Severe Cardiac Involvement Research Articles

First time evaluation of myocardium microRNA profile in Anderson-Fabry disease: implications in the pathological processes

Abstract Background Anderson Fabry disease (AFD) is an X-linked lysosomal disorder, characterized by progressive sphingolipid storage and organ dysfunction. Cardiac involvement is characterized by left ventricular hypertrophy, inflammation and fibrosis and is leading cause of mortality. MicroRNAs (miRNAs) are emerging as promising biomarkers in medicine, as they are dysregulated in many human diseases, offering opportunities to improve our understanding of disorders and discover new therapeutic targets. However, so far, only a few studies have evaluated the role of miRNAs in Fabry disease, and cardiac tissue miRNAs have never been assessed. Purpose To determine the specific tissue miRNA profile analyzing myocardial tissue of AFD patients and to evaluate their relationship with the severity of cardiac involvement. Methods 19 AFD patients (10 females [53%]; median age 53 years [IQR 43-63]) undergoing right ventricular endomyocardial biopsy (n=15) or surgical septal myectomy (n=4), standard cardiac magnetic resonance (1.5T, cines for maximum wall thickness (MWT) and indexed LV mass (LVMi) calculation) and high-sensitivity Troponin I (TnI) dosage were included and compared to 7 endomyocardial biopsies of controls. Myocardial samples were fixed in formalin and embedded in paraffin. RNA was extracted from 3-5 slides of tissue and used to generate small RNA libraries (Qiagen) for Next Generation Sequencing analysis on Illumina sequencer. Raw data were normalized and analyzed using DEseq2 pipeline. Correlations were performed using Pearson r; a p < 0.05 was considered statistically significant. Results In AFD group median MWT was 13 mm [IQR 8-17], LVMi was 72 g/m2 [IQR 46-97]. TnI was increased in 9 patients (47%) and NT-proBNP in 8 (42%). 6 patients were on specific AFD treatment. We identified 9 miRNAs differentially expressed in AFD patients compared to controls; miRPath analysis revealed that these miRNAs are associated to pathways involved in AFD pathogenesis (autophagy and mTOR signalling, HIF-1, apoptosis, TGF-beta signalling and inflammation) (figure 1). Moreover, we found 10 miRNAs that were differentially expressed in maximal wall thickness (<10 mm, 10-15 mm, >15 mm) groups (figure 2), in particular 3 miRNAs that progressively increased at the increasing of thickness. Among these miRNAs, miR-21-5p showed the strongest correlation with myocardial hypertrophy (r=0.869, p value<0.001 for MWT; r=0.905, p<0.001 for LVMi) and with cardiac damage (r=0.831, p<0.001 for TnI). Additionally, miR-21-5p had a modest correlation with age (r=0.518, p=0.05) and did not differ between patients on specific AFD treatment and patients not treated (p=0.660). Conclusions This study for the first time evaluated the myocardial miRNA profile in AFD patients and identified miR-21-5p as a cardiac biomarker correlating with clinical heart involvement, both in terms of left ventricular hypertrophy (MWT, LVMi) and myocardium damage (troponin).Figure 1Figure 2

Sustained paradoxical vasodilation and blood pressure lowering in response to sympathetic stimulation as markers of disease severity and poor survival in primary AL amyloidosis.

Abstract Background AL patients present sustained paradoxical vasodilation in response to sympathetic stimulation by cold pressor test (CPT). The clinical relevance of this finding is unknown. Purpose We investigated the association between CPT-induced vascular and hemodynamic responses with clinical characteristics of the disease in AL amyloidosis. Methods We consecutively recruited 113 newly diagnosed patients with AL amyloidosis before treatment initiation. High resolution ultrasonography was used to measure the maximum vasodilation of the brachial artery in response to a cold stimulus and 3 minutes after its withdrawal. Systolic (SBP) and diastolic blood pressure (DBP) were measured at the same timepoints. Clinical and laboratory makers of autonomic dysfunction were also measured in a subgroup of the population. All-cause and cardiovascular (CV) mortality were defined as end-points of the study. Results Sustained vasodilation post CPT (%pCPT) was associated with markers of autonomic dysfunction, namely dipping status (p<0.05) and sudomotor dysfunction (p=0.064) and with NYHA stage, baseline NTproBNP and heart failure (p<0.05 for all). DBP%pCPT was associated with the neuropathy symptom scale (NSS Autonomous, p=0.032), while SBP%pCPT was inversely associated with Mayo stage. Vasodilation%pCPT was independently associated with CV death (adjusted HR=1.154, p=0.017) while both DBP%pCPT (HR=0.955, p=0.027) and SBP%pCPT (HR=0.947, p=0.04) were independently associated with all cause death (adjusted for the core model including age, sex, SBP, Mayo stage and nerve involvement). Overall survival was worse in AL patients who demonstrated a decrease in SBP%pCPT than in those who exhibited an increase or kept it stable (log rank test, p=0.024). The same applies to DBP%pCPT(log rank test, p=0.002). Regarding CV death, Vasodilation%pCPT above 5.86% was associated with increased risk of CV death (log rank test, p=0.002). Conclusions In AL amyloidosis, sustained paradoxical vasodilation and decreased SBP and DBP in response to sympathetic stimulation were associated with autonomic dysfunction, more severe cardiac involvement and poor survival.

