scholarly journals Microvascular and mechanical improvements following bariatric surgery in the obese; mechanistic insights from advanced & automated quantitative perfusion cardiac MRI

2021 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
G Joy ◽  
JD Crane ◽  
JB Augusto ◽  
C Lau ◽  
A Seraphim ◽  
...  
Keyword(s):  
Bariatric Surgery ◽  
Myocardial Perfusion ◽  
Stroke Volume ◽  
Myocardial Contraction ◽  
Left Ventricular ◽  
Microvascular Function ◽  
Public Institution ◽  
Research Centre ◽  
Quantitative Perfusion ◽  
Myocardial Contraction Fraction

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Guy"s and St Thomas" Charity University College London Hospital Biomedical Research Centre Background   In people with obesity, bariatric surgery reduces mortality, heart failure and coronary disease, improving metabolic (blood sugar, lipid profile, inflammation) and cardiovascular (diastolic/systolic function, filling pressure, cardiac remodelling) parameters. Myocardial microvascular function is a candidate causal link of metabolic to structural cardiac abnormalities. Purpose We hypothesised that bariatric surgery could improve myocardial microvascular and mechanical function in both those with and without diabetes.  Methods Before and six months after bariatric surgery, 24 subjects with obesity were assessed with haematology, biochemistry and advanced CMR (cines, vasodilator adenosine stress and rest fully-automated quantitative perfusion mapping, tissue-tracking (CVI42, post processing).  Results. Mean age was 49± 12 years, 35%(8) were male, 63%(15), had hypertension, 17 (71%) had diabetes. Surgery resulted in decreases in BMI (44 ± 7 to 34 ± 6 kg/m2 p = 0.0001) and HbA1c (57 ± 16 to 42 ± 9mmol/mol p = 0.0001). EF% and absolute LV end-diastolic volumes remained unchanged, but mass regressed and myocardial contraction fraction (ratio of stroke volume and LV volume) increased (see Table).  There were also strain improvements (radial 35 ± 8.8 to 37.3 ± 8.7 %p = 0.029) (circumferential -19.8 ± 2.3 vs -20.7 ± 3% p = 0.017), although longitudinal did not improve (-16.3 ± 3.2 to -15.9 ± 3% p = 0.25). Myocardial perfusion significantly improved (stress myocardial blood flow, MBF 2.35 ± 0.71 to 2.80 ± 0.98 ml/g/min p = 0.008; myocardial perfusion reserve MPR 2.47 ± 0.78 to 2.97 ± 0.95 p = 0.005).  Improvement in stress MBF and MPR from pre-operative to post-operative was higher in the non-diabetics (n = 7 (29%)) than the diabetics (n = 17 (71%)) (stress MBF: 1.15 ± 1.00 vs 0.16 ± 0.39ml/g/min p = 0.002) MPR: (1.09 ± 0.73 vs 0.25 ± 0.66 p = 0.011). Conclusion At 6 months, bariatric surgery results in beneficial myocardial remodelling and substantial improvements in myocardial microvascular function. These improvements occur most in those without diabetes suggesting that there may be reversible and irreversible components to microvascular dysfunction. Perfusion and strain variables Variable Pre-op (n = 24) Post-op (n = 24) p-value LVEDV (ml) 163 ± 28 161 ± 29 0.64 EF (%) 70 ± 8 70 ± 7 0.78 Stroke volume (ml) 113 ± 19 111 ± 21 0.6 LV Mass (g) 117 ± 25 103 ± 21 0.001 Myocardial contraction fraction 94 ± 14 105 ± 14 0.001 LVEDV - left ventricular end-diastolic volume, EF - ejection fraction Abstract Figure.

scholarly journals Impact of obesity on myocardial microvasculature assessed using fully-automated inline myocardial perfusion mapping CMR

2021 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
G Joy ◽  
JD Crane ◽  
C Lau ◽  
J Augusto ◽  
LAE Brown ◽  
...  
Keyword(s):  
Bariatric Surgery ◽  
Myocardial Perfusion ◽  
Left Ventricular ◽  
Public Institution ◽  
Research Centre ◽  
Stress Perfusion ◽  
Metabolic Derangement ◽  
Quantitative Perfusion ◽  
Perfusion Reserve ◽  
Bariatric Patients

