Improving cardiovascular magnetic resonance access in low- and middle-income countries for cardiomyopathy assessment: rapid cardiovascular magnetic resonance.

AIMS: To evaluate the impact of a simplified, rapid cardiovascular magnetic resonance (CMR) protocol embedded in care and supported by a partner education programme on the management of cardiomyopathy (CMP) in low- and middle-income countries (LMICs). METHODS AND RESULTS: Rapid CMR focused particularly on CMP was implemented in 11 centres, 7 cities, 5 countries, and 3 continents linked to training courses for local professionals. Patients were followed up for 24 months to assess impact. The rate of subsequent adoption was tracked. Five CMR conferences were delivered (920 attendees-potential referrers, radiographers, reporting cardiologists, or radiologists) and five new centres starting CMR. Six hundred and one patients were scanned. Cardiovascular magnetic resonance indications were 24% non-contrast T2* scans [myocardial iron overload (MIO)] and 72% suspected/known cardiomyopathies (including ischaemic and viability). Ninety-eighty per cent of studies were of diagnostic quality. The average scan time was 22 ± 6 min (contrast) and 12 ± 4 min (non-contrast), a potential cost/throughput reduction of between 30 and 60%. Cardiovascular magnetic resonance findings impacted management in 62%, including a new diagnosis in 22% and MIO detected in 30% of non-contrast scans. Nine centres continued using rapid CMR 2 years later (typically 1-2 days per week, 30 min slots). CONCLUSIONS: Rapid CMR of diagnostic quality can be delivered using available technology in LMICs. When embedded in care and a training programme, costs are lower, care is improved, and services can be sustained over time.

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.

BACKGROUND: 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. PURPOSE: To characterize the relationship between the bolus-only and current gold-standard infusion ECV in patients with amyloidosis. STUDY TYPE: Bolus-only and infusion ECV were prospectively measured. POPULATION: In all, 186 subjects with systemic amyloidosis attending our clinic and 23 subjects with systemic amyloidosis who were participating in an open-label, two-part, dose-escalation, phase 1 trial. FIELD STRENGTH: Avanto 1.5T, Siemens Medical Solutions, Erlangen, Germany. ASSESSMENT: Bolus-only and infusion ECV were measured in all subjects using shortened modified Look-Locker inversion recovery (ShMOLLI) T1 mapping sequence. STATISTICAL TESTS: Pearson correlation coefficient (r); Bland-Altman; receiver operating characteristic (ROC) curve analysis. Linear regression model with a fractional polynomial transformation. RESULTS: The difference between the bolus-only and infusion myocardial ECV increased as the average of the two measures increased, with the bolus-ECV measuring higher. For an average ECV of 0.4, the difference was 0.013. The 95% limits of agreement for the two methods, after adjustment for the bias, were ±0.056. However, cardiac diagnostic accuracy was comparable (bolus-only vs. infusion ECV area under the curve [AUC] = 0.839 vs. 0.836), as were correlations with other clinical cardiac measures, and, in the trial patients, the ability to track changes in the liver/spleen with therapy. DATA CONCLUSION: In amyloidosis, with large ECVs, the bolus-only technique reads higher than the infusion technique, but clinical performance by any measure is the same. Given the work-flow advantages, these data suggest that the bolus-only approach might be acceptable for amyloidosis, and might support its use as a surrogate endpoint in future clinical trials. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2018;47:1677-1684.

Diagnostic performance of T1 and T2 mapping to detect intramyocardial hemorrhage in reperfused ST-segment elevation myocardial infarction (STEMI) patients.

