P216 Cardiac amyloidosis is not a single disease: an echocardiographic study of light chain vs transthyretin forms

Abstract Background Cardiac amyloidosis (CA) is described as one entity. However, several subtypes of amyloid can infiltrate the heart: light chain (AL) and tranthyretin (ATTR) are the most common. Purpose To characterize the specific findings of the CA subtypes as a tool to aid differential diagnosis between AL and ATTR CA. Material and methods: Consecutive patients with CA were evaluated by clinical examination, ECG, cardiac biomarkers and echocardiography with both conventional and myocardial deformation study of the left ventricle (LV), left atrium (LA) and right ventricle (RV). Amyloid subtype was described using light chain assessment for AL-CA and 99Tc-HMPD scintigraphy and TTR gene sequencing for ATTR-CA. Results 32 patients with CA were included, 13 with ATTR and 19 with AL. Patients in AL group were significantly older, with higher levels of cardiac biomarkers. At similar LV EF and wall thickness, they had lower GLS. LA function parameters were also lower in AL pts (table). Using ROC curves, the best predictors for AL diagnosis were NTproBNP (AUC 0.937) and Tn levels (AUC 0.958), as well as LV GLS and pericardial fluid presence (both AUC 0.750). Conclusions At similar LV wall thickness and ejection fraction, cardiac dysfunction appears to be more severe in AL pts, with lower global LV longitudinal strain, worse LA function, higher sPAP and NTproBNP. ATTR (13 pts) AL (19 pts) p Age (years) 50 ± 12 60 ± 8 0.01 NTproBNP (pg/mL) 3066 ± 3720 11755 ± 9114 0.02 hsTnI (ng/mL) 0.005 ± 0.008 0.147 ± 0.161 0.04 Pericardial fluid (%) 53% 100% 0.002 LVEDV (mL) 88 ± 25 75 ± 38 NS LVMi (g/m2) 166 ± 47 168 ± 41 NS LVEF (%) 50 ± 8 49 ± 16 NS LV GLS (%) -12.1 ± 3.8 -8.9 ± 4.5 0.04 Septal Basal/Apical LS 0.33 ± 0.17 0.25 ± 0.27 NS LAVi (mL/m2) 46 ± 21 45 ± 14 NS LAEF 4CV (%) 35 ± 21 24 ± 8 0.05 LA systolic strain (%) 17.4 ± 11.9 10.5 ± 5.0 0.02 RV free wall thickness (mm) 7.0 ± 1.5 7.6 ± 1.4 NS RV 6-segments strain (%) -15 ± 4 -10 ± 8 0.09 sPAP (mmHg) 36.6 ± 12.0 48.6 ± 17.2 0.04

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Longitudinal systolic strain, cardiac function improvement, and survival following treatment of light-chain (AL) cardiac amyloidosis

European Heart Journal - Cardiovascular Imaging ◽

10.1093/ehjci/jew298 ◽

2016 ◽

Vol 18 (9) ◽

pp. 1057-1064 ◽

Cited By ~ 24

Author(s):

Francesco Salinaro ◽

Hans K. Meier-Ewert ◽

Edward J. Miller ◽

Shivda Pandey ◽

Vaishali Sanchorawala ◽

...

Keyword(s):

Cardiac Function ◽

Light Chain ◽

Cardiac Amyloidosis ◽

Systolic Strain

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Abstract 16784: Doxycycline Modulates Cardiomyocyte Remodeling in Light Chain-Induced Cardiac Amyloidosis

Circulation ◽

10.1161/circ.130.suppl_2.16784 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Richard M Wilson ◽

David C Seldin ◽

Flora Sam

Keyword(s):