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Guy"s and St Thomas" Charity University College London Hospitals Biomedical Research Centre Background Obesity and cardiovascular disease are associated, but the relationship is poorly understood. Myocardial perfusion, metabolic derangement and lipotoxicity appear adversely associated in many scenarios (myocardial injury, diastolic dysfunction, diabetes). Altered perfusion (by PET) predicts outcome, and it is hypothesised that perfusion derangement is part of causality for cardiac disease and adverse outcomes. Purpose To assess the presence and pattern of myocardial microvascular dysfunction in patients with obesity (scheduled for bariatric surgery) using stress quantitative perfusion mapping. Methods 38 subjects with obesity planned to undergo bariatric surgery and 38 age and sex matched healthy volunteers (no diabetes, no hypertension) underwent anthropometry, biochemistry and CMR at 1.5T (Siemens) with cine imaging, stress (adenosine 140-210 mcg/kg/min) and rest fully-automated quantitative perfusion mapping.  Results Bariatric patients had a higher BMI (44 ± 6.4 vs 26.5 ± 4kg/m2 p = 0.001); 58%(22) were diabetic and 58%(22) had hypertension. Bariatric patients had higher absolute but lower indexed end-diastolic volumes, and overall higher ejection fractions (+5%) (see Table). Rest myocardial blood flow (MBF) in bariatric patients was the same (1.00 ± 0.3 vs 0.88 ± 0.24 p = 0.052), but stress perfusion results were significantly lower both for stress MBF (2.35 ± 0.69 vs 2.93 ± 0.76ml/g/min p = 0.001) and myocardial perfusion reserve (MPR 2.48 ± 0.82 vs 3.4 ± 0.81ml/g/min p = 0.0001).  Although this was transmural, the endocardial stress MBF was particularly negatively affected in the bariatric cohort compared to controls (endocardial MBF 2.16 ± 0.65 vs 2.82 ± 0.73ml/g/min, p = 0.0001 vs epicardial MBF: 2.52 ± 0.76 vs 3.06 ± 0.79 p = 0.003), meaning there was an increased endo-epicardial stress MBF gradient in bariatric patients (0.87 ± 0.12 vs 0.92 ± 0.07 p = 0.03). Conclusion Compared to healthy controls, patients with obesity have abnormal myocardial stress perfusion with reduced global perfusion, perfusion reserve and an increased transmyocardial perfusion gradient. Table - myocardial perfusion parameters Category Bariatric patients n = 38 Controls n = 38 p value Age (years) 48 ± 11 45 ± 13 0.25 n male (%) 12 (32%) 10 (36%) 0.32 LVEDV (ml) 168 ± 37 149 ± 31 0.017 LVEDVi (ml/m2) 70.4 ± 12.3 78.8 ± 12.1 0.004 LV Mass (g) 116 ± 31 99 ± 28 0.019 EF (%) 70 ± 8 65 ± 5 0.002 LVEDV - left ventricular end-diastolic volume, EF - ejection fraction

scholarly journals Life-course burden of health deficits associates with later-life heart size and function in the 1946 British birth cohort

2020 ◽  
Author(s):  
Constantin-Cristian Topriceanu ◽  
James C Moon ◽  
Rebecca Hardy ◽  
Nishi Chaturvedi ◽  
Alun Hughes ◽  
...  
Keyword(s):  
Life Course ◽  
Birth Cohort ◽  
Later Life ◽  
Myocardial Contraction ◽  
Left Ventricular ◽  
Heart Size ◽  
Time Periods ◽  
And Function ◽  
The Life Course ◽  
Myocardial Contraction Fraction

