Ana Martinez-Naharro

Prognostic utility of the Perugini grading of 99mTc-DPD scintigraphy in transthyretin (ATTR) amyloidosis and its relationship with skeletal muscle and soft tissue amyloid

Aims High-grade (Perugini grade 2 or 3) cardiac uptake on bone scintigraphy with 99mTechnetium labelled 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) has lately been confirmed to have high diagnostic sensitivity and specificity for cardiac transthyretin (ATTR) amyloidosis. We sought to determine whether patient stratification by Perugini grade on 99mTc-DPD scintigraphy has prognostic significance in ATTR amyloidosis. Methods and results Patient survival from time of 99mTc-DPD scintigraphy was determined in 602 patients with ATTR amyloidosis, including 377 with wild-type ATTR (ATTRwt) and 225 with mutant ATTR (ATTRm) amyloidosis. Patients were stratified according to Perugini grade (0-3) on 99mTc-DPD scan. The prognostic significance of additional patient and disease-related factors at baseline were determined. In the whole cohort, the finding of a Perugini grade 0 99mTc-DPD scan (n = 28) was invariably associated with absence of cardiac amyloid according to consensus criteria as well as significantly better patient survival compared to a Perugini grade 1 (n = 28), 2 (n = 436) or 3 (n = 110) 99mTc-DPD scan (P < 0.005). There were no differences in survival between patients with a grade 1, grade 2 or grade 3 99mTc-DPD scan in ATTRwt (n = 369), V122I-associated ATTRm (n = 92) or T60A-associated ATTRm (n = 59) amyloidosis. Cardiac amyloid burden, determined by equilibrium contrast cardiac magnetic resonance imaging, was similar between patients with Perugini grade 2 and Perugini grade 3 99mTc-DPD scans but skeletal muscle/soft tissue to femur ratio was substantially higher in the latter group (P < 0.001). Conclusion 99mTc-DPD scintigraphy is exquisitely sensitive for identification of cardiac ATTR amyloid, but stratification by Perugini grade of positivity at diagnosis has no prognostic significance.

CMR-Verified Regression of Cardiac AL Amyloid After Chemotherapy

Systemic light-chain (AL) amyloidosis is characterized by interstitial deposition of aggregated misfolded monoclonal immunoglobulin light chains in the form of amyloid fibrils. Cardiac involvement is the main driver of prognosis. Brain natriuretic peptides and echocardiography are currently the

Prospective comparison of novel dark blood late gadolinium enhancement with conventional bright blood imaging for the detection of scar

BackgroundConventional bright blood late gadolinium enhancement (bright blood LGE) imaging is a routine cardiovascular magnetic resonance (CMR) technique offering excellent contrast between areas of LGE and normal myocardium. However, contrast between LGE and blood is frequently poor. Dark blood LGE (DB LGE) employs an inversion recovery T2 preparation to suppress the blood pool, thereby increasing the contrast between the endocardium and blood. The objective of this study is to compare the diagnostic utility of a novel DB phase sensitive inversion recovery (PSIR) LGE CMR sequence to standard bright blood PSIR LGE.MethodsOne hundred seventy-two patients referred for clinical CMR were scanned. A full left ventricle short axis stack was performed using both techniques, varying which was performed first in a 1:1 ratio. Two experienced observers analyzed all bright blood LGE and DB LGE stacks, which were randomized and anonymized. A scoring system was devised to quantify the presence and extent of gadolinium enhancement and the confidence with which the diagnosis could be made.ResultsA total of 2752 LV segments were analyzed. There was very good inter-observer correlation for quantifying LGE. DB LGE analysis found 41.5% more segments that exhibited hyperenhancement in comparison to bright blood LGE (248/2752 segments (9.0%) positive for LGE with bright blood; 351/2752 segments (12.8%) positive for LGE with DB; p < 0.05). DB LGE also allowed observers to be more confident when diagnosing LGE (bright blood LGE high confidence in 154/248 regions (62.1%); DB LGE in 275/324 (84.9%) regions (p < 0.05)). Eighteen patients with no bright blood LGE were found to have had DB LGE, 15 of whom had no known history of myocardial infarction.ConclusionsDB LGE significantly increases LGE detection compared to standard bright blood LGE. It also increases observer confidence, particularly for subendocardial LGE, which may have important clinical implications.

A case report in cardiovascular magnetic resonance: the contrast agent matters in amyloid

BackgroundCardiac amyloidosis is a progressive but underdiagnosed and underappreciated cause of heart failure. In the last few years, cardiovascular magnetic resonance (CMR) has become the gold standard for non invasive diagnosis of cardiac amyloidosis with the characteristic subendocardial late gadolinium enhancement.Case presentationWe describe a case of a patient who, in the process of aligning protocols for a trial between different centers, had a paired study with two different contrast agents, Dotarem® and MultiHance®. MultiHance® surprisingly failed to demonstrate the characteristic imaging pattern, showing only non specific late gadolinium enhancement at the inferior right ventricular insertion point and different myocardial extracellular volume fraction compared to the one obtained with Dotarem®. MultiHance® is used by many centres, because its partial blood protein binding is a strength for MR angiography, but late gadolinium enhancement, particularly non-ischemic, appears to be compromised.ConclusionsThis case report suggests that contrast agents should be selected with caution, especially with new therapies lining up for amyloid and CMR being used as exploratory end point in clinical trials.

