Abstract
Introduction
Cardiac involvement is the main driver of clinical outcomes in systemic amyloidosis; however many clinical observations are not explained by the concept of replacement of the ...interstitium by amyloid material. Preliminary studies support the hypothesis that myocardial ischaemia contributes to cellular damage.
Purpose
This study assesses the presence and mechanisms of myocardial ischaemia using cardiovascular magnetic resonance (CMR) with multiparametric mapping and histopathological assessment.
Methods
Ninety-two patients with cardiac amyloidosis (CA) (AL = 41, ATTR = 51) and 97 without CA (3-vessel coronary disease (3VD) = 47, unobstructed coronary arteries = 26, healthy volunteers (HV) = 24) underwent quantitative stress perfusion CMR with myocardial blood flow (MBF) mapping. Twenty-six myocardial biopsies and 3 explanted hearts with CA were analysed histopathologically.
Results
Stress MBF was severely reduced in patients with CA with lower values than patients with 3VD, unobstructed coronary arteries and HV (CA = 1.03±0.51 ml/min/g, 3VD = 1.35±0.50 ml/min/g, Unobstructed coronaries = 2.92±0.52 ml/min/g, HV = 3.14±0.69 ml/min/g; CA vs 3VD p=0.008, CA vs Unobstructed coronaries p<0.001, CA vs HV p<0.001). After adjustment for intracellular volume the MBF in patients with CA remained significantly lower than in HV (stress MBF/ICV: AL = 2.24±1.12, ATTR = 2.22±0.93, HV = 4.38±1.06; AL vs. ATTR p=1.000, AL vs HV p<0.001, ATTR vs. HV p<0.001). Myocardial perfusion reserve (MPR) was severely reduced in CA patients, compared to HV and patients with unobstructed coronary arteries, with the degree of reduction being comparable only to patients with 3VD (CA = 1.55±0.60, 3VD = 1.54±0.51, unobstructed coronaries = 2.78±0.70, HV = 4.08±0.86; CA vs 3VD p=1.000, 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 diffuse hypoxia with abnormal VEGF staining in cardiomyocytes and endothelial cells. Amyloid infiltration in intramural arteries was associated with severe lumen reduction in 20% of vessels, and severe reduction in capillary density.
Conclusion
CA is associated with severe myocardial ischaemia demonstrable by histology and CMR stress perfusion mapping. Histological evaluation indicates a complex pathophysiology, where 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.
Funding Acknowledgement
Type of funding sources: None.
Diagnostic cardiac ultrasound are commonly assumed to pose no hazard to the patient-but this is not synonymous with being biologically inert. The production of intracellular reactive oxygen species ...(ROS) on endothelial cells is a key modulator of atheroprotective (at low level) and atherogenic (at high levels) actions. The aim of the study was to evaluate in vitro the effects on intracellular ROS of endothelial cells after ultrasound exposure of variable duration with commercially available cardiac imaging systems. Endothelial cells fluorescence was evaluated in vitro after sham (transducer off) exposure to ultrasound and after 5', 15' and 30' of ultrasound irradiation with second harmonic 1.3/2.6 MHz cardiac ultrasound scan (mechanical index 1.5). Intracellular ROS were 83 at baseline, and rose to 86, 112 and 122 fluorescence intensity at 1 h incubation after 5', 15' and 30' of ultrasound exposure respectively (P<0.01 for 30' versus baseline and 5' comparison). There were microscopic signs of endothelial damage only following 30' stage. Ultrasound exposure induced significant DNA laddering and LDH leakage after 15' of ultrasound exposure. Effects on endothelial cells could be reproduced by adding exposed extracellular medium to unexposed cells, and could be prevented removing exposed medium from cell culture or pretreating the medium with catalase. Cardiac ultrasound of current clinical diagnostic use increases intracellular oxidative stress on endothelial cells in vitro. This increase is accompanied by morphological evidence of endothelial damage only after longer exposure times, persists 1 h after withdrawal of ultrasound, and can be modulated over a wide range according to the duration of ultrasound exposure. Free radical production in the extracellular medium is the likely mediator of ultrasound effect.
