Rohin Francis

Magnetic Resonance in Transthyretin Cardiac Amyloidosis

BACKGROUNDnCardiac transthyretin amyloidosis (ATTR) is an increasingly recognized cause of heart failure. Cardiac magnetic resonance (CMR), with late gadolinium enhancement (LGE) and T1 mapping, is emerging as a reference standard for diagnosis and characterization of cardiac amyloidosis.nnnOBJECTIVESnThe authors used CMR with extracellular volume fraction (ECV) measurement to characterize cardiac involvement in relation to outcome in ATTR.nnnMETHODSnSubjects comprised 263 patients with cardiac ATTR corroborated by grade 2 to 3 99mTc-DPD (99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid) cardiac uptake, 17 with suspected cardiac ATTR (grade 1 99mTc-DPD), and 12xa0asymptomatic individuals with amyloidogenic transthyretin (TTR) mutations. Fifty patients with cardiac light-chain (AL) amyloidosis acted as disease comparators.nnnRESULTSnUnlike cardiac AL amyloidosis, asymmetrical septal left ventricular hypertrophy (LVH) was present in 79% of patients with ATTR (70% sigmoid septum and 30% reverse septal contour), whereas symmetrical LVH was present in 18%, and 3% had no LVH. In patients with cardiac amyloidosis, the pattern of LGE was always typical forxa0amyloidosis (29% subendocardial, 71% transmural), including right ventricular LGE (96%). During follow-up (19xa0±xa014xa0months), 65 patients died. ECV independently correlated with mortality and remained independent after adjustment for age, N-terminalxa0pro-B-type natriuretic peptide, ejection fraction, E/E, and left ventricular mass (hazard ratio: 1.164; 95% confidence interval: 1.066 to 1.271; pxa0< 0.01).nnnCONCLUSIONSnAsymmetrical hypertrophy, traditionally associated with hypertrophic cardiomyopathy, was the commonest pattern of ventricular remodeling in ATTR. LGE imaging was typical in all patients with cardiac ATTR. ECVxa0correlated with amyloid burden and was an independent prognostic factor for survival in this cohort of patients.

Myocardial Edema and Prognosis in Amyloidosis

BACKGROUNDnPrognosis in light-chain (AL) and transthyretin (ATTR) amyloidosis is influenced by cardiac involvement. ATTR amyloidosis has better prognosis than AL amyloidosis despite more amyloid infiltration, suggesting additional mechanisms of damage in AL amyloidosis.nnnOBJECTIVESnThe aim of the study was to assess the presence and prognostic significance of myocardial edema in patients with amyloidosis.nnnMETHODSnThe study recruited 286 patients: 100 with systemic AL amyloidosis, 163 with cardiac ATTR amyloidosis, 12 with suspected cardiac ATTR amyloidosis (grade 1 on 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid), 11 asymptomatic individuals with amyloidogenic TTR gene mutations, and 30 healthy volunteers. All subjects underwent cardiovascular magnetic resonance with T1 and T2 mapping and 16 underwent endomyocardial biopsy.nnnRESULTSnMyocardial T2 was increased in amyloidosis with the degree of elevation being highest in untreated AL patients (untreated AL amyloidosis 56.6 ± 5.1xa0ms; treated AL amyloidosis 53.6 ± 3.9xa0ms; ATTR amyloidosis 54.2 ± 4.1xa0ms; each pxa0< 0.01 compared with control subjects: 48.9 ± 2.0xa0ms). Left ventricular (LV) mass and extracellular volume fraction were higher in ATTR amyloidosis compared with AL amyloidosis while LV ejection fraction was lower (pxa0<xa00.001). Histological evidence of edema was present in 87.5% of biopsy samples ranging from 5% to 40% myocardial involvement. Using Cox regression models, myocardial T2 predicted death in AL amyloidosis (hazard ratio: 1.48; 95% confidence interval: 1.20 to 1.82) and remained significant after adjusting for extracellular volume fraction and N-terminal pro-B-type natriuretic peptide (hazard ratio: 1.32; 95% confidence interval: 1.05 to 1.67).nnnCONCLUSIONSnMyocardial edema is present in cardiac amyloidosis by histology and cardiovascular magnetic resonance T2 mapping. T2 is higher in untreated AL amyloidosis compared with treated AL and ATTR amyloidosis, and is a predictor of prognosis in AL amyloidosis. This suggests mechanisms additional to amyloid infiltration contributing to mortality in amyloidosis.

