Sabrina Nordin

Assessing for Cardiotoxicity from Metal-on-Metal Hip Implants with Advanced Multimodality Imaging Techniques

Background: High failure rates of metal-on-metal (MoM) hip implants prompted regulatory authorities to issue worldwide safety alerts. Circulating cobalt from these implants causes rare but fatal autopsy-diagnosed cardiotoxicity. There is concern that milder cardiotoxicity may be common and underrecognized. Although blood metal ion levels are easily measured and can be used to track local toxicity, there are no noninvasive tests for organ deposition. We sought to detect correlation between blood metal ions and a comprehensive panel of established markers of early cardiotoxicity. Methods: Ninety patients were recruited into this prospective single-center blinded study. Patients were divided into 3 age and sex-matched groups according to implant type and whole-blood metal ion levels. Group-A patients had a ceramic-on-ceramic [CoC] bearing; Group B, an MoM bearing and low blood metal ion levels; and Group C, an MoM bearing and high blood metal-ion levels. All patients underwent detailed cardiovascular phenotyping using cardiac magnetic resonance imaging (CMR) with T2*, T1, and extracellular volume mapping; echocardiography; and cardiac blood biomarker sampling. T2* is a novel CMR biomarker of tissue metal loading. Results: Blood cobalt levels differed significantly among groups A, B, and C (mean and standard deviation [SD], 0.17 ± 0.08, 2.47 ± 1.81, and 30.0 ± 29.1 ppb, respectively) and between group A and groups B and C combined. No significant between-group differences were found in the left atrial or ventricle size, ejection fraction (on CMR or echocardiography), T1 or T2* values, extracellular volume, B-type natriuretic peptide level, or troponin level, and all values were within normal ranges. There was no relationship between cobalt levels and ejection fraction (R = 0.022, 95% confidence interval [CI] = −0.185 to 0.229) or T2* values (R = 0.108, 95% CI = −0.105 to 0.312). Conclusions: Using the best available technologies, we did not find that high (but not extreme) blood cobalt and chromium levels had any significant cardiotoxic effect on patients with an MoM hip implant. There were negligible-to-weak correlations between elevated blood metal ion levels and ejection fraction even at the extremes of the 95% CI, which excludes any clinically important association. Level of Evidence: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Ultrafast Magnetic Resonance Imaging for Iron Quantification in Thalassemia Participants in the Developing World: The TIC-TOC Study (Thailand and UK International Collaboration in Thalassaemia Optimising Ultrafast CMR).

Thalassemia is the most common monogenetic disorder worldwide, with 60 000 infants with thalassemia major born annually.1 Survival often depends on regular blood transfusions to correct anemia and to reduce ineffective erythropoiesis, but these transfusions can result in iron overload and organ failure unless chelation therapy is undertaken. Serum ferritin levels continue to be used as a guide to chelation but are unreliable, and the availability of cardiovascular magnetic resonance (CMR) T2* imaging has transformed patient management by allowing organ-specific quantification of iron content.2,3

001 Multiparametric mapping to understand pathophysiology in cardiac amyloidosis

Background The prognosis and treatment of the 2 main types of cardiac amyloidosis, immunoglobulin light chain (AL) and transthyretin (ATTR) amyloidosis are substantially influenced by cardiac involvement. ATTR amyloidosis has better prognosis than AL despite more amyloid infiltration. This paradox suggests additional mechanisms of damage in AL amyloidosis. The aim of this study was to assess the presence and ?prognostic significance of oedema in a large population of patients with cardiac amyloidosis and compare findings among those with TTR and AL types. Methods and results 286 patients (100 with systemic AL amyloidosis (including 49 patients scanned prior to commencing chemotherapy), 163 with cardiac ATTR amyloidosis, 12 with suspected cardiac ATTR amyloidosis (grade 1 on 99mTc-DPD) and 11 asymptomatic individuals with amyloidogenic transthyretin(TTR) mutations), and 30 healthy volunteers were recruited. All subjects underwent CMR with T1 and T2 mapping, and ECV quantification. Left ventricular(LV) mass and ECV were higher in ATTR compared to AL whilst LV ejection fraction(EF) was significantly lower(p<0.001). There was no significant difference in ECV between treated and untreated AL (Figure 1a). T2 was increased in cardiac amyloidosis compared to healthy volunteers with the degree of elevation being the highest in untreated AL patients (T2: 56.3±4.9 ms AL untreated, 54.0 ±4.5 ms AL treated, 54.3±4.1 ms ATTR, 48.9±2.0 ms controls, p<0.05 for all except treated AL vs ATTR) (Figure 1b). During follow up (22.8±14.7 months), 75 (28% of AL group and 25% of ATTR group) patients died. Using Cox regression models, T2 predicted death in AL amyloidosis (hazard ratio, HR,1.48, 95% CI 1.20–1.82) and remained significant after adjusting for EF and ECV (HR 1.31, 95% CI 1.04–1.66) (Abstract 1 Figure 2). Abstract 001 Figure 1 a. Mean ECV in cardiac AL (treated and untreated patients) and ATTR amyloidosis compared to healthy volunteers. b. Mean T2 in cardiac AL (treated and untreated patients) and ATTR amyloidosis compared to healthy volunteers. Abstract 001 Figure 2 a. Examples of two patients with AL amyloidosis and transmural late gadolinium enhancement, one with eleveted T2 (top) and the other with normal T2 (bottom). b. Kaplan-Meier survival curve of patients with AL amyloidosis with high T2 and normal T2 values. Conclusion Patients with AL amyloidosis have a worse prognosis compared to ATTR despite having less cardiac amyloid infiltration. T2 was significantly higher in untreated AL amyloidosis consistent with oedema, and was an independent predictor of prognosis. The higher ECV in ATTR was consistent with higher amyloid infiltration. These findings highlight the unique role of CMR with multiparametric mapping for characterising the cardiac effects of systemic amyloidosis and risk stratification in this population.