PURPOSE: To investigate the performance of T1 and T2 mapping to detect intramyocardial hemorrhage (IMH) in ST-segment elevation myocardial infarction (STEMI) patients treated by primary percutaneous coronary intervention (PPCI). MATERIALS AND METHODS: Fifty STEMI patients were prospectively recruited between August 2013 and July 2014 following informed consent. Forty-eight patients completed a 1.5T cardiac magnetic resonance imaging (MRI) with native T1 , T2 , and T2* maps at 4 ± 2 days. Receiver operating characteristic (ROC) analyses were performed to assess the performance of T1 and T2 to detect IMH. RESULTS: The mean age was 59 ± 13 years old and 88% (24/48) were male. In all, 39 patients had interpretable T2* maps and 26/39 (67%) of the patients had IMH ( T2* <20 msec on T2* maps). Both T1 and T2 values of the hypointense core within the area-at-risk (AAR) performed equally well to detect IMH (T1 maps AUC 0.86 [95% confidence interval [CI] 0.72-0.99] versus T2 maps AUC 0.86 [95% CI 0.74-0.99]; P = 0.94). Using the binary assessment of presence or absence of a hypointense core on the maps, the diagnostic performance of T1 and T2 remained equally good (T1 AUC 0.87 [95% CI 0.73-1.00] versus T2 AUC 0.85 [95% CI 0.71-0.99]; P = 0.90) with good sensitivity and specificity (T1 : 88% and 85% and T2 : 85% and 85%, respectively). CONCLUSION: The presence of a hypointense core on the T1 and T2 maps can detect IMH equally well and with good sensitivity and specificity in reperfused STEMI patients and could be used as an alternative when T2* images are not acquired or are not interpretable. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:877-886.

Defining left ventricular remodeling following acute ST-segment elevation myocardial infarction using cardiovascular magnetic resonance.

BACKGROUND: The assessment of post-myocardial infarction (MI) left ventricular (LV) remodeling by cardiovascular magnetic resonance (CMR) currently uses criteria defined by echocardiography. Our aim was to provide CMR criteria for assessing LV remodeling following acute MI. METHODS: Firstly, 40 reperfused ST-segment elevation myocardial infarction (STEMI) patients with paired acute (4 ± 2 days) and follow-up (5 ± 2 months) CMR scans were analyzed by 2 independent reviewers and the minimal detectable changes (MDCs) for percentage change in LV end-diastolic volume (%ΔLVEDV), LV end-systolic volume (%ΔLVESV), and LV ejection fraction (%ΔLVEF) between the acute and follow-up scans were determined. Secondly, in 146 reperfused STEMI patients, receiver operator characteristic curve analyses for predicting LVEF <50% at follow-up (as a surrogate for clinical poor clinical outcome) were undertaken to obtain cut-off values for %ΔLVEDV and %ΔLVESV. RESULTS: The MDCs for %ΔLVEDV, %ΔLVESV, and %ΔLVEF were similar at 12%, 12%, 13%, respectively. The cut-off values for predicting LVEF < 50% at follow-up were 11% for %ΔLVEDV on receiver operating characteristic curve analysis (area under the curve (AUC) 0.75, 95% CI 0.6 to 0.83, sensitivity 72% specificity 70%), and 5% for %ΔLVESV (AUC 0.83, 95% CI 0.77 to 0.90, sensitivity and specificity 78%). Using cut-off MDC values (higher than the clinically important cut-off values) of 12% for both %ΔLVEDV and %ΔLVESV, 4 main patterns of LV remodeling were identified in our cohort: reverse LV remodeling (LVEF predominantly improved); no LV remodeling (LVEF predominantly unchanged); adverse LV remodeling with compensation (LVEF predominantly improved); and adverse LV remodeling (LVEF unchanged or worsened). CONCLUSIONS: The MDCs for %ΔLVEDV and %ΔLVESV between the acute and follow-up CMR scans of 12% each may be used to define adverse or reverse LV remodeling post-STEMI. The MDC for %ΔLVEF of 13%, relative to baseline, provides the minimal effect size required for investigating treatments aimed at improving LVEF following acute STEMI.