Aim: To study the association between the life course accumulation of health deficits and later life heart size and function using data from the 1946 National Survey of Heath and Development (NSHD) British birth cohort, the longest running birth cohort with continuous follow up in the world. Methods and Results: A multidimensional health deficit index (DI) looking at 45 health deficits was serially calculated at 4 time periods of the life course in NSHD participants (0 to 16, 19 to 44, 45 to 54 and 60 to 64 years), and from these the mean and total DI for the life course was derived (DImean, DIsum). The step change in deficit accumulation from one time period to another was also calculated. Echocardiographic data at 60-64 years provided: ejection fraction (EF), left ventricular mass indexed to body surface area (LVmassi, BSA), myocardial contraction fraction indexed to BSA (MCFi) and E/e. Generalized linear models assessed the association between DIs and echocardiographic parameters after adjustment for sex, socioeconomic position and body mass index. 1,375 NSHD participants were included (46.47% male). For each single new deficit accumulated at any one of the 4 time periods of the life course, LVmassi increased by 0.91 to 1.44% (p<0.013), while MCFi decreased by 0.6 to 1.02% (p<0.05 except at 45 to 54 years). One unit increase in DI at age 45 to 54 and 60 to 64 decreased LV EF by 11 to 12% (p<0.013). A single deficit step change occurring between 60-64 years and one of the earlier time periods, translated into significantly higher odds (2.1 to 78.5, p<0.020) of elevated LV filling pressure defined as E/e>13. Conclusion: The accumulation of health deficits at any time period of the life course associates with a maladaptive cardiac phenotype in older age, dominated by myocardial hypertrophy and poorer function. The burden of health deficits appears to strain the myocardium potentially leading to future cardiac dysfunction. Keywords: frailty; cardiovascular disease; ejection fraction; left ventricular mass index; myocardial contraction fraction; E/e.

Abstract P322: Myocardial Contraction Fraction is an Independent Predictor of Incident Adverse Cardiovascular Events; The Framingham Heart Study

Circulation ◽  
2014 ◽  
Vol 129 (suppl_1) ◽  
Author(s):  
Michael L Chuang ◽  
Philimon Gona ◽  
Connie W Tsao ◽  
Carol J Salton ◽  
Warren J Manning ◽  
...  
Keyword(s):  
Left Ventricle ◽  
Stroke Volume ◽  
Proportional Hazards ◽  
Independent Predictor ◽  
Myocardial Contraction ◽  
Cox Proportional Hazards ◽  
Community Dwelling ◽  
Heart Study ◽  
Myocardial Contraction Fraction

Introduction: Myocardial contraction fraction (MCF) is the ratio of left ventricular (LV) stroke volume to myocardial volume, and thus a measure of LV pumping capacity per unit of myocardium. We sought to determine whether MCF measured using current steady-state free precession (SSFP) cardiac magnetic resonance (CMR) sequences was an independent predictor of incident “hard” cardiovascular disease (CVD) events, defined by myocardial infarction (MI), stroke, unstable angina (UA), hospitalized heart failure (HF) or CVD death in a community dwelling cohort initially free of these CVD events. Methods: 1794 members of the Framingham Heart Study Offspring cohort (aged 65±9 years) underwent CMR between 2002-2006 using a 1.5-Tesla system with contiguous multislice SSFP cine imaging to encompass the left ventricle. MCF was determined from the cine images by a single observer blinded to participant characteristics. We tracked incident hard CVD events over median 6.5-year follow up and used Cox proportional hazards models (adjusted for age, sex, body mass index, systolic blood pressure, diabetes, dyslipidemia, smoking, treatment for hypertension) to determine hazard of hard CVD events per increment (0.10) of MCF. Results: MCF was determined in 1776 (99%) Offspring (835 men). Overall, MCF was greater in women (0.92±0.14 vs. 0.78±0.15 for men), p<0.0001. There were 60 incident hard CVD events during follow up. Incident hard events included 26 MI, 2 UA, 13 stroke, 14 hospitalized HF and 5 CVD deaths. Offspring experiencing an incident event had lower MCF (0.78±0.19 vs. 0.86±0.15 for those free of events), p=0.002. On MV-adjusted Cox proportional hazards analyses, a greater MCF was protective against hard CVD events, HR [95% confidence intervals] = 0.76 [0.63 - 0.93] per 0.10 increment of MCF. Conclusion: Over 6.5-year follow-up, greater MCF is protective against major adverse CVD events, even after adjustment for traditional CVD risk factors in a community dwelling cohort of middle-aged and older predominantly European-descended adults. Determination of MCF requires only knowledge of LV stroke volume and myocardial volume, both of which are routinely determined in a standard CMR examination of the left ventricle, and thus imposes no additional scan-time or analysis burden. While MCF may be clinically useful for prediction of risk for incident hard CVD events, its potential value in younger age groups and other ethnicities remains to be determined.