Reproducibility of native T1 mapping using ShMOLLI and MOLLI - implications for sample size calculation

Background Native T1 mapping is becoming established to help diagnose and monitor myocardial disease. The reproducibility of T1 mapping has not been well characterized, despite the important implications both for interpreting serial clinical studies, and for sample size calculation for surrogate endpoint in clinical trials. The SCMR consensus statement recommends measuring T1 in 2 imaging views. We investigated the test-retest reproducibility of two native T1 mapping techniques using different imaging views.

Redefining viability by cardiovascular magnetic resonance in acute ST-segment elevation myocardial infarction

In chronic myocardial infarction (MI), segments with a transmural extent of infarct (TEI) of ≤50% are defined as being viable. However, in the acute phase of an ST-segment elevation myocardial infarction (STEMI), late gadolinium enhancement (LGE) has been demonstrated to overestimate MI size and TEI. We aimed to identify the optimal cut-off of TEI by cardiovascular magnetic resonance (CMR) for defining viability during the acute phase of an MI, using ≤50% TEI at follow-up as the reference standard. 40 STEMI patients reperfused by primary percutaneous coronary intervention (PPCI) underwent a CMR at 4 ± 2 days and 5 ± 2 months. The large majority of segments with 1–25%TEI and 26–50%TEI that were viable acutely were also viable at follow-up (59/59, 100% and 75/82, 96% viable respectively). 56/84(67%) segments with 51–75%TEI but only 4/63(6%) segments with 76–100%TEI were reclassified as viable at follow-up. TEI on the acute CMR scan had an area-under-the-curve of 0.87 (95% confidence interval of 0.82 to 0.91) and ≤75%TEI had a sensitivity of 98% but a specificity of 66% to predict viability at follow-up. Therefore, the optimal cut-off by CMR during the acute phase of an MI to predict viability was ≤75% TEI and this would have important implications for patients undergoing viability testing prior to revascularization during the acute phase.

Global longitudinal strain, myocardial storage and hypertrophy in Fabry disease

Introduction Detecting early cardiac involvement in Fabry disease (FD) is important because therapy may alter disease progression. Cardiovascular magnetic resonance (CMR) can detect T1 lowering, representing myocardial sphingolipid storage. In many diseases, early mechanical dysfunction may be detected by abnormal global longitudinal strain (GLS). We explored the relationship of early mechanical dysfunction and sphingolipid deposition in FD. Methods An observational study of 221 FD and 77 healthy volunteers (HVs) who underwent CMR (LV volumes, mass, native T1, GLS, late gadolinium enhancement), ECG and blood biomarkers, as part of the prospective multicentre Fabry400 study. Results All FD had normal LV ejection fraction (EF 73%±8%). Mean indexed LV mass (LVMi) was 89±39 g/m2 in FD and 55.6±10 g/m2 in HV. 102 (46%) FD participants had left ventricular hypertrophy (LVH). There was a negative correlation between GLS and native T1 in FD patients (r=−0.515, p<0.001). In FD patients without LVH (early disease), as native T1 reduced there was impairment in GLS (r=−0.285, p<0.002). In the total FD cohort, ECG abnormalities were associated with a significant impairment in GLS compared with those without ECG abnormalities (abnormal: −16.7±3.5 vs normal: −20.2±2.4, p<0.001). Conclusions GLS in FD correlates with an increase in LVMi, storage and the presence of ECG abnormalities. In LVH-negative FD (early disease), impairment in GLS is associated with a reduction in native T1, suggesting that mechanical dysfunction occurs before evidence of sphingolipid deposition (low T1). Trial registration number NCT03199001; Results.