An overview of structures technology for future aerospace systems is given. Discussion focuses on developments in component technologies that will improve the vehicle performance, advance the ...technology exploitation process, and reduce system life-cycle costs. The component technologies described are smart materials and structures, multifunctional materials and structures, affordable composite structures, extreme environment structures, flexible load bearing structures, and computational methods and simulation-based design. The trends in each of the component technologies are discussed and the applicability of these technologies to future aerospace vehicles is described.
Abstract
Background
Bone scintigraphy is extremely valuable when assessing patients with suspected cardiac amyloidosis (CA), but the clinical significance and associated phenotype of different ...degrees of myocardial tracer uptake across different types of amyloidosis is yet to be defined.
Purpose
We sought to define the phenotypes of patients with varying degrees of cardiac uptake on bone scintigraphy, across multiple types of systemic amyloidosis using extensive characterisation comprising of biomarkers, echocardiographic and cardiac magnetic resonance (CMR) imaging.
Methods
A total of 296 patients (117 immunoglobulin light-chain AL amyloidosis, 165 transthyretin ATTR amyloidosis, 7 apolipoprotein-A1-amyloidosis AApoAI,and 7 apolipoprotein-A4-amyloidosis AApoA4) underwent deep characterisation of their cardiac phenotype.
Results
AL-amyloidosis patients with grade 0 myocardial radiotracer uptake spanned the spectrum of CMR findings from no evidence of CA to characteristic features of CA, while AL-amyloidosis patients with grade 1–3 always produced characteristic CMR features. In ATTR-amyloidosis the CA burden strongly correlated with myocardial tracer uptake (correlation between bone scintigraphy cardiac uptake and CMR derived extracellular volume: R=0.88, 95% CI 0.84–0.91, P<0.001), except in patients with the Ser77Tyr variant. AApoAI-amyloidosis presented with grade 0–1 myocardial tracer uptake, and unique features of disproportionate right sided involvement such as disproportionate right ventricular (RV) and right atrial uptake on bone scintigraphy, RV free wall thickening, and tricuspid valve thickening and dysfunction. Within our cohort, AApoAIV-amyloidosis always presented with grade 0 myocardial tracer uptake, and characteristic features of CA on CMR. All AL-amyloidosis patients with grade 1 myocardial tracer uptake had characteristic CMR features of CA (n=48, 100%), while only ATTR-amyloidosis grade 1 patients with the Ser77Tyr variant had characteristic features of CA on CMR (n=5, 11.4%). Following the exclusion of Ser77Tyr and AApoAI, a CMR showing characteristic features of CA or an extracellular volume >0.40 in a patient with grade 1 myocardial tracer uptake had a sensitivity and specificity of 100% for diagnosing AL-amyloidosis.
Conclusion
Deep characterisation of the cardiac phenotype in different types of amyloidosis, across a range of bone scintigraphy cardiac uptake grades has identified clear differences between each amyloidosis type. The distinctive characteristics in each cohort has allowed the development of a diagnostic pathway to help define the diagnostic differentials and the clinical phenotype in each individual patient, following comprehensive assessment with bone scintigraphy and CMR.
Funding Acknowledgement
Type of funding sources: None.
Abstract
Background
Patients with systemic immunoglobulin light chain (AL) amyloidosis may present with a wide array of signs and symptoms due to the multi-systemic organ involved. The presence of ...cardiac involvement is the key determinant of survival. Cardiac magnetic resonance (CMR) has the unique ability to measure the continuum of cardiac amyloidosis (CA) infiltration providing a deep characterisation from early CA involvement to severe degree of CA burden.
Purpose
The aim of this study was to characterise the clinical profiles and the severity of organ involvement in patients presenting with AL amyloidosis and to investigate implications for long-term outcome.
