To assess the ability of cardiovascular magnetic resonance (CMR) to (i) measure changes in response to chemotherapy; (ii) assess the correlation between haematological response and changes in ...extracellular volume (ECV); and (iii) assess the association between changes in ECV and prognosis over and above existing predictors.
In total, 176 patients with cardiac AL amyloidosis were assessed using serial N-terminal pro-B-type natriuretic peptide (NT-proBNP), echocardiography, free light chains and CMR with T1 and ECV mapping at diagnosis and subsequently 6, 12, and 24 months after starting chemotherapy. Haematological response was graded as complete response (CR), very good partial response (VGPR), partial response (PR), or no response (NR). CMR response was graded by changes in ECV as progression (≥0.05 increase), stable (<0.05 change), or regression (≥0.05 decrease). At 6 months, CMR regression was observed in 3% (all CR/VGPR) and CMR progression in 32% (61% in PR/NR; 39% CR/VGPR). After 1 year, 22% had regression (all CR/VGPR), and 22% had progression (63% in PR/NR; 37% CR/VGPR). At 2 years, 38% had regression (all CR/VGPR), and 14% had progression (80% in PR/NR; 20% CR/VGPR). Thirty-six (25%) patients died during follow-up (40 ± 15 months); CMR response at 6 months predicted death (progression hazard ratio 3.82; 95% confidence interval 1.95-7.49; P < 0.001) and remained prognostic after adjusting for haematological response, NT-proBNP and longitudinal strain (P < 0.01).
Cardiac amyloid deposits frequently regress following chemotherapy, but only in patients who achieve CR or VGPR. Changes in ECV predict outcome after adjusting for known predictors.
Abstract
Aims
Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure. We sought to characterize the structural and functional echocardiographic ...phenotype across the spectrum of wild-type (wtATTR-CM) and hereditary (hATTR-CM) transthyretin cardiomyopathy and the echocardiographic features predicting prognosis.
Methods and results
We studied 1240 patients with ATTR-CM who underwent prospective protocolized evaluations comprising full echocardiographic assessment and survival between 2000 and 2019, comprising 766 with wtATTR-CM and 474 with hATTR-CM, of whom 314 had the V122I variant and 127 the T60A variant. At diagnosis, patients with V122I-hATTR-CM had the most severe degree of systolic and diastolic dysfunction across all echocardiographic parameters and patients with T60AhATTR-CM the least; patients with wtATTR-CM had intermediate features. Stroke volume index, right atrial area index, longitudinal strain, and E/e’ were all independently associated with mortality (P < 0.05 for all). Severe aortic stenosis (AS) was also independently associated with prognosis, conferring a significantly shorter survival (median survival 22 vs. 53 months, P = 0.001).
Conclusion
The three distinct genotypes present with varying degrees of severity. Echocardiography indicates a complex pathophysiology in which both systolic and diastolic function are independently associated with mortality. The presence of severe AS was independently associated with significantly reduced patient survival.
This study aimed to investigate the accuracy of a broad range of echocardiographic variables to develop multiparametric scores to diagnose CA in patients with proven light chain (AL) amyloidosis or ...those with increased heart wall thickness who had amyloid was suspected. We also aimed to further characterize the structural and functional changes associated with amyloid infiltration.
Cardiac amyloidosis (CA) is a serious but increasingly treatable cause of heart failure. Diagnosis is challenging and frequently unclear at echocardiography, which remains the most often used imaging tool.
We studied 1,187 consecutive patients evaluated at 3 referral centers for CA and analyzed morphological, functional, and strain-derived echocardiogram parameters with the aim of developing a score-based diagnostic algorithm. Cardiac amyloid burden was quantified by using extracellular volume measurements at cardiac magnetic resonance.
A total of 332 patients were diagnosed with AL amyloidosis and 339 patients with transthyretin CA. Concentric remodeling and strain-derived parameters displayed the best diagnostic performance. A multivariable logistic regression model incorporating relative wall thickness, E wave/e′ wave ratio, longitudinal strain, and tricuspid annular plane systolic excursion had the greatest diagnostic performance in AL amyloidosis (area under the curve: 0.90; 95% confidence interval: 0.87 to 0.92), whereas the addition of septal apical–to–base ratio yielded the best diagnostic accuracy in the increased heart wall thickness group (area under the curve: 0.80; 95% confidence interval: 0.85 to 0.90).