49 Predicting risk of scd in fabry disease: a single centre experience

Introduction Fabry disease (FD) is a rare X-linked lysosomal storage disorder with a variable cardiac phenotype and a defined risk of ventricular arrhythmia (VA) and sudden cardiac death (SCD). To-date however, there is no accepted tool for risk prediction in FD and the ESC calculator in hypertrophic cardiomyopathy specifically excludes lysosomal storage diseases. Data on the prevalence of VA and SCD are restricted to single centre studies and registry data. These have identified individual risk factors including age, QRS duration>120 ms, left atrial dilatation (LA), late gadolinium enhancement on cardiac magnetic resonance (CMR) imaging (LGE), and left ventricular hypertrophy (LVH). The aim of this study was to assess the prevalence of these risk factors in a Regional FD centre and to examine known markers associated with increased cardiac mortality in FD to comprehensively assess risk. Methods This was a retrospective cross sectional observational study of patients with a proven diagnosis of FD (genetic and clinical markers) attending the Regional Centre for Rare Diseases in Birmingham between 2012–16. As part of routine annual assessment, patients underwent 12-lead ECG, 24 hour holter monitoring, transthoracic echocardiography and multi-parametric CMR. The cohort was divided into 2 groups: 1) a high risk group defined by presence of either VA (≥3 consecutive ventricular beats at a rate ≥120 beats per minute) or SCD; 2) all other patients. In addition to the above 5 risk factors, genotype (cardiac variant v non-cardiac variant), high sensitivity troponin (HS Tn) and NT pro-B natriuretic peptide were included. The frequency and significance of each of these proposed risk factors was studied. Fisher’s exact test was used to perform statistical analysis. Results In total 57 patients (male gender 42%, age mean 47±18 years.) were studied, of whom 13 patients had a documented VA and 2 patients suffered SCD. 11/13 in high risk group were on ERT (7±6 years.) and 21/44 in the remainder (6±3.8 years.). Identified risk factors and prevalence are outlined in Table 1. Male gender, age>50, LVH, LGE, QRS>120 ms were all more frequent in those with VA or SCD but risk was also associated with increased HS Tn and NT pro-BNP. The presence of a cardiac variant genotype did not appear to influence risk. Outcome These data confirm specific demographic, electrical and structural risk factors for VA and SCD in FD, although these are also present in those without arrhythmic events. Large multi-centre prospective studies are needed to further define the relative importance of these risk factors and their potential inter-relationship. Abstract 49 Table 1 Risk Predictors Patients with VA or SCD Patients without VA/SCD P value Male gender 9/13 (69%) 15/44 (34%) 0.05 Age>50 years 11/13 (85%) 20/44 (45%) 0.02 Left ventricular hypertrophy 13/13 (100%) 19/44 (43%) 0.0002 Presence of LGE 7/10 (70%) 12/38 (32%) 0.03 QRS duration>120 ms 7/13 (54%) 12/38 (32%) 0.03 Dilated left atrium 6/13 (46%) 9/44 (20%) 0.08 Stage ≥3 CKD 4/13 (31%) 11/44 (25%) 0.72 Classical variant 10/13 (77%) 30/44 (68%) 0.73 Positive HS troponin (>25 ng/L) 8/8 (100%) 16/33 (48%) 0.01 BNP >400 (ng/L) 10/13 (77%) 14/42 (33%) 0.009

Ultrafast CMR to deliver high volume screening of an at risk thalassemia population in the developing world: preliminary results from the TIC-TOC study (Thailand and UK international collaboration in thalassaemia using an optimised ultrafast CMR protocol)

Ultrafast CMR to deliver high volume screening of an at risk thalassemia population in the developing world: preliminary results from the TIC-TOC study (Thailand and UK international collaboration in thalassaemia using an optimised ultrafast CMR protocol) Amna Abdel-Gadir, Yongkasem Vorasettakarnkij, Hataichanok Ngamkasem, Sabrina Nordin, Emmanuel O Ako, Monravee Tumkosit, Pranee Sutcharitchan, Peter Kellman, Stefan K Piechnik, Juliano L Fernandes, Mark Westwood, John Porter, John Malcolm Walker, James Moon

ECG, LVH and T1 changes in Fabry disease - implications for screening and understanding of the disease model

Background Fabry disease is a rare X-linked condition that results in storage of sphingolipids in multiple organs including the heart. The cardiac phenotype consists mainly of conduction abnormalities, left ventricular hypertrophy (LVH) and disease progression (fibrosis, arrhythmias and heart failure). CMR LGE classically shows basal inferolateral LGE. Native T1 mapping has recently shown a low T1 likely to represent myocycte storage of fat, even when no LVH is present. We sought to understand the relationship of storage to LVH and ECG abnormalities.