Methods
Patients newly diagnosed with AL amyloidosis at the National Amyloidosis Centre underwent comprehensive clinical, laboratory and instrumental work up, including CMR imaging with left ventricular (LV) mass, late gadolinium enhancement (LGE) and extracellular volume (ECV). The clinical phenotypes were classified in cardiac, renal and other according to the symptoms at presentation. The degree of CA was investigated by CMR: 0= no features of CA (normal LV mass, no LGE and normal ECV); 1=early cardiac amyloid infiltration (normal LV mass, raised ECV no LGE); 2= characteristic of CA with normal mass (diffuse subendocardial or transmural LGE, altered gadolinium kinetics and raised ECV); 3= characteristic of CA with elevated mass (diffuse subendocardial or transmural LGE and raised ECV). The study outcome was all-cause mortality.
Results
The study population included 241 AL patients presenting with cardiac and renal (22.8%, n=55), cardiac (28.2%, n=68), renal (33.2%, n=80) and other (15.8% n=38) phenotypes. During a median follow up of 33 (IQR 7–52) months, cardiac phenotype either in isolation or in combination with renal phenotype was associated with a higher rate of all-cause mortality compared to the others (p<0.001) (Figure). On CMR imaging, 43.2% of patients without cardiac phenotype (49%, n=118/241) had characteristic scans of CA (CMR grade 2 and 3) whilst 13.8% of patients with cardiac phenotype (51%, n=123/241) had no features of CA on CMR images (CMR grade 0) in (p<0.001). With Kaplan Meier analysis, the risk of all-cause death increased in patients with characteristic features of CA on CMR scan (Figure 1) and in patients with cardiac phenotype and features of CA on CMR scans compared to the others (both p<0.001) (Figure). At multivariable analysis, age at diagnosis (hazard ratio HR 1.03, p=0.009), clinical phenotype at presentation (HR 1.35, p=0.014) and ECV measured by CMR (HR 56, p<0.001) emerged as independent prognostic parameters.
Conclusions
Patients with newly diagnosed AL amyloidosis present most frequently with renal and cardiac phenotypes. CMR detects CA in >40% of patients with non-cardiac phenotype. ECV is an independent predictor of all-cause mortality across the full clinical spectrum of AL amyloidosis.
Funding Acknowledgement
Type of funding sources: None.
Background In the stress imaging era, ECG positivity is regarded as a frequent source of false-positive responses. However, it is known that normal coronary arteries frequently coexist with abnormal ...endothelial function in patients with chest pain. Aim To evaluate the anatomical coronary epicardial, and functional systemic endothelial determinants of wall motion and electrocardiographic responses during stress testing. Method Sixty-eight in-hospital patients with chest pain syndrome, no previous myocardial infarction, and off nitrate therapy at the time of testing underwent, on different days, in random order and within 1 month: (1) stress ECG echo testing (with dipyridamole in 43, dobutamine in 3, and exercise in 22 patients); (2) coronary angiography; (3) endothelium-dependent, flow-mediated dilation of the brachial artery during reactive hyperaemia using high-resolution ultrasound. Criteria of positivity were: ST segment depression >0·1mm in the stress ECG; regional dysfunction >2 segments demonstrated by stress–echo; diameter reduction >50% on coronary angiography; and <5% flow-mediated dilation as revealed by endothelial function. Results Significant coronary artery disease was present in 39 patients, and was predicted on multivariate analysis by stress-induced wall motion abnormalities (OR=108.8; 95% CI=8·5–1389·4, P=0·0003), but not by either ST segment depression (P=0·13; OR=0·47; 95% CI=0·7–1·3) or reduced flow-mediated dilation (P=0·81; OR=0·87; 95% CI=0·27–2·8). Abnormal flow-mediated dilation was present in 53 patients (78%), and was predicted by stress-induced ST segment depression (P=0·023; OR=6·2; 95% CI=1·3–30·5), but not by either stress echo positivity (P=0·66; OR=0·77; 95% CI=0·23 to 2·5) or angiographically assessed coronary artery disease. There was no correlation between flow-mediated dilation and extent of coronary artery disease as assessed by the angiographic Duke score (from 0=normal to 100=most severe disease): r=−0·13, P=0·91. Conclusion Epicardial coronary artery anatomy affects wall motion abnormalities, and systemic endothelial dysfunction affects ST segment depression during stress. However, echocardiographic positivity is unrelated to endothelial dysfunction, and electrocardiographic positivity is an inaccurate predictor of coronary stenosis. An integration of ECG and functional markers is warranted in the stress testing lab.
