ABSTRACT
Chronically transfused sickle cell patients typically don't exhibit iron-mediated extrahepatic toxicity. However, we demonstrate that the pituitary gland is vulnerable to iron deposition, and it occurs regardless of other extrahepatic involvement. Severe pituitary siderosis is associated with early organ dysfunction.
ABSTRACT
Splenic iron decreased whereas liver iron was stable during luspatercept therapy in some individuals with thalassemia. This suggests a reduction of ineffective erythropoiesis changes the organ distribution of iron and demonstrates that liver iron concentration alone may not accurately reflect total body iron content. This article describes data from subjects enrolled in BELIEVE (NCT02604433) and BEYOND (NCT03342404).
Subject(s)
Iron , beta-Thalassemia , Humans , Activin Receptors, Type II , beta-Thalassemia/drug therapy , Erythropoiesis , LiverABSTRACT
BACKGROUND: In patients with or at risk for atherosclerotic vascular disease, statins reduce the incidence of major adverse cardiovascular events, but the majority of US adults with an indication for statin therapy are not prescribed statins at guideline-recommended intensity. Clinicians' limited time to address preventative care issues is cited as one factor contributing to gaps in statin prescribing. Centralized pharmacy services can fulfill a strategic role for population health management through outreach, education, and statin prescribing for patients at elevated ASCVD risk, but best practices for optimizing referrals of appropriate patients are unknown. STUDY DESIGN AND OBJECTIVES: SUPER LIPID (NCT05537064) is a program consisting of two pragmatic clinical trials testing the effect of nudges in increasing referrals of appropriate patients to a centralized pharmacy service for lipid management, conducted within 11 primary care practices in a large community health system. In both trials, patients were eligible for inclusion if they had an assigned primary care provider (PCP) in a participating practice and were not prescribed a high- or moderate-intensity statin despite an indication, identified via an electronic health record (EHR) algorithm. Trial #1 was a stepped wedge trial, conducted at a single practice with randomization at the PCP level, of an interruptive EHR message that appeared during eligible patients' visits and facilitated referral to the pharmacy service. For the first 3 months, no PCPs received the message; for the second 3 months, half were randomly selected to receive the message; and for the last 3 months, all PCPs received the message. Trial #2 was a cluster-randomized trial conducted at 10 practices, with randomization at the practice level. Practices were randomized to usual care or to have eligible patients automatically referred to centralized pharmacy services via a referral order placed in PCPs EHR inboxes for co-signature. In both trials, when a patient was referred to centralized pharmacy services, a pharmacist reviewed the patient's chart, contacted the patient, and initiated statin therapy if the patient agreed. The primary endpoint of both trials was the proportion of patients prescribed a statin; secondary endpoints include the proportion of patients prescribed a statin at guideline-recommended intensity, the proportion of patients filling a statin prescription, and serum low-density lipoprotein level. CONCLUSIONS: SUPER LIPID is a pair of pragmatic clinical trials assessing the effectiveness of two strategies to encourage referral of appropriate patients to a centralized pharmacy service for lipid management. The trial results will develop the evidence base for simple, scalable, EHR-based strategies to integrate clinical pharmacists into population health management and increase appropriate statin prescribing. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov; NCT05537064.
Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors , Referral and Consultation , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Male , Female , Primary Health Care , Middle AgedABSTRACT
Deoxygenation-based dynamic susceptibility contrast (dDSC) MRI uses respiratory challenges as a source of endogenous contrast as an alternative to gadolinium injection. These gas challenges induce T2*-weighted MRI signal losses, after which tracer kinetics modeling was applied to calculate cerebral perfusion. This work compares three gas challenges, desaturation (transient hypoxia), resaturation (transient normoxia), and SineO2 (sinusoidal modulation of end-tidal oxygen pressures) in a cohort of 10 healthy volunteers (age 37 ± 11 years; 60% female). Perfusion estimates consisted of cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT). Calculations were computed using a traditional tracer kinetics model in the time domain for desaturation and resaturation and in the frequency domain for SineO2. High correlations and limits of agreement were observed among the three deoxygenation-based paradigms for CBV, although MTT and CBF estimates varied with the hypoxic stimulus. Cross-modality correlation with gadolinium DSC was lower, particularly for MTT, but on a par with agreement between the other perfusion references. Overall, this work demonstrated the feasibility and reliability of oxygen respiratory challenges to measure brain perfusion. Additional work is needed to assess the utility of dDSC in the diagnostic evaluation of various pathologies such as ischemic strokes, brain tumors, and neurodegenerative diseases.