Demographics and Clinical Features Associated with Abnormal Small Bowel Motility in Systemic Sclerosis.

The small bowel is affected in up to 50% of systemic sclerosis (SSc) patients, and some patients experience severe complications. Our aim was to use specific statistical methods to compare demographic and clinical features of SSc patients with and without abnormal small bowel to better characterize patients at risk for this complication. SSc patients with gastrointestinal symptoms were prospectively enrolled and underwent a scintigraphy-based whole gut transit (WGT) study. A cross-sectional analysis was performed comparing clinical features between patients with and without abnormal small bowel transit by WGT. Univariate logistic regression models and multivariable models were used to examine the relationship between clinical features and abnormal small bowel transit. Of 130 patients enrolled in this study, 22 had abnormal small bowel transit. SSc patients with abnormal small bowel transit were more likely to be male [Odds Ratio(OR)=3.70, Confidence Interval(CI) 1.07-12.50, p= 0.038], and have more severe cardiac involvement (OR = 3.98, CI 1.10-14.38, p= 0.035), while they were less likely to have sicca symptoms (OR = 0.30, CI 0.10-0.94, p= 0.039). In multivariable analyses, sicca symptoms (OR = 0.28, CI 0.08-0.96, p= 0.043) remained negatively associated with abnormal small bowel transit. Additionally, SSc patients with abnormal small bowel transit had higher mortality than patients with normal small bowel transit [Hazard ratio(HR)=4.57, CI 1.58-13.24, p= 0.005]. These findings suggest that patients with abnormal small bowel transit in SSc are more likely to be male, have more severe cardiac involvement, higher mortality, and less sicca symptoms. Recognizing this patient subgroup is essential for risk stratification and optimizing clinical care.

Beyond the spine: a case of ankylosing spondylitis complicated by secondary amyloidosis

BackgroundAnkylosing spondylitis (AS) is a chronic inflammatory condition primarily affecting the spine and sacroiliac joints, often associated with human leukocyte antigen B27 (HLA-B27) positivity. While musculoskeletal symptoms are typical manifestations, AS can also lead to systemic complications, including secondary systemic amyloidosis (SSA), also known as Amyloid A (AA) amyloidosis, involving multiple organs.Case presentationWe present a case of a 45-year-old Asian male with a complex medical history, including diabetes and hypertension, who developed AS complicated by SSA. The patient exhibited a diverse range of symptoms, including cardiac, renal, gastrointestinal, and musculoskeletal manifestations. He reported shortness of breath on exertion, orthopnea, pedal edema, generalized weakness, back pain, neck pain, low-grade fever, decreased appetite, frothy urine, and significant weight loss over the past year. Diagnostic evaluations revealed HLA-B27 positivity and histologically confirmed AA amyloidosis, providing a comprehensive understanding of the systemic involvement.ConclusionThis case report highlights the intricate interplay between AS and SSA, particularly AA amyloidosis, with a focus on its systemic impact beyond musculoskeletal symptoms. The tragic outcome, marked by severe cardiac involvement, underscores the challenges in managing such complex cases. This report emphasizes the importance of early diagnosis and treatment of AS to prevent severe complications, along with vigilant monitoring and individualized treatment plans, as well as the need for further research to enhance our understanding and improve management strategies for AS-related amyloidosis.

Helical superstructures between amyloid and collagen in cardiac fibrils from a patient with AL amyloidosis

Systemic light chain (LC) amyloidosis (AL) is a disease where organs are damaged by an overload of a misfolded patient-specific antibody-derived LC, secreted by an abnormal B cell clone. The high LC concentration in the blood leads to amyloid deposition at organ sites. Indeed, cryogenic electron microscopy (cryo-EM) has revealed unique amyloid folds for heart-derived fibrils taken from different patients. Here, we present the cryo-EM structure of heart-derived AL amyloid (AL59) from another patient with severe cardiac involvement. The double-layered structure displays a u-shaped core that is closed by a β-arc lid and extended by a straight tail. Noteworthy, the fibril harbours an extended constant domain fragment, thus ruling out the variable domain as sole amyloid building block. Surprisingly, the fibrils were abundantly concatenated with a proteinaceous polymer, here identified as collagen VI (COLVI) by immuno-electron microscopy (IEM) and mass-spectrometry. Cryogenic electron tomography (cryo-ET) showed how COLVI wraps around the amyloid forming a helical superstructure, likely stabilizing and protecting the fibrils from clearance. Thus, here we report structural evidence of interactions between amyloid and collagen, potentially signifying a distinct pathophysiological mechanism of amyloid deposits.

Enhanced stabilisation and reduced fibril forming potential of an amyloidogenic light chain using a variable heavy domain to mimic the homodimer complex.