Prognostic Value of Late Gadolinium Enhancement Cardiovascular Magnetic Resonance 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. Cardiovascular magnetic resonance with late gadolinium enhancement (LGE) is a reference standard for the diagnosis of cardiac amyloidosis, but its potential for stratifying risk is unknown. METHODS AND RESULTS: Two hundred fifty prospectively recruited subjects, 122 patients with ATTR amyloid, 9 asymptomatic mutation carriers, and 119 patients with AL amyloidosis, underwent LGE cardiovascular magnetic resonance. Subjects were followed up for a mean of 24±13 months. LGE was performed with phase-sensitive inversion recovery (PSIR) and without (magnitude only). These were compared with extracellular volume measured with T1 mapping. PSIR was superior to magnitude-only inversion recovery LGE because PSIR always nulled the tissue (blood or myocardium) with the longest T1 (least gadolinium). LGE was classified into 3 patterns: none, subendocardial, and transmural, which were associated with increasing amyloid burden as defined by extracellular volume (P<0.0001), with transitions from none to subendocardial LGE at an extracellular volume of 0.40 to 0.43 (AL) and 0.39 to 0.40 (ATTR) and to transmural at 0.48 to 0.55 (AL) and 0.47 to 0.59 (ATTR). Sixty-seven patients (27%) died. Transmural LGE predicted death (hazard ratio, 5.4; 95% confidence interval, 2.1-13.7; P<0.0001) and remained independent after adjustment for N-terminal pro-brain natriuretic peptide, ejection fraction, stroke volume index, E/E', and left ventricular mass index (hazard ratio, 4.1; 95% confidence interval, 1.3-13.1; P<0.05). CONCLUSIONS: There is a continuum of cardiac involvement in systemic AL and ATTR amyloidosis. Transmural LGE is determined reliably by PSIR and represents advanced cardiac amyloidosis. The PSIR technique provides incremental information on outcome even after adjustment for known prognostic factors.

Detection of metallic cobalt and chromium liver deposition following failed hip replacement using T2* and R2 magnetic resonance.

BACKGROUND: Failed hip prostheses can cause elevated circulating cobalt and chromium levels, with rare reports of fatal systemic organ deposition, including cobalt cardiomyopathy. Although blood cobalt and chromium levels are easily measured, organ deposition is difficult to detect without invasive biopsy. The T2* magnetic resonance (MR) method is used to quantify tissue iron deposition, and plays an important role in the management of iron-loading conditions. Cobalt and chromium, like iron, also affect magnetism and are proposed MR contrast agents. CASE PRESENTATION: We describe a case of a 44-year-old male with a failed hip implant and very elevated blood cobalt and chromium levels. Despite normal cardiac MR findings, liver T2* and R2 values were abnormal, triggering tissue biopsy. Liver tissue analysis, including X-ray fluorescence, demonstrated heavy elemental cobalt and chromium deposition in macrophages, and no detectable iron. CONCLUSIONS: Our case demonstrates T2* and R2 quantification of liver metal deposition in a patient with a failed hip implant. Further work is needed to investigate the role of T2* and R2 MR in the detection of metal deposition from metal on metal hip prostheses.

Differential Myocyte Responses in Patients with Cardiac Transthyretin Amyloidosis and Light-Chain Amyloidosis: A Cardiac MR Imaging Study.

PURPOSE: To investigate cardiac magnetic resonance (MR) imaging measurements of extracellular volume (ECV) and total cell volume in immunoglobulin light-chain amyloidosis (AL) and transthyretin amyloidosis (ATTR) in order to evaluate the amyloid and myocyte volumes. MATERIALS AND METHODS: All ethics were approved, and participants provided written informed consent. Of the 257 subjects who were recruited, 92 had AL (mean age, 62 years ± 10), 44 had mutant ATTR (mean age, 68 years ± 10), and 66 had wild-type ATTR (mean age, 75 years ± 7). In addition, eight healthy subjects with ATTR mutations (mean age, 47 years ± 6) and 47 healthy volunteers (mean age, 45 years ± 15) participated. All participants underwent equilibrium contrast material-enhanced cardiac MR imaging. ECV and total cell volume were measured in the heart. T test, χ(2), and one-way analysis of variance with posthoc Bonferroni correction were used. RESULTS: Both the left ventricular indexed mass and ECV were elevated in patients with amyloidosis. For left ventricular indexed mass, mean AL was 107 g/m(2) ± 30; mean mutant ATTR was 137 g/m(2) ± 29; and mean wild-type ATTR was 133 g/m(2) ± 27 versus 65 g/m(2) ± 15 in healthy subjects (P < .0001 for all measures). For ECV, mean AL was 0.54 ± 0.07, mean mutant ATTR was 0.60 ± 0.07, and mean wild-type ATTR was 0.57 ± 0.06 versus 0.27 ± 0.03 in healthy subjects (P < .0001 for all measures). Patients with ATTR had a higher total cell volume than did healthy subjects (mean, 53 mL/m(2) ± 12 vs 45 mL/m(2) ± 11; P = .001), but in patients with AL, total cell volume was normal (mean, 47 mL/m(2) ± 17 vs 45 mL/m(2) ± 11; P > .99). The result is that, in patients with AL, all of the increase in left ventricular indexed mass is extracellular volume, whereas in patients with ATTR, the increase is extracellular, with an additional 18% increase in the intracellular space. CONCLUSION: Quantification of ECV measures cardiac amyloid deposition in both types of amyloidosis and shows that amyloid deposition is more extensive in patients with ATTR than in those with AL; however, ATTR is associated with higher cell volume, which suggests concomitant cell hypertrophy.