scholarly journals Myocardial contraction fraction predicts mortality for patients with hypertrophic cardiomyopathy

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Hang Liao ◽  
Ziqiong Wang ◽  
Liming Zhao ◽  
Xiaoping Chen ◽  
Sen He
Keyword(s):  
Mortality Rate ◽  
Myocardial Contraction ◽  
Left Ventricular ◽  
Adverse Outcomes ◽  
The Third ◽  
All Cause Mortality ◽  
Secondary Endpoints ◽  
Myocardial Contraction Fraction ◽  
Related Mortality

Abstract The myocardial contraction fraction (MCF: stroke volume to myocardial volume) is a novel volumetric measure of left ventricular myocardial shortening. The purpose of the present study was to assess whether MCF could predict adverse outcomes for HCM patients. A retrospective cohort study of 438 HCM patients was conducted. The primary and secondary endpoints were all-cause mortality and HCM-related mortality. The association between MCF and endpoints was analysed. During a follow-up period of 1738.2 person-year, 76 patients (17.2%) reached primary endpoint and 50 patients (65.8%) reached secondary endpoint. Both all-cause mortality rate and HCM-related mortality rate decreased across MCF tertiles (24.7% vs. 17.9% vs. 9.5%, P trend = 0.003 for all-cause mortality; 16.4% vs. 9.7% vs. 6.1%, P trend = 0.021 for HCM-related mortality). Patients in the third tertile had a significantly lower risk of developing adverse outcomes than patients in the first tertile: all-cause mortality (adjusted HR: 0.26, 95% CI: 0.12–0.56, P = 0.001), HCM-related mortality (adjusted HR: 0.17, 95% CI: 0.07–0.42, P < 0.001). At 1-, 3-, and 5-year of follow-up, areas under curve were 0.699, 0.643, 0.618 for all-cause mortality and 0.749, 0.661, 0.613 for HCM-related mortality (all P value < 0.001), respectively. In HCM patients, MCF could independently predict all-cause mortality and HCM-related mortality, which should be considered for overall risk assessment in clinical practice.

Abstract 18894: The Myocardial Contraction Fraction Predicts Survival in Patients With AL Cardiac Amyloidosis. A Report From iCCAT, The International Consortium for Cardiac Amyloid Transplantation

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Van N Selby ◽  
Karla Verkouw ◽  
Jerry D Estep ◽  
Ronald M Witteles ◽  
Giuseppe Feltrin ◽  
...  
Keyword(s):  
Heart Transplant ◽  
Cardiac Amyloidosis ◽  
Myocardial Contraction ◽  
Left Ventricular ◽  
Hazard Ratio ◽  
Left Ventricular Ejection ◽  
Transplant Evaluation ◽  
The Mean ◽  
Myocardial Contraction Fraction ◽  
Absolute Decrease

Background: Cardiac amyloidosis is characterized by progressive ventricular thickening and diastolic heart failure. The left ventricular ejection fraction (EF) often remains normal even in advanced disease. The myocardial contraction fraction (MCF, the ratio of left ventricular stroke volume to myocardial volume) is a novel measure of myocardial shortening and may be superior to EF for predicting survival in cardiac amyloidosis. Methods: We measured MCF and EF from two-dimensional echocardiograms obtained in 86 subjects undergoing heart transplant evaluation for AL cardiac amyloidosis. Cox proportional hazards models and Kaplan-Meier survival analysis were used to compare MCF and EF as predictors of all-cause mortality. Subjects were censored at the time of heart transplant. Results: The mean age was 54.6 ± 7.9 years. The mean EF was 49.3 ± 12.7% and the mean MCF was 13.0 ± 5.5%. Over a median follow-up of 59 days (IQR 29-110 days), 38 subjects (44.2%) died and 48 (55.8%) underwent heart transplant. In unadjusted analyses, both MCF (HR 0.89, 95% CI 0.82-0.96, p = 0.002) and EF (HR 0.96, 95% CI 0.94-0.99, p = 0.015) predicted overall survival. In multivariate analyses adjusted for serum free light chain difference, the hazard ratio associated with each 5% absolute decrease in MCF was 2.11 (95% CI 1.32-3.38, p= 0.002). The hazard ratio associated with each 5% absolute decrease in EF was not statistically significant (HR 1.16, 95% CI 0.97-1.39, p=0.09). Conclusions: Myocardial contraction fraction is superior to EF for predicting survival in patients undergoing heart transplant evaluation for AL cardiac amyloidosis.