Specific functional and structural parameters characterize different burdens of CA deposition with different diagnostic performances and enable the definition of 2 scores that are sensitive and specific tools with which diagnose or exclude CA.
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The aim of this study was to characterize left atrial (LA) pathology in explanted hearts with transthyretin amyloid cardiomyopathy (ATTR-CM); LA mechanics using echocardiographic speckle-tracking in ...a large cohort of patients with ATTR-CM; and to study the association with mortality.
The clinical significance of LA involvement in ATTR-CM is of great clinical interest.
Congo red staining and immunohistochemistry was performed to assess the presence, type, and extent of amyloid and associated changes in 5 explanted ATTR-CM atria. Echo speckle tracking was used to assess LA reservoir, conduit, contractile function, and stiffness in 906 patients with ATTR-CM (551 wild-type (wt)-ATTR-CM; 93 T60A-ATTR-CM; 241 V122I-ATTR-CM; 21 other).
There was extensive ATTR amyloid infiltration in the 5 atria, with loss of normal architecture, vessels remodeling, capillary disruption, and subendocardial fibrosis. Echo speckle tracking in 906 patients with ATTR-CM demonstrated increased atrial stiffness (median 25th-75th quartile 1.83 1.15-2.92) that remained independently associated with prognosis after adjusting for known predictors (lnLA stiff: HR: 1.23; 95% CI: 1.03-1.49; P = 0.029). There was substantial impairment of the 3 phasic functional atrial components (reservoir 8.86% 5.94%-12.97%; conduit 6.5% 4.53%-9.28%; contraction function 4.0% 2.29%-6.56%). Atrial contraction was absent in 22.1% of patients whose electrocardiograms showed sinus rhythm (SR) “atrial electromechanical dissociation” (AEMD). AEMD was associated with poorer prognosis compared with patients with SR and effective mechanical contraction (P = 0.0018). AEMD conferred a similar prognosis to patients in atrial fibrillation.
The phenotype of ATTR-CM includes significant infiltration of the atrial walls, with progressive loss of atrial function and increased stiffness, which is a strong independent predictor of mortality. AEMD emerged as a distinctive phenotype identifying patients in SR with poor prognosis.
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Quantitative cardiovascular magnetic resonance (CMR) T1 and T2 mapping are used to detect diffuse disease such as myocardial fibrosis or edema. However, post gadolinium contrast mapping often lacks ...visual contrast needed for assessment of focal scar. On the other hand, late gadolinium enhancement (LGE) CMR which nulls the normal myocardium has excellent contrast between focal scar and normal myocardium but has poor ability to detect global disease. The objective of this work is to provide a calculated bright-blood (BB) and dark-blood (DB) LGE based on simultaneous acquisition of T1 and T2 maps, so that both diffuse and focal disease may be assessed within a single multi-parametric acquisition.
The prototype saturation recovery-based SASHA T1 mapping may be modified to jointly calculate T1 and T2 maps (known as multi-parametric SASHA) by acquiring additional saturation recovery (SR) images with both SR and T2 preparations. The synthetic BB phase sensitive inversion recovery (PSIR) LGE may be calculated from the post-contrast T1, and the DB PSIR LGE may be calculated from the post-contrast joint T1 and T2 maps. Multi-parametric SASHA maps were acquired free-breathing (45 heartbeats). Protocols were designed to use the same spatial resolution and achieve similar signal-to-noise ratio (SNR) as conventional motion corrected (MOCO) PSIR. The calculated BB and DB LGE were compared with separate free breathing (FB) BB and DB MOCO PSIR acquisitions requiring 16 and 32 heart beats, respectively. One slice with myocardial infarction (MI) was acquired with all protocols within 4 min.