T1 mapping and T2 mapping at 3T for quantifying the area-at-risk in reperfused STEMI patients.

BACKGROUND: Whether T1-mapping cardiovascular magnetic resonance (CMR) can accurately quantify the area-at-risk (AAR) as delineated by T2 mapping and assess myocardial salvage at 3T in reperfused ST-segment elevation myocardial infarction (STEMI) patients is not known and was investigated in this study. METHODS: 18 STEMI patients underwent CMR at 3T (Siemens Bio-graph mMR) at a median of 5 (4-6) days post primary percutaneous coronary intervention using native T1 (MOLLI) and T2 mapping (WIP #699; Siemens Healthcare, UK). Matching short-axis T1 and T2 maps covering the entire left ventricle (LV) were assessed by two independent observers using manual, Otsu and 2 standard deviation thresholds. Inter- and intra-observer variability, correlation and agreement between the T1 and T2 mapping techniques on a per-slice and per patient basis were assessed. RESULTS: A total of 125 matching T1 and T2 mapping short-axis slices were available for analysis from 18 patients. The acquisition times were identical for the T1 maps and T2 maps. 18 slices were excluded due to suboptimal image quality. Both mapping sequences were equally prone to susceptibility artifacts in the lateral wall and were equally likely to be affected by microvascular obstruction requiring manual correction. The Otsu thresholding technique performed best in terms of inter- and intra-observer variability for both T1 and T2 mapping CMR. The mean myocardial infarct size was 18.8 ± 9.4 % of the LV. There was no difference in either the mean AAR (32.3 ± 11.5 % of the LV versus 31.6 ± 11.2 % of the LV, P = 0.25) or myocardial salvage index (0.40 ± 0.26 versus 0.39 ± 0.27, P = 0.20) between the T1 and T2 mapping techniques. On a per-slice analysis, there was an excellent correlation between T1 mapping and T2 mapping in the quantification of the AAR with an R(2) of 0.95 (P < 0.001), with no bias (mean ± 2SD: bias 0.0 ± 9.6 %). On a per-patient analysis, the correlation and agreement remained excellent with no bias (R(2) 0.95, P < 0.0001, bias 0.7 ± 5.1 %). CONCLUSIONS: T1 mapping CMR at 3T performed as well as T2 mapping in quantifying the AAR and assessing myocardial salvage in reperfused STEMI patients, thereby providing an alternative CMR measure of the the AAR.

Free-breathing T2* mapping using respiratory motion corrected averaging.