Light chain amyloidosis (AL), is classified as a plasma cell dyscrasia, whereby a mutant plasma cell multiplies uncontrollably and secretes enormous amounts of immunoglobulin-free light chain (FLC) fragments. These FLCs undergo a process of misfolding and aggregation into amyloid fibrils, that can cause irreversible system-wide damage. Current treatments that focus on depleting the underlying plasma cell clone are often poorly tolerated, particularly in patients with severe cardiac involvement, meaning patient prognosis is poor. An alternative treatment approach currently being explored is the inhibition of FLC aggregation by stabilisation of the native conformer. Here, we aimed to identify and characterise antibody fragments that target FLC domains and promote their stabilisation. Using phage-display screening methods, we identified a variable heavy (VH) domain, termed VH1, targeted towards the FLC. Using differential scanning fluorimetry and surface plasmon resonance, VH1 was characterised to bind and kinetically stabilise an amyloidogenic FLC, whereby a > 5.5 °C increase in thermal stability was noted. This improved stability corresponded to the inhibition of fibril formation, where 10 : 1 LC : VH1 concentration reduced aggregation to baseline levels. X-ray crystallographic structures of the LC : VH1 complex at atomic resolution revealed binding in a 1 : 1 ratio, mimicking the dimeric antigen binding sites of the native immunoglobulin molecule and the native LC homodimer.

Inflammatory Myocardial Disease Case Report Following COVID-19 Infection: Giant Cell Myocarditis versus Cardiac Sarcoidosis: To Be or Not to Be

Abstract COVID-19 can induce cardiac involvement, which can include myocardial infarction, various types of arrhythmia, atrioventricular block, myocarditis, acute heart failure, and sudden cardiac death, in approximately 30% of infected patients. There are some reports on the triggering of sarcoid-like reactions and inflammatory myocardial processes by various types of infections. However, little is known about the relationship between COVID-19 and inflammatory cardiomyopathies such as cardiac sarcoidosis (CS) and giant cell myocarditis (GCM). Herein, we describe the clinical course, management, and follow-up of an unmasked inflammatory cardiomyopathy in a 57-year-old Iranian woman, who presented with ventricular arrhythmia 4 months after mild COVID-19 infection. The onset of symptomatic inflammatory myocardial disorders such as CS or GCM may be triggered by COVID-19 infection. The best approach to the management of myocardial inflammatory COVID-19 should probably be individualized based on the patient’s clinical presentation and severity of cardiac involvement.

MIS-C Treatment: Is glucocorticoid monotherapy enough for mild cases?

BackgroundThe effectiveness of using only glucocorticoids (GCs) in mild multisystem inflammatory syndrome (MIS-C) cases was compared with combined treatment [GCs + Intravenous immune globulin (IVIG)]. MethodsThis retrospective cohort study was conducted between June 1, 2020, and June 1, 2022, in a tertiary care center in Istanbul, Turkey. Clinical and investigational data of the MIS-C patients were analyzed. The patients were divided into two groups: those who received only GCs and those who received the GCs + IVIG combination. The primary outcome focused on assessing the deterioration of the patient's clinical condition, the occurrence of shock, admission to the pediatric intensive care unit (PICU), and the need for additional immunosuppressive medication. Secondary outcomes included evaluating the course of cardiovascular and infection-related complications observed at the one-year follow-up. ResultsNinety-seven MIS-C patients with a median age of 41 (3‐ 214) months were enrolled. Fifty-six (57.7%) patients were male. All the patients had fever at admission with a temperature of 39 °C (37.5 °C–40.1 °C). Thirty-two patients (33%) had cardiac findings on echocardiography [left ventricular dysfunction (n= 13, 13.5%), coronary artery involvement (n= 11, 11.3%), and dilation of cardiac cavities and/or increased cardiac muscle thickness (n= 8, 8.2%)]. Thirteen patients (13.5%) required intensive care. All patients received GCs [only GCs (group I; n= 65, 67%)], and 32 patients (33%) with severe manifestations and/or cardiac involvement received GCs + IVIG (group II). No mortality was observed. None of the patients had any complaints at the one-year follow-up, and all echocardiography findings were normal. ConclusionThis study provides preliminary evidence that GC monotherapy is a safe treatment alternative for mild MIS-C cases without cardiac involvement.

The HyperPed-COVID international registry: Impact of age of onset, disease presentation and geographical distribution on the final outcome of MIS-C

ObjectivesThe aim of the study was to establish an international multicenter registry to collect data on patients with Multisystem Inflammatory Syndrome in Children (MIS-C), in order to highlight a relationship between clinical presentation, age of onset and geographical distribution on the clinical outcome. Study designMulticenter retrospective study involving different international societies for rare immunological disorders.1009 patients diagnosed with MIS-C between March and September 2022, from 48 centers and 22 countries were collected. Five age groups (<1, 1–4, 5–11, 12–16, >16 years) and four geographic macro-areas, Western Europe, Central-Eastern Europe, Latin America, Asian-African resource-limited countries (LRC), were identified. ResultsTime to referral was significantly higher in LRC. Intensive anti-inflammatory treatment, including biologics, respiratory support and mechanic ventilation were more frequently used in older children and in European countries. The mortality rate was higher in very young children (<1 year), in older patients (>16 years of age) and in LRC. Multivariate analysis identified the residence in LRC, presence of severe cardiac involvement, renal hypertension, lymphopenia and non-use of heparin prophylaxis, as the factors most strongly associated with unfavorable outcomes. ConclusionsThe stratification of patients by age and geographic macro-area provided insights into the clinical presentation, treatment and outcome of MIS-C. The mortality and sequelae rates exhibited a correlation with the age and geographical areas. Patients admitted and treated in LRC displayed more severe outcomes, possibly due to delays in hospital admission and limited access to biologic drugs and to intensive care facilities.

Value of SLE-DAS in assessing disease activity in patients with systemic lupus erythematosus: a single-centre retrospective study

ObjectivesThis study aimed to evaluate the clinical value of the Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) for assessing disease activity in patients with SLE.MethodsClinical data were collected from patients...