scholarly journals Myocardial Contraction Fraction for Risk Stratification in Low-Gradient Aortic Stenosis With Preserved Ejection Fraction

2021 ◽  
Vol 14 (8) ◽  
Author(s):  
Dan Rusinaru ◽  
Yohann Bohbot ◽  
Maciej Kubala ◽  
Momar Diouf ◽  
Alexandre Altes ◽  
...  
Keyword(s):  
Aortic Stenosis ◽  
Ejection Fraction ◽  
Severe Aortic Stenosis ◽  
Myocardial Contraction ◽  
Left Ventricular ◽  
Mortality Prediction ◽  
Hazard Ratio ◽  
Adjusted Hazard Ratio ◽  
Preserved Ejection Fraction ◽  
Myocardial Contraction Fraction

Background: Myocardial contraction fraction (MCF) is a volumetric measure of myocardial shortening independent of left ventricular size and geometry. This multicenter study investigates the usefulness of MCF for risk stratification in low-gradient severe aortic stenosis with preserved ejection fraction. Methods: We included 643 consecutive patients with low-gradient severe aortic stenosis with preserved ejection fraction in whom MCF was computed at baseline and analyzed mortality during follow-up. Results: Throughout follow-up with medical and surgical management (34.9 [16.1–65.3] months), lower MCF tertiles had higher mortality than the highest tertile. Eighty-month survival was 56±4% for MCF>41%, 41±4% for MCF 30% to 41%, and 40±4% for MCF<30% ( P <0.001). After comprehensive adjustment, mortality risk remained high for MCF 30% to 41% (adjusted hazard ratio, 1.53 [1.08–2.18]) and for MCF<30% (adjusted hazard ratio, 1.82 [1.24–2.66]) versus MCF>41%. The optimal MCF cutoff point for mortality prediction was 41%. Age, body mass index, Charlson index, peak aortic velocity, and ejection fraction were independently associated with mortality. MCF (χ 2 to improve 10.39; P =0.001), provided greater additional prognostic value over the baseline parameters than stroke volume (SV) index (χ 2 to improve 5.41; P =0.042), left ventricular mass index (χ 2 to improve 2.15; P =0.137), or global longitudinal strain (χ 2 to improve 3.67; P =0.061). MCF outperformed ejection fraction for mortality prediction. When patients were classified by SV index and MCF, mortality risk was low when SV index was ≥30 mL/m 2 and MCF>41%, higher for patients with SV index ≥30 mL/m 2 and MCF≤41% (adjusted hazard ratio, 1.47 [1.05–2.07]) and extremely high for patients with SV index <30 mL/m 2 (adjusted hazard ratio, 2.29 [1.45–3.62]). Conclusions: MCF is a valuable marker of risk in low-gradient severe aortic stenosis with preserved ejection fraction and could improve decision-making, especially in normal-flow low-gradient severe aortic stenosis with preserved ejection fraction.

In Patients with Light-Chain (AL) Amyloidosis Myocardial Contraction Fraction (MCF) Is a Simple, but Powerful Prognostic Measure That Can be Calculated from a Standard Echocardiogram (ECHO)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1774-1774 ◽  
Author(s):  
Paolo Milani ◽  
Angela Dispenzieri ◽  
Morie A. Gertz ◽  
Martha Q. Lacy ◽  
Francis K. Baudi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Pericardial Effusion ◽  
Ejection Fraction ◽  
Research Funding ◽  
Univariate Analysis ◽  
Myocardial Contraction ◽  
Left Ventricular ◽  
Al Amyloidosis ◽  
Left Ventricular Chamber ◽  
Myocardial Contraction Fraction