Light Chain ◽

Cardiac Dysfunction ◽

Intracellular Signaling ◽

Cardiac Amyloidosis ◽

Mapk Pathway ◽

Therapeutic Interventions ◽

High Dose ◽

Cell Transplant ◽

Rat Cardiomyocytes ◽

Definitive Therapy

Cardiac amyloidosis due to clonal immunoglobulin light chain (AL) is a potentially fatal disease. The mechanism(s) of cardiac dysfunction and myocardial damage caused by amyloid fibrils deposition represents the least understood aspect of amyloid pathology. Once diagnosed with heart failure (HF), the median survival of AL cardiac amyloidosis (ALCMP) patients is <6months if left untreated. However, only a minority of ALCMP patients are eligible for definitive therapy which includes autologous stem cell transplant and high dose melphalan. Despite this most patients continue to have evidence of HF and marked LVH on echocardiogram without regression even when this aggressive regimen is successful. Extracellular matrix turnover is implicated in the pathogenesis of ALCMP. Increased matrix metalloproteinase (MMP) activity may contribute to ALCMP. Doxycycline (DOX), an MMP inhibitor, reduces fibril formation and aggregates in murine models of AL and TTR amyloidosis. Autophagy plays a role in adverse cardiac remodeling, but it is unknown if LC deposition causes cardiomyocyte autophagy. We sought to test the hypothesis that DOX modulates LC-induced cardiac dysfunction and whether autophagy is part of the pathogenesis of the disease. Isolated adult rat cardiomyocytes were exposed to AL-LC (20μg/mL) or control LC (20μg/mL). MMP activities, proteins and intracellular signaling molecule expressions were measured. AL-LC increased MMP-2 (28±8%) and MMP-9 (25±6% P<0.05 for both) activities. U0126, a MEK/ERK inhibitor, blocked these increases, suggesting that the MAPK pathway is involved. DOX also decreased MMP-9 (-35±6%) and MMP-2 (-35±6% P<0.001 for both) activities vs AL-LC alone. AL-LC increased LC3II:LC3I protein expression ratio by 112±11% and ROS-regulated ATG4B expression by 156±13% (P<0.05 vs control for both). DOX decreased AL-LC induced LC3II:LC3I ratio by 42±8% (P=0.05) but did not significantly modulate ATG4B expression vs AL-LC. Thus, AL-LC induces autophagy and MMP-2 and MMP-9 activities in cardiomyocytes, which is modulated by DOX via a MEK/ERK pathway. Since ATG4B is not involved it may be independent of ROS. These pathways may provide potential targets for future therapeutic interventions for this near fatal form of cardiomyopathy.

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Human amyloidogenic light chain proteins result in cardiac dysfunction, cell death, and early mortality in zebrafish

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00186.2013 ◽

2013 ◽

Vol 305 (1) ◽

pp. H95-H103 ◽

Cited By ~ 73

Author(s):

Shikha Mishra ◽

Jian Guan ◽

Eva Plovie ◽

David C. Seldin ◽

Lawreen H. Connors ◽

...

Keyword(s):

Cell Death ◽

Cardiac Function ◽

P38 Mapk ◽

Light Chain ◽

Cardiac Dysfunction ◽

Cardiac Amyloidosis ◽

Model System ◽

In Vivo Model ◽

Zebrafish Model

Systemic amyloid light-chain (AL) amyloidosis is associated with rapidly progressive and fatal cardiomyopathy resulting from the direct cardiotoxic effects of circulating AL light chain (AL-LC) proteins and the indirect effects of AL fibril tissue infiltration. Cardiac amyloidosis is resistant to standard heart failure therapies, and, to date, there are limited treatment options for these patients. The mechanisms underlying the development of cardiac amyloidosis and AL-LC cardiotoxicity are largely unknown, and their study has been limited by the lack of a suitable in vivo model system. Here, we establish an in vivo zebrafish model of human AL-LC-induced cardiotoxicity. AL-LC isolated from AL cardiomyopathy patients or control nonamyloidogenic LC protein isolated from multiple myeloma patients (Con-LC) was directly injected into the circulation of zebrafish at 48 h postfertilization. AL-LC injection resulted in impaired cardiac function, pericardial edema, and increased cell death relative to Con-LC, culminating in compromised survival with 100% mortality within 2 wk, independent of AL fibril deposition. Prior work has implicated noncanonical p38 MAPK activation in the pathogenesis of AL-LC-induced cardiotoxicity, and p38 MAPK inhibition via SB-203580 rescued AL-LC-induced cardiac dysfunction and cell death and attenuated mortality in zebrafish. This in vivo zebrafish model of AL-LC cardiotoxicity demonstrates that antagonism of p38 MAPK within the AL-LC cardiotoxic signaling response may serve to improve cardiac function and mortality in AL cardiomyopathy. Furthermore, this in vivo model system will allow for further study of the molecular underpinnings of AL cardiotoxicity and identification of novel therapeutic strategies.