Multisystem inflammatory syndrome in children: A review.

To comprehensively review the literature on multisystem inflammatory syndrome in children (MIS-C). Narrative review of relevant studies published between April 2020 and January 2024. MIS-C is a SARS-CoV-2-related hyperinflammatory syndrome developing 2-6 weeks after COVID-19 in genetically susceptible individuals. Persisting fever, mucocutaneous manifestations, GI and cardiac involvement, together with lymphopenia and elevated inflammatory and cardiac markers are the main clinical features. It is believed to recognise some pathogenetic and clinical overlap with Kawasaki disease. New case definitions have been proposed after an assessment of the diagnostic performance of existing criteria; epidemiological criterion is however progressively losing its usefulness as the pandemic turns into an endemic and in the areas with the highest rates of COVID-19 vaccination. Current guidelines recommend both intravenous immunoglobulin and glucocorticoids in the first-line immunomodulatory treatment, mainly based on comparative retrospective cohorts; the actual role of biologics remains to be adequately established. Strict follow-up is mandatory, especially for those with severe cardiac involvement, as longitudinal studies evaluate the long-term evolution of cardiac damage. In this paper, we review the epidemiological, pathogenetic, clinical and prognostic features of MIS-C, and outline the main questions which still remain unanswered after more than 3 years of research.

The Real-World Data on Patients With Cardiac Stage IIIb AL Amyloidosis

BackgroundMorbidity and mortality of patients with immunoglobulin light chain (AL) amyloidosis are strongly associated with the severity of cardiac involvement, especial in patients with cardiac stage IIIb, but the real-world data on these patients is still limited. Patients and MethodsA retrospective analysis was conducted on 77 patients diagnosed with cardiac stage IIIb AL amyloidosis at our center. We analyzed the clinical characteristics, treatment and outcome of the patients. ResultsThe median age of patients was 57 years and 49.4% were male. Median serum N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponin T (cTnT) were 13,384 ng/L and 0.166 ug/L, and 42 (54.5%) patients had heart failure at diagnosis. Fifty-seven (74.0%) patients received antiplasma cell treatment, and the main treatment options include bortezomib or thalidomide combined with dexamethasone. The hematologic overall response rate was 70% (28/40), and at 6-month landmark analysis, patients with hematologic responses had a higher survival rate. Cardiac and renal responses were achieved in 14 (37.8%) and 13 (32.5%) patients, respectively. After a median follow-up of 10 months (range 1-115 months), median overall survival (OS) was 18 months, and the estimated survival rates at 3, 6, and 12 months were 79.9%, 75.6%, and 54.5%, respectively. In Cox regression models, age, hypotension and cTnT were independently predictive of mortality after adjusting for heart failure. ConclusionThe hematologic, cardiac and renal responses were relative lower in patients with cardiac stage IIIb AL amyloidosis. The overall prognosis of patients was poor, and age, hypotension, and cTnT can be used to predict mortality.

IgG Isotypes Targeting a Recombinant Chimeric Protein of Trypanosoma cruzi in Different Clinical Presentations of Chronic Chagas Disease.

Chagas disease (CD) is caused by the protozoan Trypanosoma cruzi, which leads to a spectrum of clinical presentations that range from asymptomatic to severe cardiac involvement. The host immune response plays a pivotal role in disease progression. Ig isotypes may contribute to disease pathogenesis. Investigating these components can provide insights into the immunopathogenic mechanisms underlying CD. This cross-sectional study aims to establish a correlation between the Ig profile of individuals infected with T. cruzi with the clinical forms of chronic CD. Serum samples were collected from partner institutions in different states of Brazil. Individuals diagnosed with chronic CD were categorized based on the clinical form of the disease. The indirect ELISA method using the recombinant chimeric Molecular Biology Institute of Paraná membrane protein 8.4 as the antigen was used to determine the Ig profile, including total IgG, IgG1, IgG2, IgG3, and IgG4. Ninety-seven serum samples from patients classified as negative (NEG, n = 38), indeterminate (IND, n = 24), mild cardiac (MC, n = 20), and severe cardiac (SC, n = 15) forms were analyzed. IgG1 exhibited greater levels compared with the other isotypes, showing a significant difference between the MC and IND groups. IgG3 levels were greater in individuals from the MC group compared with the SC group. IgG1 and IgG3 isotypes can serve as biomarkers to evaluate the progression of CD because they exhibit variations across clinical groups. Additional longitudinal studies are necessary to explore the relationship between antibody kinetics and the development of tissue damage.

Clinical characteristics and risk factors of cardiac involvement in pediatric immunoglobulin A vasculitis: A 7-year retrospective study from a single tertiary medical center.