Subject(s)
Contrast Media , Gadolinium , Humans , Female , Adult , Middle Aged , Male , Reproducibility of Results , Magnetic Resonance Imaging , Brain/pathology , Oxygen , Cerebrovascular Circulation/physiologyABSTRACT
BACKGROUND: Tilts can induce alterations in cerebral hemodynamics in healthy neonates, but prior studies have only examined systemic parameters or used small tilt angles (<90°). The healthy neonatal population, however, are commonly subjected to large tilt angles (≥90°). We sought to characterize the cerebrovascular response to a 90° tilt in healthy term neonates. METHODS: We performed a secondary descriptive analysis on 44 healthy term neonates. We measured cerebral oxygen saturation (rcSO2), oxygen saturation (SpO2), heart rate (HR), breathing rate (BR), and cerebral fractional tissue oxygen extraction (cFTOE) over three consecutive 90° tilts. These parameters were measured for 2-min while neonates were in a supine (0°) position and 2-min while tilted to a sitting (90°) position. We measured oscillometric mean blood pressure (MBP) at the start of each tilt. RESULTS: rcSO2 and BR decreased significantly in the sitting position, whereas cFTOE, SpO2, and MBP increased significantly in the sitting position. We detected a significant position-by-time interaction for all physiological parameters. CONCLUSION: A 90° tilt induces a decline in rcSO2 and an increase in cFTOE in healthy term neonates. Understanding the normal cerebrovascular response to a 90° tilt in healthy neonates will help clinicians to recognize abnormal responses in high-risk infant populations. IMPACT: Healthy term neonates (≤14 days old) had decreased cerebral oxygen saturation (~1.1%) and increased cerebral oxygen extraction (~0.01) following a 90° tilt. We detected a significant position-by-time interaction with all physiological parameters measured, suggesting the effect of position varied across consecutive tilts. No prior study has characterized the cerebral oxygen saturation response to a 90° tilt in healthy term neonates.
Subject(s)
Cerebrovascular Circulation , Heart Rate , Oxygen Saturation , Humans , Infant, Newborn , Cerebrovascular Circulation/physiology , Male , Female , Blood Pressure , Oxygen/metabolism , Supine Position , Posture , Hemodynamics , Respiratory Rate , Healthy Volunteers , Brain/metabolismABSTRACT
BACKGROUND: In the Fontan palliation for single ventricle heart disease (SVHD), pulmonary blood flow is non-pulsatile/passive, low velocity, and low shear, making viscous power loss a critical determinant of cardiac output. The rheologic properties of blood in SVHD patients are essential for understanding and modulating their limited cardiac output and they have not been systematically studied. We hypothesize that viscosity is decreased in single ventricle circulation. METHODS: We evaluated whole blood viscosity, red blood cell (RBC) aggregation, and RBC deformability to evaluate changes in healthy children and SVHD patients. We altered suspending media to understand cellular and plasma differences contributing to rheologic differences. RESULTS: Whole blood viscosity was similar between SVHD and healthy at their native hematocrits, while viscosity was lower at equivalent hematocrits for SVHD patients. RBC deformability is increased, and RBC aggregation is decreased in SVHD patients. Suspending SVHD RBCs in healthy plasma resulted in increased RBC aggregation and suspending healthy RBCs in SVHD plasma resulted in lower RBC aggregation. CONCLUSIONS: Hematocrit corrected blood viscosity is lower in SVHD vs. healthy due to decreased RBC aggregation and higher RBC deformability, a viscous adaptation of blood in patients whose cardiac output is dependent on minimizing viscous power loss. IMPACT: Patients with single ventricle circulation have decreased red blood cell aggregation and increased red blood cell deformability, both of which result in a decrease in blood viscosity across a large shear rate range. Since the unique Fontan circulation has very low-shear and low velocity flow in the pulmonary arteries, blood viscosity plays an increased role in vascular resistance, therefore this work is the first to describe a novel mechanism to target pulmonary vascular resistance as a modifiable risk factor. This is a novel, modifiable risk factor in this patient population.