Extracellular volume with bolus-only technique in amyloidosis patients: Diagnostic accuracy, correlation with other clinical cardiac measures, and ability to track changes in amyloid load over time: Extracellular Volume in Amyloidosis

Extracellular volume (ECV) by T1 mapping requires the contrast agent distribution to be at equilibrium. This can be achieved either definitively with a primed contrast infusion (infusion ECV), or sufficiently with a delay postbolus (bolus‐only ECV). For large ECV, the bolus‐only approach measures higher than the infusion ECV, causing some uncertainty in diseases such as amyloidosis.

3 Treatment response in cardiac al amyloidosis assessed by CMR: findings at 3 months, 6 months and 1 year post-chemotherapy

Introduction Cardiac involvement in immunoglobulin light chain (AL) amyloidosis is the major determinant of survival. Cardiac response to chemotherapy is conventionally assessed by serum brain natriuretic peptide (NT-proBNP) and echocardiography, but neither quantify amyloid burden. The aim of this study was to evaluate cardiac AL amyloid by CMR at 3 months, 6 months and 1 year post-chemotherapy. Methods 78 patients with cardiac AL amyloidosis were studied serially using CMR with T1 mapping and extracellular volume at baseline and 3 months, 6 months and 12 months post-chemotherapy. Results At 6 months, 60% of patients achieved a complete or very good partial haematological response, and 40% patients a partial response or no response. Amyloid regression was not detectable, however, amyloid progression was detectable in 30% patients at 6 months. Although this occurred in the PR group, it also occurred in the CR and VGPR groups (47%). At one year, 66% patients achieved a CR or VGPR. Regression of amyloid was seen in 32% patients, all with CR or VGPR and 0 patients in PR or NR (p<0.05). 46% patients with changes in ECV consistent with regression of amyloid had changes in LGE. Amyloid regression was associated with significant reduction in LV mass and increased LVEDV (p<0.05). Conclusion In newly diagnosed and treated AL amyloidosis, CMR demonstrates the dynamic biology of infiltration: increasing rapidly, particularly if chemotherapy fails to switch off light chain production; regressing more slowly (by 1 year) if effective. Serial monitoring of myocardial infiltration has the potential for new AL amyloidosis therapeutic regimes based on myocardial organ response.

015 Clinical utility of T1 mapping in cardiac ATTR amyloidosis – diagnostic performance and prognostic capability

Objectives Cardiac failure caused by transthyretin amyloidosis (ATTR) is an underdiagnosed clinical entity which has an important overlapping clinical phenotype with hypertrophic cardiomyopathy (HCM). Native myocardial T1 mapping by CMR is useful for diagnosis in cardiac amyloidosis. Here, we investigate the diagnostic and prognostic value of T1 mapping in the largest ATTR population studied so far as well as patients with HCM. We aimed to: 1) assess the ability of native T1 to diagnose cardiac amyloidosis; 2) compare native T1 to extracellular volume (ECV), and; 3) stratify prognosis. Methods 134 wild-type ATTR (ATTRwt) (122 males, age 76±7 years), 95 mutant-type (ATTRm) (64 males, age 66±12 years) and 12 mutation carriers (4 males, age 46±8 years) were compared to 44 HCM patients. All subjects underwent CMR with standard SSFP-cine imaging, T1 mapping and ECV measurement. ATTR patients underwent 99mTc-DPD scintigraphy, the current diagnostic imaging reference standard for ATTR, with uptake determined by semi-quantitative score. Results Native T1 and ECV were elevated in ATTR compared to HCM (p<0.001) (mean T1: in ATTRwt 1091±52 ms, in ATTRm 1084±68 ms, in HCM 1026±64 ms; mean ECV: in ATTRwt 0.6±0.1, in ATTRm 0.58±0.2 ms, in HCM 0.38±0.1 ms). No significant difference between native T1 and ECV was found between ATTRwt and ATTRm. Native T1 and ECV diagnostic performance was similar for ATTRwt and ATTRm (vs HCM: T1 AUC 0.89; ECV AUC 0.93; p=0.11 for the significance of the difference between areas under the ROC curves). During follow-up, 63 deaths occurred: 34 ATTRwt, 29 ATTRm. Whilst native T1 was not predictive of death, ECV was (HR, 1.130; 95% confidence interval, 1.06–1.2; p<0.001) and remained independent after adjustment for age, N-terminal pro b-type natriuretic peptide, left ventricular (LV) ejection fraction, E/E’, LV mass index, global longitudinal strain and tricuspid annular plane systolic excursion. Conclusions CMR-determined native myocardial T1 and ECV provide excellent diagnostic accuracy for identification of ATTR cardiac amyloidosis and both variables track DPD-determined amyloid burden well. In this study, whilst T1 was not a predictor of mortality, ECV was independently associated with mortality. Abstract 015 Figure 1 Diagnostic performance and prognostic capability. (A) Receiver operator characteristics curve (ROC) for the discrimination of possible or definite transthyretin (ATTR) cardiac amyloidosis by native T1 and ECV from HCM. Kaplan-Meier survival curves for (B) pre-contrast myocardial T1 and (C) extracellular volume at bolus. The median native myocardial T1 (1092ms) (B) and median extracellular volume (ECV) (0.61) (C) were used as the respective cut points for survival. Abstract 015 Figure 2 Characteristics Examples from CMR Scans. CMR end-diastolic cine (far left), shortened modified look locker inversion recovery native T1 map (middle) and late gadolinium enhancement (LGE) images (far right), in two patients with definite transthyretin amyloidosis (ATTR amyloidosis), one (top) with normal T1 map, mildly eleveted native myocardial T1 (1039ms) and very elevated ECV (0.7), the other (bottom) with abnormal T1 map, markedly elevated native myocardial T1 (1224ms) and very elevated ECV (0.7).