Immunoglobulin A vasculitis(IgAV) is the most common form of systemic vasculitis affecting children. To date, cardiac involvement in pediatric IgAV has not been fully investigated and its prevalence may be underestimated. This study aims to reveal the clinical and laboratory characteristics of cardiac involvement in pediatric IgAV and further determine its risk factors. A total of 1451 children with IgAV were recruited between January 2016 and December 2022. According to the severity of cardiac involvement, the patients were divided into the myocarditis/suspected myocarditis group, cardiac abnormalities group, and non-cardiac involvement group. Demographic, clinical, and laboratory characteristics were retrospectively extracted from the individual data collected in the medical records. Among the 1451 pediatric IgAV patients, 179 (12.3%) were identified with cardiac involvement, including 154 (10.6%) with cardiac abnormalities and 25 (1.7%) with myocarditis/suspected myocarditis. Cardiac involvement in pediatric IgAV mainly manifested as elevated cardiac biomarker levels (n = 162), electrocardiogram abnormalities (n = 46), and echocardiogram/chest X-ray abnormalities (n = 15); however, cardiac-related symptoms were only observed in 15.1% of patients with cardiac involvement. Multivariate analysis demonstrated that interval from disease onset to diagnosis > 7days (OR, 2.157; 95% CI, 1.523-3.057; p < 0.001), IgAV with multi-organ involvement (OR, 1.806; 95% CI, 1.242-2.627; p = 0.002), and elevated D-dimer levels (OR, 1.939; 95% CI, 1.259-2.985; p < 0.001) were independent risk factors for cardiac involvement in pediatric IgAV. The length of hospital stay was significantly longer in the myocarditis/suspected myocarditis group compared with the other two groups (p < 0.05). Conclusion:This study suggests that cardiac involvements in pediatric IgAV is non-negligible, and cardiac involvement is associated with interval from disease onset to diagnosis > 7days, IgAV with multi-organ involvement, and elevated D-dimer levels. Severe cardiac involvement may affect the prognosis of pediatric IgAV. What is Known: • Immunoglobulin A vasculitis (IgAV) is the most common form of systemic vasculitis affecting children and adolescents, which exhibits diverse clinical manifestations. Cases of severe IgAV complicated by cardiac involvement have been anecdotally reported. What is New: • The present study suggests that cardiac involvements in pediatric IgAV is non-negligible, and cardiac involvement is associated with interval from disease onset to diagnosis > 7days, IgAV with multi-organ involvement, and elevated D-dimer levels. Severe cardiac involvement may affect the prognosis of pediatric IgAV.

Echocardiographic Screening of Rheumatic Heart Disease: Current Concepts and Challenges.

The incidence of acute rheumatic fever (ARF), which most commonly affects children aged 5-15 years after group A Streptococcus (GAS) infection, ranges from 8 to 51 per 100 000 people worldwide. Rheumatic heart disease (RHD), which occurs when patients with ARF are inappropriately treated or not given regular prophylaxis, is the most common cause of non-congenital heart disease in children and young adults in low-income countries. Timely treatment of GAS infection can prevent ARF, and penicillin prophylaxis can prevent recurrence of ARF. Secondary prophylaxis with benzathine penicillin G has been shown to decrease the incidence of RHD and is a key aspect of RHD control. The most important factor determining the prognosis of RHD is the severity of cardiac involvement. Although approximately 70% of patients with carditis in the acute phase of the disease recover without sequelae, carditis is important because it is the only complication of ARF that causes sequelae. One-third of patients with ARF are asymptomatic. Patients with mild symptoms of recurrent ARF and silent RHD will develop severe morbidities within 5-10 years if they do not receive secondary preventive treatments. A new screening program should be established to prevent cardiac morbidities of ARF in moderate- and highrisk populations. In the present study, we examined the applicability of echocardiographic screening programs for RHD. Cite this article as: Topçu S, Uçar T. Echocardiographic screening of rheumatic heart disease: Current concepts and challenges. Turk Arch Pediatr. 2024;59(1):3-12.

Pediatric multi-systemic inflammatory syndrome complicated by severe cardiac and renal involvement

Pediatric multi-systemic inflammatory syndrome complicated by severe cardiac and renal involvement

Prevalence, Characteristics, and Clinical Impact of Clonal Hematopoiesis of Indeterminate Potential in AL Amyloidosis