Subject(s)
Blood Viscosity , Erythrocyte Aggregation , Erythrocyte Deformability , Fontan Procedure , Humans , Child , Heart Defects, Congenital/surgery , Heart Defects, Congenital/physiopathology , Male , Female , Hematocrit , Univentricular Heart/surgery , Univentricular Heart/physiopathology , Child, Preschool , Heart Ventricles/physiopathology , Heart Ventricles/abnormalities , Cardiac Output , Adolescent , ErythrocytesABSTRACT
Sickle cell disease (SCD) is characterized by chronic hemolytic anemia associated with impaired cerebral hemodynamics and oxygen metabolism. Hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for patients with SCD. Whereas normalization of hemoglobin levels and hemolysis markers has been reported after HSCT, its effects on cerebral perfusion and oxygenation in adult SCD patients remain largely unexplored. This study investigated the effects of HSCT on cerebral blood flow (CBF), oxygen delivery, cerebrovascular reserve (CVR), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2 ) in 17 adult SCD patients (mean age: 25.0 ± 8.0, 6 females) before and after HSCT and 10 healthy ethnicity-matched controls (mean age: 28.0 ± 8.8, 6 females) using MRI. For the CVR assessment, perfusion scans were performed before and after acetazolamide as a vasodilatory stimulus. Following HSCT, gray and white matter (GM and WM) CBF decreased (p < .01), while GM and WM CVR increased (p < .01) compared with the baseline measures. OEF and CMRO2 also increased towards levels in healthy controls (p < .01). The normalization of cerebral perfusion and oxygen metabolism corresponded with a significant increase in hemoglobin levels and decreases in reticulocytes, total bilirubin, and LDH as markers of hemolysis (p < .01). This study shows that HSCT results in the normalization of cerebral perfusion and oxygen metabolism, even in adult patients with SCD. Future follow-up MRI scans will determine whether the observed normalization of cerebral hemodynamics and oxygen metabolism prevents new silent cerebral infarcts.
Subject(s)
Anemia, Sickle Cell , Hematopoietic Stem Cell Transplantation , Adult , Female , Humans , Hemolysis , Magnetic Resonance Imaging/methods , Hemodynamics , Oxygen/metabolism , Hematopoietic Stem Cell Transplantation/adverse effects , Stem Cell Transplantation , Hemoglobins/metabolism , Cerebrovascular Circulation/physiology , Brain/diagnostic imaging , Brain/metabolism , Oxygen ConsumptionABSTRACT
Primum non nocere! Can iron deficiency, an abnormality that causes anemia, benefit people with sickle cell disease (SCD) who already have an anemia? The published literature we review appears to answer this question in the affirmative: basic science considerations, animal model experiments, and noncontrolled clinical observations all suggest a therapeutic potential of iron restriction in SCD. This is because SCD's clinical manifestations are ultimately attributable to the polymerization of hemoglobin S (HbS), a process strongly influenced by intracellular HbS concentration. Even small decrements in HbS concentration greatly reduce polymerization, and iron deficiency lowers erythrocyte hemoglobin concentration. Thus, iron deficiency could improve SCD by changing its clinical features to those of a more benign anemia (i.e., a condition with fewer or no vaso-occlusive events). We propose that well-designed clinical studies be implemented to definitively determine whether iron restriction is a safe and effective option in SCD. These investigations are particularly timely now that pharmacologic agents are being developed, which may directly reduce red cell hemoglobin concentrations without the need for phlebotomies to deplete total body iron.
Subject(s)
Anemia, Sickle Cell , Hemoglobin, Sickle , Iron , Anemia, Sickle Cell/complications , Anemia, Sickle Cell/blood , Humans , Animals , Iron/metabolism , Iron/blood , Hemoglobin, Sickle/metabolism , Hemoglobin, Sickle/analysis , Anemia, Iron-Deficiency/drug therapy , Erythrocytes/metabolismABSTRACT
Importance: Most research to understand postacute sequelae of SARS-CoV-2 infection (PASC), or long COVID, has focused on adults, with less known about this complex condition in children. Research is needed to characterize pediatric PASC to enable studies of underlying mechanisms that will guide future treatment. Objective: To identify the most common prolonged symptoms experienced by children (aged 6 to 17 years) after SARS-CoV-2 infection, how these symptoms differ by age (school-age [6-11 years] vs adolescents [12-17 years]), how they cluster into distinct phenotypes, and what symptoms in combination could be used as an empirically derived index to assist researchers to study the likely presence of PASC. Design, Setting, and Participants: Multicenter longitudinal observational cohort study with participants recruited from more than 60 US health care and community settings between March 2022 and December 2023, including school-age children and adolescents with and without SARS-CoV-2 infection history. Exposure: SARS-CoV-2 infection. Main Outcomes and Measures: PASC and 89 prolonged symptoms across 9 symptom domains. Results: A total of 898 school-age children (751 with previous SARS-CoV-2 infection [referred to as infected] and 147 without [referred to as uninfected]; mean age, 8.6 years; 49% female; 11% were Black or African American, 34% were Hispanic, Latino, or Spanish, and 60% were White) and 4469 adolescents (3109 infected and 1360 uninfected; mean age, 14.8 years; 48% female; 13% were Black or African American, 21% were Hispanic, Latino, or Spanish, and 73% were White) were included. Median time between first infection and symptom survey was 506 days for school-age children and 556 days for adolescents. In models adjusted for sex and race and ethnicity, 14 symptoms in both school-age children and adolescents were more common in those with SARS-CoV-2 infection history compared with those without infection history, with 4 additional symptoms in school-age children only and 3 in adolescents only. These symptoms affected almost every organ system. Combinations of symptoms most associated with infection history were identified to form a PASC research index for each age group; these indices correlated with poorer overall health and quality of life. The index emphasizes neurocognitive, pain, and gastrointestinal symptoms in school-age children but change or loss in smell or taste, pain, and fatigue/malaise-related symptoms in adolescents. Clustering analyses identified 4 PASC symptom phenotypes in school-age children and 3 in adolescents. Conclusions and Relevance: This study developed research indices for characterizing PASC in children and adolescents. Symptom patterns were similar but distinguishable between the 2 groups, highlighting the importance of characterizing PASC separately for these age ranges.
