dl, NR=0.64-1.42). Total T3 was low (42 ng/dl, NR=87-178), which was attributed to hypoalbuminemia and altered peripheral thyroid hormone metabolism with underlying ESRD. Further evaluation revealed elevated ESR, CRP and thyroglobulin levels (625.9 ng/mL, NR=1.5-38.5), while thyroid stimulating immunoglobulin, thyroid receptor antibodies and thyroid peroxidase antibodies were undetectable. A thyroid ultrasound revealed an enlarged fatty thyroid consistent with DTL. A radioactive iodine uptake scan revealed normal 24-hour uptake (14.1%, NR=7-32%) in a slightly heterogeneous thyroid with no aberrant functioning thyroid tissue. She was started on atenolol, with significant improvement in her tachycardia, but her FT4 continued to increase. Methimazole was initiated. Dose uptitration and administration after dialysis resulted in near-normalization of FT4 levels. She subsequently underwent renal and thyroid biopsies, both of which showed apple green birefringence under polarized light with Congo Red stain, indicating amyloidosis. Core thyroid biopsy additionally showed benign adipose tissue with entrapped thyroid follicles, confirming concomitant DTL. Although other authors have found thyroid amyloid deposits in DTL, and yet others have reported hyperthyroidism in DTL without amyloidosis, this is the first reported case of hyperthyroidism in a patient with DTL with amyloid deposits. Interestingly, chronic hypoxia in amyloid goiters has been hypothesized to cause fibroblast-to-adipocyte metaplasia leading to DTL. We speculate that excess thyroid hormone release could also be mediated by follicular cells’ response to hypoxia induced by amyloid and fatty infiltration of the thyroid. Conclusion: To the best of our knowledge, this is the first reported case of diffuse thyroid lipomatosis with amyloid deposits to be associated with concurrent hyperthyroidism. Presentation Date: Saturday, June 17, 2023