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P29 Arrest of progression of cardiac amyloidosis after chemotherapy predicts favorable outcome in patients with light-chain amyloidosis

European Heart Journal ◽

10.1093/ehjci/ehz872.029 ◽

2020 ◽

Vol 41 (Supplement_1) ◽

Author(s):

J Koyama ◽

M Minamisawa ◽

K Kuwahara

Keyword(s):

Wall Thickness ◽

Light Chain ◽

Cardiac Amyloidosis ◽

Cardiac Involvement ◽

Left Ventricular ◽

Favorable Outcome ◽

Rank Test ◽

Al Amyloidosis ◽

Interval Change ◽

Light Chain Amyloidosis

Abstract Funding Acknowledgements none Background Many studies demonstrated that cardiac involvement predicts poor prognosis in patients with systemic light-chain amyloidosis (AL). There is no data about the effect of the arrest of progression of cardiac amyloidosis on prognosis after chemotherapy. Hypothesis Arrest of progression of cardiac amyloidosis is associated with favorable outcome in patients with light-chain amyloidosis. Methods Among 126 consecutive patients with AL, we prospectively examined 94 patients serially after optimal therapy. The mean follow-up period was 1405 ± 1510 days (median value 734 days, inter quartile range 176-2343 days). Wall thickness was measured from left ventricular (LV) m-mode trace. We defined the cardiac involvement as mean LV wall thickness >12mm, and the regression or progression of cardiac amyloidosis as change in LV mean wall thickness >1mm. Results Among 94 patients with AL, 28 patients (30%) showed regression by definition above, 35 patients (37%) showed no interval change and 31 patients (33%) showed progression of cardiac amyloidosis. Survival analysis of 3 groups demonstrated that the regression and arrest of progression groups showed better outcome compared with the progression group (Log-rank test P < 0.0001). Conclusions The arrest of progression of cardiac amyloidosis predicts favorable outcome in patients with AL amyloidosis. Abstract P29 Figure. Kaplan-Meier Curve of 3 groups

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Cardiac biomarkers in acute respiratory distress syndrome: a systematic review and meta-analysis

Journal of Intensive Care ◽

10.1186/s40560-021-00548-6 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Dilip Jayasimhan ◽

Simon Foster ◽

Catherina L. Chang ◽

Robert J. Hancox

Keyword(s):

Systematic Review ◽

Acute Respiratory Distress Syndrome ◽

Intensive Care ◽

Cardiac Dysfunction ◽

Distress Syndrome ◽

Troponin I ◽

Meta Analysis ◽

Cardiac Injury ◽

Cardiac Biomarkers ◽

Risk Of Death

Abstract Background Acute respiratory distress syndrome (ARDS) is a leading cause of morbidity and mortality in the intensive care unit. Biochemical markers of cardiac dysfunction are associated with high mortality in many respiratory conditions. The aim of this systematic review is to examine the link between elevated biomarkers of cardiac dysfunction in ARDS and mortality. Methods A systematic review of MEDLINE, EMBASE, Web of Science and CENTRAL databases was performed. We included studies of adult intensive care patients with ARDS that reported the risk of death in relation to a measured biomarker of cardiac dysfunction. The primary outcome of interest was mortality up to 60 days. A random-effects model was used for pooled estimates. Funnel-plot inspection was done to evaluate publication bias; Cochrane chi-square tests and I2 tests were used to assess heterogeneity. Results Twenty-two studies were included in the systematic review and 18 in the meta-analysis. Biomarkers of cardiac stretch included NT-ProBNP (nine studies) and BNP (six studies). Biomarkers of cardiac injury included Troponin-T (two studies), Troponin-I (one study) and High-Sensitivity-Troponin-I (three studies). Three studies assessed multiple cardiac biomarkers. High levels of NT-proBNP and BNP were associated with a higher risk of death up to 60 days (unadjusted OR 8.98; CI 4.15-19.43; p<0.00001). This association persisted after adjustment for age and illness severity. Biomarkers of cardiac injury were also associated with higher mortality, but this association was not statistically significant (unadjusted OR 2.21; CI 0.94-5.16; p= 0.07). Conclusion Biomarkers of cardiac stretch are associated with increased mortality in ARDS.