Backgrounds: AL Amyloidosis is a plasma cell dyscrasia whose hallmark is the circulation and deposition of immunoglobulin free light chains in target organs. The extent and severity of cardiac involvement are the primary determinants of mortality in AL amyloidosis. Patients harboring clonal hematopoiesis of indeterminate potential (CHIP) have an increased cardiovascular risk compared to the general population. In the setting of multiple myeloma receiving autologous stem cell transplants, CHIP presence has been associated with decreased overall survival. Still, large studies looking at the incidence and outcome of patients with concurrent CHIP and AL amyloidosis are missing. Herby, we present the results of a single-center, retrospective cohort study, where we assessed the prevalence of CHIP in AL amyloidosis and associated disease characteristics and outcomes. Methods: We collected the demographics and clinical characteristics of patients with AL amyloidosis at Dana Farber Cancer Institute (DFCI) from January 2018 to April 2023 who underwent a bone marrow aspirate/biopsy with a rapid heme panel. Variables of interest included age, ethnicity, Mayo 2004 stage, Palladini renal stage, involved organs, FISH abnormalities, left ventricular ejection fraction (LVEF), documented coronary artery disease (CAD), orthostatic hypotension (OH), chemotherapy (CT) treatment received and related response. The primary outcome was major organ dysfunction progression-free survival (MOD-PFS), defined by Kastritis et al. The variant allele fraction (VAF) to define CHIP was set at 2%. Two samples t-test, Wilcoxon rank sum test, and Fisher's exact test were used to compare groups. Univariate and stratified multivariate Cox proportional hazard regression models were used to estimate the association between CHIP status and MOD-PFS. Analyses were carried out with the Stata statistical package. This study was approved by the DFCI Institutional Review Board and performed in accordance with the Declaration of Helsinki. Results: We identified 76 patients as meeting the inclusion criteria. The median age was 67 years. FISH was available for 54 patients. All patients received cytoreductive CT (CyborD 47%, DaraCyborD 37%). CHIP was identified in 16 patients (21%), a significantly higher figure as compared to historical age-matched healthy controls. DNMT3A was the most frequently involved gene (7/16, 44%), followed by GNB1, TET2, ATM (each 2/16, 12.5%), and SF3B1, ZRSR2, EZH2, BRCC3, PPM1D, ASXL1 (6%) (Figure 1). The presence of CHIP strongly associated with t(11;14) (11/13, 85% in patients with CHIP, versus 15/41, 37%, in patients without CHIP, p=0.004) and with a lower Palladini renal stage in patients with renal involvement (p=0.001). The median follow-up time for the entire cohort was 25 months (range 1 - 175 months). In a univariate analysis, CHIP presence was not associated with lower MOD-PFS (hazard ratio [HR] 0.998, 95% CI 0.38 - 2.64). In a univariate analysis, a Mayo stage &amp;gt;2 (HR 4.82, 95% CI 1.95 - 11.91, p = 0.001), the presence of CAD (HR 4.97, 95% CI 1.79 - 13.79, p=0.02), LVEF ≤40% (HR 3.18, 95% CI 1.17 - 8.66, p = 0.023), and OH requiring treatment (HR 2.65, 95% CI 1.74 - 5.97, p = 0.019) were associated with a decreased MOD-PFS. In a multivariate model stratified for age, only the presence of CAD and OH requiring treatment remained associated with worse MOD-PFS (HR 5.65, 95% CI, 1.33 - 23.99, p = 0.019; HR 4.57, 95% CI, 1.30 - 16.05, p = 0.018, respectively). In the multivariate Cox regression model (Figure 2), CHIP presence was not associated with a decreased MOD-PFS (HR 1.32, 95% CI, 0.44 - 3.98, p = 0.624). When focusing on the impact of only DNMT3A, a tendency towards a statistically significant association with worse MOD-PFS was noted in the multivariate model (HR 3.72, 95% CI 0.92 - 15.01, p = 0.065). Conclusion: We present the largest dataset exploring the prevalence of CHIP in AL amyloidosis patients and its clinical correlates. We noted an association between the presence of CHIP and t(11;14), the most frequent cytogenetic abnormality in AL amyloidosis, and adverse prognostic factors. Patients with CHIP were also found to have a lower Palladini renal risk score. Harboring CHIP was not associated with worse MOD-PFS; however, DNMT3A mutation tended to correlate with worse MOD-PFS. Larger prospective studies are warranted to validate these findings and better elucidate the impact of CHIP in patients with AL amyloidosis.

Curability of Light Chain (AL) Amyloidosis with Conventional Dose Regimens

Novel immunotherapies in AL amyloidosis (AL) are associated with improved outcomes while the use of ASCT in selected patients can offer long term remissions. Since the plasma cell clones are usually small or modest, sustained hematologic remissions are not uncommon in AL amyloidosis; however, the “curability” of the disease remains to be demonstrated: even in patients (pts) who achieve deep and sustained hematologic responses, irreversible organ damage can lead to inferior survival. To identify clinical and disease characteristics that are associated with potential “functional cure” (“cure”) of the disease we analyzed a cohort of patients with AL treated without ASCT and with a follow up of at least 5 years. We defined“ ”cure“ as survival of at least 5 years without hematologic disease progression (PD) and without need for any salvage therapy. The analysis included consecutive pts with AL, treated in the Department of Clinical Therapeutics, Athens Greece, diagnosed until 6/2018; pts who survived &amp;lt; 6 months were excluded to adjust for early mortality associated with severe cardiac involvement. The final cohort included 210 pts and we focused on pts who: had not had hematologic PD, had not received any salvage therapy, were still alive or had died from causes not related to AL. These pts were defined as “functionally cured” while the rest as “non-cured”. Among the “cured” we identified a group of pts that despite hematologic response they progressed to end-stage renal disease. We considered that this was “predetermined” due to the advanced organ damage already at diagnosis. Lastly, we compared the outcome of “cured” pts with the outcome of “non-cured” pts who were on CR/VGPR and had ≥1-year or ≥5-year OS. The rate of “curability” was 17% (N=35). “Cured” pts had more often renal (84% vs 61%, p=0.045) and less frequent cardiac involvement (53% vs 62%, p=0.049), lower BM infiltration (8% vs 15%, p&amp;lt;0.001) and lower baseline dFLC (p=0.031) but higher levels of baseline proteinuria (p=0.031). The characteristics as well as the differences between “cured” and “non-cured” pts, are shown in Table 1. Most “cured” pts received bortezomib-based therapies (27 pts, 77%), oral melphalan was given in 4 pts (11%), while in 15 pts (42%) treatment also included lenalidomide and in 7 (20%) daratumumab (with or without bortezomib). Regarding hematologic response, 33 (94%) “cured” pts had achieved ≥ VGPR (CR: 22, VGPR: 11) vs 46% for “non-cured” (p&amp;lt;0.001), 18 pts (51%) had ≥ VGPR with low dFLC response criteria (dFLC &amp;lt;10mg/L) vs 20% (p&amp;lt;0.001); 6 pts (17%) had only low dFLC VGPR and 4 (11%) were not evaluable for response due to low dFLC levels. At 1- and 3-months from start of therapy, 24 (68%) and 27 pts (77%) “cured” pts had achieved ≥VGPR. MRD evaluation was available in 19 “cured” pts, and 11 (31%) were MRD negative (vs 3 (2%) for “non-cured” pts, p&amp;lt;0.001). Cardiac response was observed in 9 pts (25%) and renal response in 18 “cured” pts (51%). Among “cured” pts there was a group of 7 pts (20%) with end-stage renal disease; 1 (2.8%) was already on dialysis at the time of diagnosis, while 6 (17%) initiated dialysis during disease course, despite deep hematologic responses (3 CR, 3 VGPR); 3 pts were renal stage 2 and 3 were renal stage 3. Median time to dialysis was 27 months. Baseline clinical and disease characteristics were comparable among pts with and without end-stage renal disease. The median follow-up of the whole cohort was 88 months, and among “cured” pts, 3 (8.5%) died from causes unrelated to AL amyloidosis. The 7- year OS rate for “cured” pts was 100% and for “non-cured” was 41%, respectively. In 1- and 5-year landmark survival analysis, “cured” pts had significantly superior outcome compared to “non-cured” pts with CR/VGPR, with median OS not reached vs 66 months (p&amp;lt;0.001) and not reached vs 98 months (p=0.014), respectively (Fig 1). In conclusion, a subgroup of pts with AL, not treated with ASCT, can have long-term survival (≥ 5 years) without need for additional or salvage therapy. Such patients could be considered as functionally “cured”. High rates of rapid and deep hematologic responses, relatively high rates of MRD negativity and relatively low tumor and free light chain burden characterize this subset, further emphasizing the need for early diagnosis and active therapy to maximize clonal responses. Thus, “curability” in AL amyloidosis is feasible, especially in the era of novel therapies.