Abstract
Background
Transthyretin Amyloid Cardiomyopathy (ATTR-CM) is a progressive condition characterised by the infiltration of the myocardial extracellular space resulting in progressive heart ...failure and mortality. Owing to advances in imaging and diagnostics, ATTR-CM is an increasingly recognised form of heart failure worldwide. ATTR-CM can be hereditary (hATTR) and associated with a pathogenic TTR gene variant which exhibits an autosomal dominant pattern of inheritance. Studies have shown that homozygosity in Mendelian diseases confers a more severe clinical phenotype. This has yet to be determined for hATTR-CM.
Purpose
To determine the clinical significance of TTR gene variant homozygosity in hATTR-CM.
Methods
All patients whom were diagnosed with hATTR-CM at a single UK national referral centre for amyloidosis were identified retrospectively. TTR gene zygosity, clinical, biochemical and echocardiographic parameters were obtained from patient clinical records.
Results
Only patients that were homozygous for the V122I TTR gene variant were identified in sufficient numbers for meaningful analysis. Twenty three patients with hATTR-CM whom were homozygous for the V122I variant were identified. Three hundred and ninety heterozygous V122I hATTR-CM patients were identified as a control group. There were no statistically significant differences in echocardiographic parameters (heterozygous vs homozygous means were as follows: IVSd 16.9mm v 16.6mm, LVEF 43.8% v 44.8%, stroke volume 30.7ml v 34.4ml, TAPSE 14.4mm v 15.3mm and GLS -9.7% vs -9.0%). Median NT-proBNP was lower in the homozygotes compared to heterozygotes (2480ng/L v 3179ng/L, p<0.05). Median survival from baseline was similar between the two groups (Figure 1), with homozygous and heterozygous patients having median survivals of 28.7 months and 24.5 months, respectively. However, homozygous patients were significantly younger at baseline diagnosis (mean age 66.4 years v 76.3 years, p<0.01) and therefore died at a much younger age (mean age at death 72.5 years v 79.9 years, p<0.01).
Conclusions
To our knowledge, this is the first study reporting outcomes in hATTR-CM patients whom are homozygous TTR gene variant carriers. Whilst the cardiac phenotype, natural history and length of survival were not substantially different between heterozygotes and homozygotes, the mean age at first diagnosis was substantially younger. Given the natural course of the disease was relatively similar between the groups, this resulted in a significantly younger age at death in hATTR patients whom are homozygous TTR variant carriers. Larger studies are required to confirm if this is applicable across all TTR variants. Nonetheless our study suggests that hATTR patients whom are homozygous carriers of TTR variants should be afforded closer clinical surveillance from a younger age than their heterozygous counterparts.Figure 1
Abstract
Background
The presence and severity of cardiac involvement in AL amyloidosis is the main driver of prognosis 1; patients with symptomatic heart failure frequently die within 6 months 1 but ...median survival has nearly doubled over the past decade, mainly due to significant improvements in chemotherapy. The haematological response to chemotherapy is principally evaluated with serial measurements of serum-free light-chains (FLC) 2. The cardiac response to chemotherapy is assessed through changes in serum concentrations of brain natriuretic peptides (including NT-proBNP) and echocardiographic parameters 3–5. Neither are able to directly measure cardiac amyloid burden. Cardiovascular magnetic resonance (CMR) with extra-cellular volume (ECV) mapping can measure the extent cardiac amyloid infiltration 6.