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Improvements in Cardiac Biomarkers are Associated with Better Health-Related Quality of Life in Patients with Light Chain Amyloidosis

Journal of Cardiac Failure ◽

10.1016/j.cardfail.2017.07.336 ◽

2017 ◽

Vol 23 (8) ◽

pp. S114

Author(s):

Kristen McCausland ◽

Spencer D. Guthrie ◽

Tiffany Quock ◽

Miyo Yokota ◽

Martha Bayliss ◽

...

Keyword(s):

Quality Of Life ◽

Light Chain ◽

Cardiac Biomarkers ◽

Health Related Quality ◽

Light Chain Amyloidosis ◽

Related Quality ◽

Health Related

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Natural history and disease progression of early cardiac amyloidosis evaluated by echocardiography

European Heart Journal - Cardiovascular Imaging ◽

10.1093/ehjci/jeaa356.387 ◽

2021 ◽

Vol 22 (Supplement_1) ◽

Author(s):

O Itzhaki Ben Zadok ◽

A Eisen ◽

Y Shapira ◽

D Monakier ◽

Z Iakobishvili ◽

...

Keyword(s):

Disease Progression ◽

Wall Thickness ◽

Cardiac Amyloidosis ◽

Time Course ◽

Right Ventricular Dysfunction ◽

Disease Diagnosis ◽

Left Ventricular ◽

Funding Sources ◽

Lv Mass ◽

Echocardiographic Findings

Abstract Funding Acknowledgements Type of funding sources: None. Background Since the diagnosis of cardiac amyloidosis (CA) is often delayed, echocardiographic findings are frequently indicative of already advanced cardiomyopathy. Aims to describe early echocardiographic features in patients subsequently diagnosed with CA and to delineate disease progression. Methods Pre-amyloid diagnosis echocardiographic studies were screened for structural and functional parameters and stratified according to the pathogenetic amyloid subtype (immunoglobulin light-chain (AL) or amyloid transthyretin (ATTR)). Abnormalities were defined based on published guidelines. Results Our cohort included 75 CA patients of whom 42 (56%) were diagnosed with AL and 33 (44%) with ATTR. Forty-two patients had an earlier echocardiography exam available for review. Patients presented with increased wall thickness (1.3 (IQR 1.0, 1.5)cm) ≥3 years before the diagnosis of CA and relative wall thickness (RWT) was increased (0.47 (IQR 0.41, 0.50)) ≥7 years pre-diagnosis. Between 1 to 3 years before CA diagnosis restrictive left ventricular (LV) filling pattern was present in 19% of patients and LV ejection fraction (LVEF)≤50% was present in 21% of patients. Right ventricular dysfunction was detected concomitantly with disease diagnosis. The echocardiographic phenotype of ATTR versus AL-CA showed increased RWT (0.74 (IQR 0.62, 0.92) vs. 0.62 (IQR 0.54, 0.76), p = 0.004) and LV mass index (144 (IQR 129, 191) vs. 115 (IQR 105, 146)g/m2,p = 0.020) and reduced LVEF (50 (IQR 44, 58) vs. (60 (IQR 53, 60)%, p = 0.009) throughout the time course of CA progression, albeit survival time was similar. Conclusions Increased wall thickness and diastolic dysfunction in CA develop over a time course of several years and can be diagnosed in their earlier stages by standard echocardiography Abstract Figure. Schematic proposed timeline of CA

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