Multiparametric T1 and T2 maps and calculated BB and DB PSIR LGE images were acquired for patients with subendocardial chronic MI (n = 10), acute MI (n = 3), and myocarditis (n = 1). The contrast-to-noise (CNR) between scar (MI and myocarditis) and remote was 26.6 ± 7.7 and 20.2 ± 7.4 for BB and DB PSIR LGE, and 31.3 ± 10.6 and 21.8 ± 7.6 for calculated BB and DB PSIR LGE, respectively. The CNR between scar and the left ventricualr blood pool was 5.2 ± 6.5 and 29.7 ± 9.4 for conventional BB and DB PSIR LGE, and 6.5 ± 6.0 and 38.6 ± 11.6 for calculated BB and DB PSIR LGE, respectively.
A single free-breathing acquisition using multi-parametric SASHA provides T1 and T2 maps and calculated BB and DB PSIR LGE images for comprehensive tissue characterization.
Transthyretin amyloid cardiomyopathy (ATTR-CM) is increasingly diagnosed at an early stage of the disease natural history, defined as National Amyloidosis Centre (NAC) ATTR Stage I. The natural ...history of early-stage ATTR-CM remains poorly characterized.
A retrospective multi-centre observational study of 879 patients with ATTR-CM, either wild-type TTR genotype or carrying the p.V142I TTR variant, and NAC ATTR Stage I biomarkers at the time of diagnosis who did not receive disease-modifying therapy for amyloidosis. Disease characteristics at diagnosis that were independently associated with mortality by Cox regression analysis were N-terminal pro-B-type natriuretic peptide (NT-proBNP), TTR genotype, and troponin T. Patients were categorized into NAC ATTR Stage Ia, defined as a furosemide equivalent diuretic requirement of <0.75 mg/kg and an NT-proBNP ≤500 ng/L or ≤1000 ng/L in the presence of atrial fibrillation, and NAC ATTR Stage Ib comprising all remaining Stage I patients. Median estimated survival among the 88% NAC ATTR Stage Ib patients was 75 (95% CI 57-93) months compared with >100 months in the 12% with Stage Ia disease hazard ratio for death 5.06 (95% confidence interval 1.23-20.87); P = 0.025 despite significant cardiovascular morbidity at the time of diagnosis which increased during follow-up, including among patients diagnosed in NAC ATTR Stage Ia. Estimated survival among UK NAC ATTR Stage Ia patients was comparable to UK general population controls (P = 0.297).
Patients with NAC ATTR Stage I ATTR-CM can be further stratified according to NT-proBNP concentration and diuretic requirement at diagnosis. Patients with Stage Ia ATTR-CM have significant cardiovascular morbidity despite good short- and mid-term survival.
Abstract
Aims
Assessment of hyperaemia during adenosine stress cardiovascular magnetic resonance (CMR) remains a clinical challenge with lack of a gold-standard non-invasive clinical marker to ...confirm hyperaemic response. This study aimed to validate maximum stress myocardial blood flow (SMBF) measured using quantitative perfusion mapping for assessment of hyperaemic response and compare this to current clinical markers of adenosine stress.
Methods and results
Two hundred and eighteen subjects underwent adenosine stress CMR. A derivation cohort (22 volunteers) was used to identify a SMBF threshold value for hyperaemia. This was tested in a validation cohort (37 patients with suspected coronary artery disease) who underwent invasive coronary physiology assessment on the same day as CMR. A clinical cohort (159 patients) was used to compare SMBF to other physiological markers of hyperaemia splenic switch-off (SSO), heart rate response (HRR), and blood pressure (BP) fall. A minimum SMBF threshold of 1.43 mL/g/min was derived from volunteer scans. All patients in the coronary physiology cohort demonstrated regional maximum SMBF (SMBFmax) >1.43 mL/g/min and invasive evidence of hyperaemia. Of the clinical cohort, 93% had hyperaemia defined by perfusion mapping compared to 71% using SSO and 81% using HRR. There was no difference in SMBFmax in those with or without SSO (2.58 ± 0.89 vs. 2.54 ± 1.04 mL/g/min, P = 0.84) but those with HRR had significantly higher SMBFmax (2.66 1.86 mL/g/min, P < 0.001). HRR >15 bpm was superior to SSO in predicting adequate increase in SMBF (AUC 0.87 vs. 0.62, P < 0.001).