Abstract Background: Amyloidosis is a multisystem disease with extracellular deposition of pathological insoluble beta-fibrillar proteins. Involvement of the heart is seen in more than one-half of the patients with systemic AL amyloidosis and it is the most important determinant of clinical outcome. Cardiac amyloidosis is a restrictive infiltrative cardiomyopathy in which, despite declines in stroke volume that accompany disease progression, the ejection fraction (EF) often remains preserved even in advanced stages of the disease. King et al. proposed a novel index of myocardial function, the myocardial contraction fraction (MCF), defined as the ratio of stroke volume (SV) to myocardial volume (MV). MCF is a measure of myocardial shortening, which differentiated myocardial performance in patients with similar degrees of hypertrophy and in a recent small cohort of AL amyloidosis patients appeared superior to left ventricular ejection fraction (EF) in predicting overall survival (OS). It was our goal to assess the prognostic role of MCF in a large cohort of patients with AL amyloidosis in the context of other prognostic variables. Methods: Patients seen between 4/1/1999 and 2/1/2015 were eligible for this retrospective study if they had an ECHO at the Mayo Clinic, Rochester, MN within 30 days of their AL amyloidosis diagnosis with measurements of left ventricular chamber size and wall thickness needed to calculate MCF, EF, and the presence or absence of pericardial effusion. To capture the full cohort, modeling was done first excluding Mayo (2012) staging and global averaged left ventricular longitudinal peak systolic strain (LV strain) since limited numbers of patients had these studies, 342 and 294, respectively. Thresholds of continuous variables were chosen based on receiver operator curves targeting death at 1-year. Cox proportional hazards analysis was used to identify factors that were prognostic for OS. Statistical analyses were done using JMP 9.0 (SAS, Cary, NC). Results: Among the 722 patients satisfying entry criteria,median age was 64 years (range 32-94) and 66% were male. The best cutoff for MCF was 21% (sensitivity: 74%, specificity: 60%; AUC=0.699) and distinguished two groups with different OS (median 53 vs. 9 months, P<0.0001; Figure). On univariate analysis the baseline ECHO variables predicting OS were interventricular septum thickness (IVS) >12 mm (RR 1.8, P=0.0002), EF <60% (RR 1.7), MCF ≤21% (RR 2.1), and presence of pericardial effusion (RR 2.0), all with P<0.0001. On multivariate MCF ≤21% (RR 1.6, P <0.0001), EF <60% (RR 1.4, P=0.0007) and the presence of pericardial effusion (RR 1.3, P=0.002) were independent predictors of OS. Additional modeling was done with the subset of 342 patients who were assessable for Mayo (2012) staging, (i.e. measurements of immunoglobulin free light chain, NT-proBNP, and troponin T). On univariate analysis, patients with a Mayo (2012) stage ≥ 3 had a RR 2.1, p<0.0001. On multivariate, only MCF ≤21% (RR 1.5, P =0.01), Mayo (2012) stage ≥ 3 (RR 1.5, P=0.01) and EF<60% (RR 1.7, P=0.0006) were independent prognostic determinants. Finally, we addressed LV-strain among the 294 patients in whom the study was performed. There was a significant correlation between MCF and LV strain (rho =-0.86, P<0.0001). On univariate, LV-strain less negative than -13 generated a RR of 2.3, p<0.0001. In contrast to the model containing MCF, on LV-strain multivariate, EF was no longer significant, but LV-strain less negative than -13 (RR 2.0, P=0.008) and Mayo (2012) stage ≥ 3 (RR 2.0, P=0.008) predicted independently OS. Conclusions: MCF ≤21% identified a subgroup of patients with a high mortality risk, and it was independent of the Mayo (2012) staging but highly correlated with LV strain. An advantage of MCF, which is a novel volumetric measurement of the left ventricular chamber, is that, unlike LV-strain, MCF is simple to calculate from routine ECHO measures. Figure 1. Overall survival of 722 patients according to MCF<21%. Figure 1. Overall survival of 722 patients according to MCF<21%. Disclosures Kumar: AbbVie: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Skyline, Noxxon: Honoraria; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Sanofi: Research Funding; Millenium/Takeda: Research Funding; Onyx: Research Funding.

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