Real-World Outcomes and Treatment Patterns in AL-Amyloidosis in Austria: An Analysis from the Austrian Interdisciplinary Amyloidosis Registry (AIDA)

Introduction This project aimed to provide an overview of the treatment landscape for AL - Amyloidosis (AL-A) in Austria as documented in AIDA, the Austrian Interdisciplinary Amyloidosis Registry. By examining the existing body of knowledge surrounding treatments and demographics, we seeked to shed light on the potential benefits and challenges for new treatment modalities in the context of AL-A. Methods We identified 210 AL- pts. from AIDA (cut off May 15, 2023). Statistics were descriptive. Kaplan Meier was chosen for survival plots and analyses were carried out with Excel and SPSS. Results We present data from 210 AL-A pts. recruited from AIDA. This constitutes 45.95% of all pts. in AIDA, with the major parts of the residual population made up by wt-ATTR amyloidosis pts. (47.48%), with some rare other amyloidosis subtypes accounting for the rest. There was a male pre-dominance in the cohort (62.38%) well in line with published data. Pts. with AL-A were found to be much younger (median age 66a vs. 78a) compared to pts. suffering from wt-ATTR. Diagnosis of AL-A was made between 1997 and 2023, with the median year of first diagnosis being 2016, resulting in median follow up in the cohort of ~ 7 years. The pattern of organ involvement by AL-A were quite typical with heart (78.6%), kidney (58.1%), GI-tract (23.3%) and PNS (21.4%) being the dominant manifestations. Advanced stages by either the classical Mayo staging, as well as the revised one were regrettably still by far more frequent at time of diagnosis as early disease stages (classical Mayo III in 65.8%, and revised MAYO III and IV in 27.8% and 42.3% of pts. respectively). This is mirrored in a high number of pts. with severe to moderate renal insufficiency (GFR &amp;lt; 30ml/min in 4.6% and between 30-60 ml/min in 42.2% of pts.) and/or moderate to severe cardiac involvement (NT-pro BNP &amp;gt; 5000 ng/l in 37.2%, and between 500 - 5000 ng/l in another 51.2% of pts.). Detailed data on comorbidities and toxicities will be added. Treatments Only 141/210 pts. ever received a documented 1 st line of treatment (LoT), of which only 35.5% received a 2 nd LoT, and even less a 3 rd LoT (20.6%), while more LoTs were applied only in a handful of pts. This horrendous attrition rate per LoT is far above, what has been described for Myeloma (20% / LoT). Time to next tretament was found to be median of 9.9 months. 54 pts. received a 1st LoT with the intent of pursuing an autologous stem cell transplantation (ASCT), but only 54% of these actually were transplanted. This compares inferior to Myeloma, although MM pts. are usually significantly older. The most frequently used therapeutic regimes were VCd-D (Andromeda) with or without Dara-maintenance. The widespread use of anti-CD38 based treatments in this sub-cohort is mirrored in a quite high rate of high-quality hematologic responses (CR+VGPR = 51.9%). 90 pts. received 1st LoTs not intending to lead to ASCT. Again, Daratumumab based regimes were the most used, but treatment outcomes were much inferior (hematologic CR+ VGPR = 18.9%) probably based on dosages, time on therapy, and not applied ASCT. Only 40 pts. received conventional 2nd LoTs usually classical Myeloma therapies, with modest treatment results. Even hematologic high-quality responses (CR+VGPR = 25%) were rare not to mention organ responses. Survival Median survival in the AIDA cohort was found to be 45 months. Broken down by Mayo stages, both classic and revised, was found to be quite unfavorable for advanced disease (14 months in revised Mayo stage IV or classical Mayo stage III). Conclusions Compared to other plasma cell dyscrasias overall outcomes in AL-A are still dismal, despite the introduction of recent effective anti-plasma cell therapeutics in the treatment algorithm. Disease modifying therapies are urgently needed and should be preferentially introduced in 1 st line, as only few pts. will receive 2 nd or later LoTs. Furthermore, efforts to improve awareness for this dreadful disease are urgently needed to enable more therapies to be applied in less advanced disease settings. Take home-messages: 1. Efforts needed to improve early diagnosis of AL-A when treatment options will not be hampered by progressive organ dysfunctions 2. Absolute necessity to explore disease modifying therapies going beyond stopping excess free light chain production 3. As only a limited number of pts. received multiple LoTs any new therapeutics should be integrated in effective 1 st LoTs preferentially.