Aims
We investigated the ability of CMR to: 1) measure changes in response to chemotherapy; 2) assess the correlation between haematological response (HMR) and changes in cardiac amyloid; 3) assess the association between changes in cardiac amyloid and prognosis over and above existing predictors.
Methods
In total, 176 patients with cardiac light-chain amyloidosis treated with chemotherapy were assessed with FLC, NT-proBNP and CMR with ECV mapping at baseline (before chemotherapy), 6-months, 12-months & 24-months after commencing chemotherapy. Haematological response was categorized by reductions in FLC as: complete response (CR), very good partial response (VGPR), partial response (PR) or no response (NR). CMR response was categorized by changes in ECV as: progression (≥0.05 increase), stable (<0.05 change) or regression (≥0.05 decrease).
Results
A progressive increase in patients achieving either CR or VGPR was observed at each time point (61% of patients at 6-months, 71% at 12-months and 80% at 24-months). At 6-months, CMR regression was observed in 3% (all had either CR or VGPR) and progression in 32% (61% had either PR or NR; 39% had either CR or VGPR). At 1-year, CMR regression was observed in 22% (all had either CR or VGPR); progression in 22% (63% had either PR or NR; 37% had either CR or VGPR). At 2-years, CMR regression was observed in 38% (all had CR/VGPR); progression in 14% (80% had either PR or NR; 20% had either CR or VGPR). During follow-up (40±15 months), 36 (25%) patients died. CMR response at 6-months predicted death (progression HR 3.821; 95% CI 1.950–7.487; p<0.001) and remained independently associated with prognosis after adjusting for haematological response, NT-proBNP and longitudinal strain on echocardiography (p<0.01).
Conclusions
CMR demonstrates that cardiac amyloid deposits frequently regress following chemotherapy, but only in patients who achieve CR or VGPR, highlighting the need for deep haematological response. Changes in amyloid burden (ECV) predict outcomes after adjusting for known predictors, showing the crucial role of CMR in redefining treatment response.
Funding Acknowledgement
Type of funding sources: Foundation.
Abstract
Background
Transthyretin amyloid cardiomyopathy (ATTR-CM) is most often diagnosed in men (1–5). The few available studies suggest affected women have a more favourable cardiac phenotype ...(5–8), but remain unclear regarding differences in outcomes.
Objectives and methods
To characterise sex differences among consecutive patients with non-hereditary and two prevalent forms of hereditary ATTR-CM diagnosed over a 20-year period at our specialist centre through analysis of deep phenotyping at presentation, changes on serial echocardiography and overall prognosis.
Results
In total, 1732 patients were studied, comprising: 1095 with wild-type (wt)ATTR-CM; 206 with T60A-hATTR-CM; and 431 with V122I-hATTR-CM. Female prevalence was greater in T60A-hATTR-CM (29.6%) and V122I-hATTR-CM (27.8%) compared to wtATTR-CM (6%). At presentation, females were 3.3 years older than males (81.9 vs 77.8 years for wtATTR-CM; 68.7 vs 65.1 years for T60A-hATTR-CM; 77.1 vs 74.9 years for V122I-hATTR-CM). At diagnosis, non-indexed measures of wall thickness were significantly greater in males (interventricular septum in diastole (IVSd) of 17.13mm in males & 16.15mm in females; p<0.001). When indexed for body surface area (BSA), we observed that the mean indexed IVSd was fairly constant in males throughout the study period, but in females, had a tendency to decrease over the same study period. Furthermore, BSA significantly influenced measures of disease severity. When indexed for BSA, overall structural and functional phenotype was similar between sexes; the few observed significant differences including indexed IVSd (9.62mm/m2 in females & 8.88mm/m2 in males; p<0.001), indexed left ventricular (LV) end-diastolic volume (35.07ml/m2 in females & 41.05ml/m2 in males; p<0.001) and indexed LV end-systolic volume (17.95ml/m2 in females & 21.74ml/m2 in males; p<0.001) suggested a mildly worse phenotype in females. No significant differences were observed in disease progression on serial echocardiography and mortality across the overall population (p=0.459) and when divided by genotype (p=0.730 for wtATTR-CM; p=0.161 for T60A-hATTR-CM; p=0.056 for V122I-hATTR-CM).