024 Spectrum and significance of CMR findings in cardiac transthyretin amyloidosis

Background Cardiac transthyretin amyloidosis (ATTR amyloidosis) is an increasingly recognised cause of heart failure. Cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) and T1 mapping is emerging as a reference standard for diagnosis and characterisation of cardiac amyloid. Objectives We used CMR with extracellular volume fraction (ECV) measurement to characterise cardiac involvement in relation to outcome in ATTR amyloidosis. Methods Subjects comprised 263 patients with cardiac ATTR amyloidosis corroborated by grade 2–3 99mTc-DPD cardiac uptake, 17 with suspected cardiac ATTR amyloidosis (grade 1 99mTc-DPD) and 12 asymptomatic individuals with amyloidogenic transthyretin (TTR) mutations. Fifty patients with cardiac AL amyloidosis acted as disease controls. Results In contrast to AL amyloidosis, asymmetric septal hypertrophy was present in 79% of ATTR patients (70% sigmoid septum and 30% reverse septal curvature), whilst symmetric left ventricular hypertrophy (LVH) was present in only 18%; 3% of patients has no LVH. In patients with cardiac amyloidosis, the pattern of LGE was always typical for amyloidosis (29% subendocardial, 71% transmural) including right ventricular LGE (96%). 65 patients died during follow-up (19±14 months). ECV independently correlated with mortality and remained independent after adjustment for age, N-terminal pro-brain natriuretic peptide, ejection fraction, E/E’ and left ventricular mass index (hazard ratio, 1.164; 95% confidence interval, 1.066–1.271; p<0.01). Conclusions Asymmetric hypertrophy, traditionally associated with hypertrophic cardiomyopathy, is the commonest pattern of ventricular remodelling in ATTR amyloidosis. LGE imaging is typical in all patients with cardiac ATTR amyloidosis. ECV correlates with amyloid burden and provides incremental information on outcome even after adjustment for known prognostic factors. Abstract 024 Figure 1 Left: four-chamber SSEP cine image in diastole and corresponding late gadolinium enhancement (LGE) images of four patients; asymmetric hypertropy with sigmoid septal contour and transmural LGE (top); asymmetric hypertrophy with reverse septal contour and transmural LGE (second from top); symmetric hypertrophy pattern and transmural LGE (third from top); eft ventricular hypertrophy and subendocardial LGE (bottom). Right top; Kaplan-Meier curve for ECV. Right bottom: four-chamber SSFP cine image in diastole and corresponding LGE images, native T1 maps and ECV maps of there patients, showing no LGE (top), subendocardial LGE (middle) and transmural LGE (bottom).

Staging Cardiac Amyloidosis With CMR: Understanding the Different Phenotypes.

C ardiac involvement is the leading cause of morbidity and mortality in systemic amyloidosis (1). It occurs in about 50% of patients with systemic light-chain (AL) amyloidosis and is the dominant clinical feature in patients with wild-type transthyretin (ATTR) amyloidosis and many genetic variant forms of the latter. Accurate identification and staging of cardiac amyloidosis is the crucial first step in management of these patients, involving confirmation of amyloid deposits, identification of fibril type, and evaluation of the extent and severity of amyloid-related organ damage. Cardiac magnetic resonance (CMR) has unique advantages in identifying cardiac involvement in systemic amyloidosis. CMR provides information about cardiac structure and function, but most importantly informs us on tissue composition. CMR leverages its intrinsic capacity to characterize tissue on the basis of fundamental MR properties (T1 and T2), and these intrinsic properties can be accentuated by administration of gadolinium-based contrast agents. The latest MR techniques for evaluating late gadolinium enhancement (LGE) provide images that are virtually pathognomonic in AL and ATTR cardiac amyloidosis (2) with excellent diagnostic accuracy. Recently, the role of CMR in systemic amyloidosis has evolved beyond just diagnostic utility (3–7). CMR tracks the continuum of amyloid accumulation as determined by the transmurality of LGE pattern, progressing from normal through subendocardial to transmural LGE. This has greatly elucidated how amyloid infiltration leads to dysfunction and has highlighted the potential role of LGE as a new