Limited Utility of Mayo 2012 Cardiac Staging System for Risk Stratification of Patients with Advanced Cardiac AL Amyloidosis - Analysis of a Uniformly Treated Cohort of 1275 Patients

Introduction: Systemic light chain (AL) amyloidosis is a rare incurable disorder caused by extracellular deposition of misfolded light chain protein fibrils causing organ dysfunction. Cardiac involvement is present in approximately two thirds of cases at diagnosis. Survival depends largely on the severity of cardiac involvement as well as haematological response to treatment. Two validated cardiac staging systems, Mayo 2012 (stage I-IV) (Kumar, Dispenzieri et al. 2012) and European modification of the standard Mayo staging system 2004 (stage I-IIIb) (Wechalekar, Schonland et al. 2013, Palladini, Sachchithanantham et al. 2015), stratify patients according to different thresholds of biomarkers markers of disease involvement (NTproBNP, troponin T and, additionally for Mayo 2012, difference between involved and uninvolved free light chain [dFLC]). Patients included in these original models were not treated with a uniform induction protocol and treated with regimens such as oral melphalan dexamethasone, which are now rarely used. There is a need to re-assess the predictive performance and robustness of these staging systems with current treatment approaches. We report here the comparison of cardiac staging in a large cohort of patients with AL amyloidosis uniformly treated bortezomib-containing regimens in the first-line setting from the ALChemy study. Methods: Patients enrolled in a prospective observational study at the United Kingdom National Amyloidosis Centre from 2010-2019 treated with bortezomib-based regimens were analysed. Outcomes were stratified according to Mayo 2012 and the European modified Mayo classification. Written consent was obtained from all patients in accordance with the Declaration of Helsinki. Results: 1275 patients (755 male, 520 female) were included. Median age at presentation was 67 years (range 29-89), with a median of two involved organs (range 1-5); 812 (64%) had cardiac involvement, 892 (70%) had renal and 154 (12%) liver involvement. All patients were treated with first-line bortezomib-based therapy: bortezomib-cyclophosphamide-dexamethasone in 1190 [93%]; bortezomib-dexamethasone in 48 [4%]; bortezomib-thalidomide-dexamethasone in 21 [2%] and 16 others. None were treated with a daratumumab based combination or autologous stem cell transplant (ASCT) upfront; 95 (7%) had ASCT at a subsequent line of therapy. Patients were classified by Mayo 2012 staging as: stage I, II, III, IV in 199 (16%), 329 (26%), 413 (32%) and 334 (26%) cases, respectively and by European modified staging as: stages I, II, IIIa and IIIb in 219 (17%), 436 (34%), 424 (33%) and 196 (15%), respectively. The median follow-up was 47 months (95% CI 45-50), median overall survival (OS) was 59 months (95% CI 51-67) and 3-year OS was 59% (95% CI 56-61). Whilst both Mayo 2012 and European modification models were predictive of overall survival, the European modification discernibly discriminated those with the poorest and best outcomes. Median OS by European staging for stage I, II, IIIa, IIIb was: not reached (NR), 76, 34 and 8 months respectively, compared with Mayo 2012 stage I, II, III, IV: NR, 74, 36, and 26 months respectively. European stage II, IIIa, IIIb had a hazard ratio (HR) for death of: 2.42 (95% CI 1.69-3.49), 4.65 (95% CI 3.27-6.61) and 9.18 (95% CI 6.36-13.25), respectively. Mayo stage II, III, IV had a HR of: 2.54 (95% CI 1.72-3.76), 4.66 (95% CI 3.21-6.76) and 5.99 (95% CI 4.12-8.71), respectively. Conclusion: Advanced stage cardiac involvement remains a prognostic predictor of adverse outcomes. In a cohort of bortezomib-treated patients, the European modification has a stronger predictive value for poorer outcome. The Mayo 2012 staging, utilising additional dFLC, did not discriminate the most advanced disease as well suggesting that treatment markedly impacts the predictive capability of cardiac staging systems. Daratumumab-based treatments may have an even greater impact in ameliorating the adverse prognostic significance of high presenting dFLC. Until cardiac staging is revalidated for the modern treatment era of AL amyloidosis, our data should be taken into consideration when using cardiac staging systems in the clinic as well as for clinical trial design.