Cardiac Structural and Functional Consequences of Amyloid Deposition by Cardiac Magnetic Resonance and Echocardiography and Their Prognostic Roles

OBJECTIVESnThis cross-sectional study aimed to describe the functional and structural cardiac abnormalities that occur across a spectrum of cardiac amyloidosis burden and to identify the strongest cardiac functional and structural prognostic predictors in amyloidosis using cardiac magnetic resonance (CMR) and echocardiography.nnnBACKGROUNDnCardiac involvement in light chain and transthyretin amyloidosis is the main driver of prognosis and influences treatment strategies. Numerous measures of cardiac structure and function are assessed by multiple imaging modalities in amyloidosis.nnnMETHODSnA total f 322 subjects (311 systemic amyloidosis and 11 transthyretin gene mutation carriers) underwent comprehensive CMR and transthoracic echocardiography. The probabilities of 11 commonly measured structural and functional cardiac parameters being abnormal with increasing cardiac amyloidosis burden were evaluated. Cardiac amyloidosis burden was quantified using CMR-derived extracellular volume. The prognostic capacities of these parameters to predict death in amyloidosis were assessed using Cox proportional hazards models.nnnRESULTSnLeft ventricular mass and mitral annular plane systolic excursion by CMR along with strain and E/e by echocardiography have high probabilities of being abnormal at low cardiac amyloid burden. Reductions in biventricular ejection fractions and elevations in biatrial areas occur at high burdens of infiltration. The probabilities of indexed stroke volume, myocardial contraction fraction, and tricuspid annular plane systolic excursion (TAPSE) being abnormal occur more gradually with increasing extracellular volume. Ninety patients (28%) died during a median follow-up of 22 months (interquartile range: 10 to 38 months). Univariable analysis showed that all imaging markers studied significantly predicted outcome. Multivariable analysis showed that TAPSE (hazard ratio: 1.46; 95% confidence interval: 1.16 to 1.85; pxa0< 0.01) and indexed stroke volume (hazard ratio: 1.24; 95% confidence interval: 1.04 to 1.48; pxa0< 0.05) by CMR were the only independent predictors of mortality.nnnCONCLUSIONSnSpecific functional and structural abnormalities characterize different burdens of cardiac amyloid deposition. In a multimodality imaging assessment of a large cohort of amyloidosis patients, CMR-derived TAPSE and indexed stroke volume are the strongest prognostic cardiac functional markers.

Full left ventricular coverage is essential for the accurate quantification of the area-at-risk by T1 and T2 mapping

T2-weighted cardiovascular magnetic resonance (CMR) using a 3-slice approach has been shown to accurately quantify the edema-based area-at-risk (AAR) in ST-segment elevation myocardial infarction (STEMI). We aimed to compare the performance of a 3-slice approach to full left ventricular (LV) coverage for the AAR by T1 and T2 mapping and MI size. Forty-eight STEMI patients were prospectively recruited and underwent a CMR at 4u2009±u20092 days. There was no difference between the AARfull LV and AAR3-slices by T1 (Pu2009=u20090.054) and T2-mapping (Pu2009=u20090.092), with good correlations but small biases and wide limits of agreements (T1-mapping: Nu2009=u200930, R2u2009=u20090.85, biasu2009=u20091.7u2009±u20099.4%u2009LV; T2-mapping: Nu2009=u200948, R2u2009=u20090.75, biasu2009=u20091.7u2009±u200912.9%u2009LV). There was also no significant difference between MI size3-slices and MI sizefull LV (Pu2009=u20090.93) with an excellent correlation between the two (R2 0.92) but a small bias of 0.5% and a wide limit of agreement of ±7.7%. Although MSI was similar between the 2 approaches, MSI3-slices performed poorly when MSI was <0.50. Furthermore, using AAR3-slices and MI sizefull LV resulted in ‘negative’ MSI in 7/48 patients. Full LV coverage T1 and T2 mapping are more accurate than a 3-slice approach for delineating the AAR, especially in those with MSIu2009<u20090.50 and we would advocate full LV coverage in future studies.