BACKGROUND: Pixel-wise T2* maps based on breath-held segmented image acquisition are prone to ghost artifacts in instances of poor breath-holding or cardiac arrhythmia. Single shot imaging is inherently immune to ghost type artifacts. We propose a free-breathing method based on respiratory motion corrected single shot imaging with averaging to improve the signal to noise ratio. METHODS: Images were acquired using a multi-echo gradient recalled echo sequence and T2* maps were calculated at each pixel by exponential fitting. For 40 subjects (2 cohorts), two acquisition protocols were compared: (1) a breath-held, segmented acquisition, and (2) a free-breathing, single-shot multiple repetition respiratory motion corrected average. T2* measurements in the interventricular septum and liver were compared for the 2-methods in all studies with diagnostic image quality. RESULTS: In cohort 1 (N = 28) with age 51.4 ± 17.6 (m ± SD) including 1 subject with severe myocardial iron overload, there were 8 non-diagnostic breath-held studies due to poor image quality resulting from ghost artifacts caused by respiratory motion or arrhythmias. In cohort 2 (N = 12) with age 30.9 ± 7.5 (m ± SD), including 7 subjects with severe myocardial iron overload and 4 subjects with mild iron overload, a single subject was unable to breath-hold. Free-breathing motion corrected T2* maps were of diagnostic quality in all 40 subjects. T2* measurements were in excellent agreement (In cohort #1, T2*FB = 0.95 x T2*BH + 0.41, r2 = 0.93, N = 39 measurements, and in cohort #2, T2*FB = 0.98 x T2*BH + 0.05, r2 > 0.99, N = 22 measurements). CONCLUSIONS: A free-breathing approach to T2* mapping is demonstrated to produce consistently good quality maps in the presence of respiratory motion and arrhythmias.

Myocardial T1 mapping.

Cardiovascular magnetic resonance is a well-established tool for the quantification of focal fibrosis. With the introduction of T1 mapping, diffuse myocardial processes can be detected and quantified. In particular, infiltration and storage disorders with large disease-related changes, and diffuse fibrosis where measurement is harder but the potential impact larger. This has added a new dimension to the understanding and assessment of various myocardial diseases. T1 mapping promises to detect early disease, quantify disease severity and provide prognostic insights into certain conditions. It also has the potential to be a robust surrogate marker in drug development trials to monitor therapeutic response and be a prognostic marker in certain diseases. T1 mapping is an evolving field and numerous factors currently preclude its standardization. In this review, we describe the current status of T1 mapping and its potential promises and pitfalls.

Use of rapid cardiac magnetic resonance imaging to guide chelation therapy in patients with transfusion-dependent thalassaemia in India: UMIMI study.

AIMS: To explore the impact of incorporating a faster cardiac magnetic resonance (CMR) imaging protocol in a low-middle-income country (LMIC) and using the result to guide chelation in transfusion-dependent patients. METHODS AND RESULTS: A prospective UK-India collaborative cohort study was conducted in two cities in India. Two visits 13 months apart included clinical assessment and chelation therapy recommendations based on rapid CMR results. Participants were recruited by the local patient advocate charity, who organized the patient medical camps. The average scanning time was 11.3 ± 2.5 min at the baseline and 9.8 ± 2.4 min (P < 0.001) at follow-up. The baseline visit was attended by 103 patients (mean age 25 years) and 83% attended the second assessment. At baseline, 29% had a cardiac T2* < 20 ms, which represents significant iron loading, and 12% had left ventricular ejection fraction <60%, the accepted lower limit in this population. Only 3% were free of liver iron (T2* ≥ 17 ms). At 13 months, more patients were taking intensified dual chelation therapy (43% vs. 55%, P = 0.002). In those with cardiac siderosis (baseline T2* < 20 ms), there was an improvement in T2*-10.9 ± 5.9 to 13.5 ± 8.7 ms, P = 0.005-and fewer were classified as having clinically important cardiac iron loading (T2* < 20 ms, 24% vs. 16%, P < 0.001). This is the first illustration in an LMIC that incorporating CMR results into patient management plans can improve cardiac iron loading. CONCLUSION: For thalassaemia patients in an LMIC, a simplified CMR protocol linked to therapeutic recommendation via the patient camp model led to enhanced chelation therapy and a reduction in cardiac iron in 1 year.

Noninvasive rapid cardiac magnetic resonance for the assessment of cardiomyopathies in low-middle income countries.