Conclusion
Adenosine-induced increase in myocardial blood flow is accurate for confirmation of hyperaemia during stress CMR studies and is superior to traditional, clinically used markers of adequate stress such as SSO and BP response.
Abstract
Aims
Technetium-99m-labelled 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD scintigraphy) is recognized as highly accurate for the non-invasive diagnosis of transthyretin (ATTR) ...cardiac amyloidosis (CA). A proportion of patients with immunoglobulin light chain (AL) CA have also been reported to show cardiac 99mTc-DPD uptake. Herein, we assessed the frequency and degree of cardiac 99mTc-DPD uptake and its clinical significance among patients with AL CA.
Methods and results
Between 2010 and 2017, 292 consecutive patients with AL CA underwent 99mTc-DPD scintigraphy and were included in this study: 114 (39%) had cardiac 99mTc-DPD uptake: grade 1 in 75%, grade 2 in 17%, and grade 3 in 8% of cases. Patients with cardiac 99mTc-DPD uptake had poorer cardiac systolic function and higher N-terminal pro-brain natriuretic peptide. No differences were noted in cardiac magnetic resonance parameters between patients with and without cardiac 99mTc-DPD uptake (N = 19 and 42, respectively). Patients with cardiac 99mTc-DPD uptake showed a trend to worse survival than those with no uptake (log-rank P = 0.056). Among 22 patients who underwent serial 99mTc-DPD scintigraphy, 5 (23%) showed reduction in the grade of cardiac uptake.
Conclusions
In this large cohort of patients with AL CA, 99mTc-DPD scintigraphy ∼40% of cases showed cardiac uptake, including grade 2–3 in 10% of all patients (25% of those with cardiac 99mTc-DPD uptake). Cardiac 99mTc-DPD uptake was associated with poorer cardiac function and outcomes. These data highlight the critical importance of ruling out AL amyloidosis in all patients with cardiac 99mTc-DPD uptake to ensure such patients are not assumed to have ATTR CA.
Aims
Cardiac transthyretin amyloidosis (ATTR‐CM) is a progressive and fatal condition. Prognosis can be determined at diagnosis according to the National Amyloidosis Centre (NAC) transthyretin ...amyloidosis (ATTR) stage. We sought to examine how NAC ATTR stage changes during follow‐up and whether it maintains its prognostic value throughout the disease course.
Methods and results
We performed a retrospective study of 945 patients with wild‐type ATTR‐CM (wtATTR‐CM) or hereditary ATTR‐CM associated with the V122I variant (V122I‐hATTR‐CM) who were diagnosed and serially evaluated at the UK NAC. Patients who commenced any disease‐modifying therapy for amyloidosis were censored at the time of doing so. Landmark Kaplan–Meier survival analyses were performed at diagnosis (n = 945) and at 6 ± 1 (n = 432), 12 ± 3 (n = 562), and 24 ± 3 (n = 316) months and stratified by recalculated NAC ATTR stage at the relevant time point. Cox regression analyses were performed to assess the prognostic significance during follow‐up of an increase in NAC ATTR stage from Stage I at diagnosis. Mortality in ATTR‐CM was predicted by NAC ATTR stage at each time point Stage II vs. I, hazard ratios (HRs) 1.95–2.67; P < 0.001; Stage III vs. II, HRs 1.64–2.25; P < 0.001–0.013. An increase from NAC ATTR Stage I, which occurred in 21%, 32%, and 44% of evaluable patients at 6, 12, and 24 months of follow‐up respectively, was highly predictive of ongoing mortality at each time point (HRs 2.58–3.22; P < 0.001) and in each genotypic subgroup (HRs 1.86–4.38; P < 0.05). Increase in NAC ATTR stage occurred earlier in V122I‐hATTR‐CM than in wtATTR‐CM (43% vs. 27% at 12 months of follow‐up; P = 0.003).
Conclusions
National Amyloidosis Centre ATTR stage predicts ongoing survival throughout the disease natural history in ATTR‐CM, and an increase from NAC ATTR Stage I at diagnosis to a higher NAC ATTR stage predicts mortality throughout follow‐up. Serial calculation of NAC ATTR stage suggests a more aggressive phenotype in V122I‐hATTR‐CM than in wtATTR‐CM.
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