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; pu2009<u20090.05). 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 (pu2009<u20090.05)). 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.

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 1u2009year 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 1u2009year) 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 44u2009HCM 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±14u2009months). 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).

028 Routine identification of hypoperfusion in cardiac amyloidosis by myocardial blood flow mapping

Background Cardiac involvement is the main driver of outcome in systemic amyloidosis, but the relationship between amyloid deposits and cellular injury is not well understood. The simple explanation of physical, mechanical replacement of parenchymal tissue seems insufficient, and preliminary studies support the hypothesis that myocardial hypoperfusion could contribute to cell damage in amyloidosis. The aim of this study was: 1) To assess feasibility of fully automated pixel-wise rest myocardial blood flow (MBF) mapping in cardiac amyloidosis during routine clinical scans; 2) To assess the prevalence of myocardial hypoperfusion and correlation with amyloid deposits and disease severity. Methods Patients (n=56) with systemic amyloidosis and healthy volunteers (n=16) were recruited. All subjects underwent CMR at 1.5T (Siemens) with standard SSFP cine imaging, Phase Sensitive Inversion Recovery Reconstruction Late Gadolinium Enhancement (PSIR-LGE), T1 mapping, Extracellular Volume (ECV) mapping and rest MBF mapping. Results The pixel-wise MBF maps for all slices were generated automatically in all patients within 2.5u2009min after image acquisition. Myocardial perfusion was globally reduced in patients with cardiac amyloidosis compared to healthy volunteers (0.66±0.26u2009ml/min/g vs 0.84±0.19u2009ml/min/g, p<0.05). Myocardial perfusion inversely correlated with amyloid burden measured as extracellular volume fraction (r=−0.46, p<0.001) (figure 1) and with the transmurality of LGE (no LGE 0.88±0.18u2009ml/min/g, subendocardial LGE 0.73±0.28u2009ml/min/g and transmural LGE 0.58±0.20u2009ml/min/g, p<0.01) (figure 2). There was a correlation between myocardial perfusion and markers of systolic dysfunction (EF, r=0.39, p<0.01) as well as blood biomarkers (NT-proBNP, r=−0.41, p<0.01 and Troponin T, r=−0.41, p<0.01), current reference prognostic markers in cardiac amyloidosis. There was no significant correlation between myocardial perfusion and native T1 values (r=−0.07, p=0.59). Conclusions Myocardial perfusion can be measured in cardiac amyloidosis during routine clinical scans with fully automated MBF mapping. Myocardial hypoperfusion at rest is highly prevalent in subjects with cardiac amyloidosis, and correlates with the degree of amyloid infiltration and disease severity.

Journal clubs in the digital age: Twitter for continuing professional development

ABSTRACT The departmental journal club (JC) is a well-established form of continuing professional development (CPD). Social media offers a range of interactive online platforms, allowing the traditional JC to move from a formal educational meeting with local health professionals to a digital platform with users across the world. The authors created the General Internal Medicine JC (@GIMJClub) on Twitter and following a year of activity retrospectively analysed the participation and impact of this medium of JC delivery. There were 61 different participants across different continents, specialties and levels who participated in the 12 JC sessions and sent 1,543 tweets in total. Factors that appeared to influence the success of an individual JC session included choosing diverse, topical papers to discuss and a wide range of hosts. This work demonstrates the success of a Twitter-based general internal medicine JC for CPD. @GIMJClub facilitated unique and diverse interactions not otherwise available.