Introduction: Cardiac Magnetic Resonance (CMR) is a crucial diagnostic imaging test that redefines diagnosis and enables targeted therapies, but the access to CMR is limited in low-middle Income Countries (LMICs) even though cardiovascular disease is an emergent primary cause of mortality in LMICs. New abbreviated CMR protocols can be less expensive, faster, whilst maintaining accuracy, potentially leading to a higher utilization in LMICs.Areas covered: This article will review cardiovascular disease in LMICs and the current role of CMR in cardiac diagnosis and enable targeted therapy, discussing the main obstacles to prevent the adoption of CMR in LMICs. We will then review the potential utility of abbreviated, cost-effective CMR protocols to improve cardiac diagnosis and care, the clinical indications of the exam, current evidence and future directions.Expert opinion: Rapid CMR protocols, provided that they are utilized in potentially high yield cases, could reduce cost and increase effectiveness. The adoption of these protocols, their integration into care pathways, and prioritizing key treatable diagnoses can potentially improve patient care. Several LMIC countries are now pioneering these approaches and the application of rapid CMR protocols appears to have a bright future if delivered effectively.

Recreational marathon running does not cause exercise-induced left ventricular hypertrabeculation.

BACKGROUND: Marathon running in novices represents a natural experiment of short-term cardiovascular remodeling in response to running training. We examine whether this stimulus can produce exercise-induced left ventricular (LV) trabeculation. METHODS: Sixty-eight novice marathon runners aged 29.5 ± 3.2 years had indices of LV trabeculation measured by echocardiography and cardiac magnetic resonance imaging 6 months before and 2 weeks after the 2016 London Marathon race, in a prospective longitudinal study. RESULTS: After 17 weeks unsupervised marathon training, indices of LV trabeculation were essentially unchanged. Despite satisfactory inter-observer agreement in most methods of trabeculation measurement, criteria defining abnormally hypertrabeculated cases were discordant with each other. LV hypertrabeculation was a frequent finding in young, healthy individuals with no subject demonstrating clear evidence of a cardiomyopathy. CONCLUSION: Training for a first marathon does not induce LV trabeculation. It remains unclear whether prolonged, high-dose exercise can create de novo trabeculation or expose concealed trabeculation. Applying cut off values from published LV noncompaction cardiomyopathy criteria to young, healthy individuals risks over-diagnosis.

Cardiovascular Remodeling Experienced by Real-World, Unsupervised, Young Novice Marathon Runners.

AIMS: Marathon running is a popular ambition in modern societies inclusive of non-athletes. Previous studies have highlighted concerning transient myocardial dysfunction and biomarker release immediately after the race. Whether this method of increasing physical activity is beneficial or harmful remains a matter of debate. We examine in detail the real-world cardiovascular remodeling response following competition in a first marathon. METHODS: Sixty-eight novice marathon runners (36 men and 32 women) aged 30 ± 3 years were investigated 6 months before and 2 weeks after the 2016 London Marathon race in a prospective observational study. Evaluation included electrocardiography, cardiopulmonary exercise testing, echocardiography, and cardiovascular magnetic resonance imaging. RESULTS: After 17 weeks unsupervised marathon training, runners revealed a symmetrical, eccentric remodeling response with 3-5% increases in left and right ventricular cavity sizes, respectively. Blood pressure (BP) fell by 4/2 mmHg (P < 0.01) with reduction in arterial stiffness, despite only 11% demonstrating a clinically meaningful improvement in peak oxygen consumption with an overall non-significant 0.4 ml/min/kg increase in peak oxygen consumption (P = 0.14). CONCLUSION: In the absence of supervised training, exercise-induced cardiovascular remodeling in real-world novice marathon runners is more modest than previously described and occurs even without improvement in cardiorespiratory fitness. The responses are similar in men and women, who experience a beneficial BP reduction and no evidence of myocardial fibrosis or persistent edema, when achieving average finishing times.

T2* Mapping Techniques: Iron Overload Assessment and Other Potential Clinical Applications.

T2* mapping techniques has evolved significantly since their introduction in the early 2000s and a significant amount of evidence has been gathered to support their clinical routine use for iron overload assessment. This article focuses on the most important aspects of how to perform T2* imaging, from acquisition, to postprocessing, to analyzing the data with clinical concentration. Newer techniques have made T2* mapping more robust and accurate, allowing a broader use of this technique for noncontrast ischemia imaging based on blood oxygen levels, in addition to evaluation of intramyocardial hemorrhage and microvascular obstruction.