Conclusion
This study of a well-characterized large cohort of ATTR-CM patients, contrary to previous dogmas, did not demonstrate overall differences between sexes in either clinical phenotype, when indexed, or with respect to disease progression and prognosis. The analysis highlighted the deficiencies in using non-indexed values which can not only lead to the inaccurate perception of a milder clinical phenotype in women compared to men, but has been shown to result in female patients presenting at an older age and with a worse phenotype compared to men. These findings indicate the need for revision of existing clinical guidelines regarding awareness and diagnosis of ATTR-CM in women, and modification of clinical trials which currently use single non-indexed threshold for wall thickness as key inclusion criterion.
Funding Acknowledgement
Type of funding sources: Foundation.
Abstract
Background
Diagnostic and therapeutic advances have led to much increased awareness of transthyretin (ATTR) cardiac amyloidosis (CA).
Purpose
We sought to characterise the impact of this on ...referral practice, cardiac phenotype at diagnosis and specifically to determine whether patients are now being diagnosed at an earlier stage in their disease process.
Methods
We studied 1845 patients diagnosed with ATTR-CA at the National Amyloidosis Centre (NAC) from 2002–2021, all of whom underwent deep clinical phenotyping and follow-up.
Results
Analysis by 5-year quartiles revealed a substantial incremental increase in patients diagnosed with ATTR-CA (35 vs 260 vs 704 vs 846), which was associated with greater proportions of patients referred following advanced cardiac imaging (referrals following cardiac magnetic resonance and bone scintigraphy: 3% vs 44% vs 67% vs 76%; P<0.001). Over time, median duration of symptoms prior to diagnosis diminished from 36-months between 2002–2006 to 12-months between 2017–2021 (P<0.001) and a greater proportion of patients presented with milder disease across the 5-yearly quartiles (NAC stage 1: 40% vs 43% vs 44% vs 57%; P<0.001). The latter was associated with more favourable echocardiographic parameters of structure and function, including an incremental reduction in maximal left ventricular wall thickness (18.26mm vs 17.41mm vs 17.09mm vs 16.68mm; P=0.017). This was associated with improved survival in the overall population (2007–2011 vs 2012–2016: HR=1.65, 95% CI 1.33–2.06; P<0.001 and 2012–2016 vs 2017–2021: HR =1.83, 95% CI 1.45–2.31; P<0.001) and in each genotype (wtATTR, T60A and V122I). Despite a significant increase in the proportion of patients enrolled into clinical trials (0.0% vs 0.0% vs 2.6% vs 23.9%; P<0.001) and prescribed disease modifying therapy (5.7% vs 0.4% vs 4.8% vs 13.5%; P<0.001); the improved survival remained significant even after adjusting for clinical trials and disease modifying therapy (2012–2016 vs. 2017–2021: HR=1.65 95% CI 1.29–2.11, P<0.001).
Conclusion
Increased awareness and advances in cardiac imaging have been associated with a substantial increase in the diagnosis of ATTR-CA and at a progressively earlier stage of the disease, which has contributed to improved survival in recent years. These changes may have important implications for initiation and outcome of therapy. Given that ATTR-CA is now being diagnosed earlier, more data are needed to guide decisions on in whom and when to initiate treatment, and which treatments should be used at each disease stage. Furthermore, the changes in ATTR-CA phenotype at diagnosis urgently need to be factored into clinical trial design, given that pre-determined end-points based on trials performed in the past may no longer be appropriate, or at least sufficiently powered, or of adequate duration to evaluate efficacy of novel agents.
Funding Acknowledgement
Type of funding sources: None.
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