Proposed Stages of Myocardial Phenotype Development in Fabry Disease.

OBJECTIVES: This study sought to explore the Fabry myocardium in relation to storage, age, sex, structure, function, electrocardiogram changes, blood biomarkers, and inflammation/fibrosis. BACKGROUND: Fabry disease (FD) is a rare, x-linked lysosomal storage disorder. Mortality is mainly cardiovascular with men exhibiting cardiac symptoms earlier than women. By cardiovascular magnetic resonance, native T1 is low in FD because of sphingolipid accumulation. METHODS: A prospective, observational study of 182 FD (167 adults, 15 children; mean age 42 ± 17 years, 37% male) who underwent cardiovascular magnetic resonance including native T1, late gadolinium enhancement (LGE), and extracellular volume fraction, 12-lead electrocardiogram, and blood biomarkers (troponin and N-terminal pro-brain natriuretic peptide). RESULTS: In children, T1 was never below the normal range, but was lower with age (9 ms/year, r = -0.78 children; r = -0.41 whole cohort; both p < 0.001). Over the whole cohort, the T1 reduction with age was greater and more marked in men (men: -1.9 ms/year, r = -0.51, p < 0.001; women: -1.4 ms/year, r = -0.47 women, p < 0.001). Left ventricular hypertrophy (LVH), LGE, and electrocardiogram abnormalities occur earlier in men. Once LVH occurs, T1 demonstrates major sex dimorphism: with increasing LVH in women, T1 and LVH become uncorrelated (r = -0.239, p = 0.196) but in men, the correlation reverses and T1 increases (toward normal) with LVH (r = 0.631, p < 0.001), a U-shaped relationship of T1 to indexed left ventricular mass in men. CONCLUSIONS: These data suggest that myocyte storage starts in childhood and accumulates faster in men before triggering 2 processes: a sex-independent scar/inflammation regional response (LGE) and, in men, apparent myocyte hypertrophy diluting the T1 lowering of sphingolipid.

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

OBJECTIVES: This 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. BACKGROUND: Cardiac 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. METHODS: A 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. RESULTS: Left 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; p < 0.01) and indexed stroke volume (hazard ratio: 1.24; 95% confidence interval: 1.04 to 1.48; p < 0.05) by CMR were the only independent predictors of mortality. CONCLUSIONS: Specific 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.

Role of T1 mapping as a complementary tool to T2* for non-invasive cardiac iron overload assessment.

BACKGROUND: Iron overload-related heart failure is the principal cause of death in transfusion dependent patients, including those with Thalassemia Major. Linking cardiac siderosis measured by T2* to therapy improves outcomes. T1 mapping can also measure iron; preliminary data suggests it may have higher sensitivity for iron, particularly for early overload (the conventional cut-point for no iron by T2* is 20ms, but this is believed insensitive). We compared T1 mapping to T2* in cardiac iron overload. METHODS: In a prospectively large single centre study of 138 Thalassemia Major patients and 32 healthy controls, we compared T1 mapping to dark blood and bright blood T2* acquired at 1.5T. Linear regression analysis was used to assess the association of T2* and T1. A "moving window" approach was taken to understand the strength of the association at different levels of iron overload. RESULTS: The relationship between T2* (here dark blood) and T1 is described by a log-log linear regression, which can be split in three different slopes: 1) T2* low, <20ms, r2 = 0.92; 2) T2* = 20-30ms, r2 = 0.48; 3) T2*>30ms, weak relationship. All subjects with T2*<20ms had low T1; among those with T2*>20ms, 38% had low T1 with most of the subjects in the T2* range 20-30ms having a low T1. CONCLUSIONS: In established cardiac iron overload, T1 and T2* are concordant. However, in the 20-30ms T2* range, T1 mapping appears to detect iron. These data support previous suggestions that T1 detects missed iron in 1 out of 3 subjects with normal T2*, and that T1 mapping is complementary to T2*. The clinical significance of a low T1 with normal T2* should be further investigated.