ABSTRACT
Accumulation of excess iron in the body, or systemic iron overload, results from a variety of causes. The concentration of iron in the liver is linearly related to the total body iron stores and, for this reason, quantification of liver iron concentration (LIC) is widely regarded as the best surrogate to assess total body iron. Historically assessed using biopsy, there is a clear need for noninvasive quantitative imaging biomarkers of LIC. MRI is highly sensitive to the presence of tissue iron and has been increasingly adopted as a noninvasive alternative to biopsy for detection, severity grading, and treatment monitoring in patients with known or suspected iron overload. Multiple MRI strategies have been developed in the past 2 decades, based on both gradient-echo and spin-echo imaging, including signal intensity ratio and relaxometry strategies. However, there is a general lack of consensus regarding the appropriate use of these methods. The overall goal of this article is to summarize the current state of the art in the clinical use of MRI to quantify liver iron content and to assess the overall level of evidence of these various methods. Based on this summary, expert consensus panel recommendations on best practices for MRI-based quantification of liver iron are provided.
Subject(s)
Iron Overload , Liver , Humans , Liver/diagnostic imaging , Liver/pathology , Iron Overload/diagnostic imaging , Iron Overload/pathology , Magnetic Resonance Imaging/methods , Iron , BiopsyABSTRACT
BACKGROUND: Oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2 ) may serve as biomarkers in several diseases. OEF and CMRO2 can be estimated from venous blood oxygenation (Yv ) levels, which in turn can be calculated from venous blood T2 values (T2b ). T2b can be measured using different MRI sequences, including T2-relaxation-under-spin-tagging (TRUST) and T2-prepared-blood-relaxation-imaging-with-inversion-recovery (T2-TRIR). The latter measures both T2b and T1 (T1b ) but was found previously to overestimate T2b compared to TRUST. It remained unclear, however, if this bias is constant across higher and lower oxygen saturations. PURPOSE: To compare TRUST and T2-TRIR across a range of O2 saturations using hypoxic and hypercapnic gas challenges. STUDY TYPE: Prospective. POPULATION: Twelve healthy volunteers (four female, age 36 ± 10 years). FIELD STRENGTH/SEQUENCE: A 3T; turbo-field echo-planar-imaging (TFEPI), echo-planar-imaging (EPI), and fast-field-echo (FFE). ASSESSMENT: TRUST- and T2-TRIR-derived T2b , Yv , OEF, and CMRO2 were compared across different respiratory challenges. T1b from T2-TRIR was used to estimate Hct (HctTRIR ) and compared with venipuncture (HctVP ). STATISTICAL TESTS: Shapiro-Wilk, one-sample and paired-sample t-test, repeated measures ANOVA, Friedman test, Bland-Altman, and correlation analysis. Bonferroni multiple-comparison correction was performed. Significance level was 0.05. RESULTS: A significant bias was observed between TRUST- and T2-TRIR-derived T2b , Yv , and OEF values (-13 ± 11 msec, -5.3% ± 3.5% and 5.9 ± 4.1%, respectively). For Yv and OEF, this bias was constant across the range of measured values. T1b was significantly lower during severe hypoxia and hypercapnia compared to baseline (1712 ± 86 msec and 1634 ± 79 msec compared to 1757 ± 90 msec). While no significant bias was found between HctVP and HctTRIR (0.02% ± 0.06%, P = 0.20), the correlation between these Hct values was significant but weak (r = 0.19). DATA CONCLUSION: Given the constant bias, TRUST- and T2-TRIR-derived venous T2b values can be used interchangeably to estimate Yv , OEF, and CMRO2 across a broad range of oxygen saturations. Hct from T2-TRIR-derived T1-values only weakly correlated with Hct from venipuncture. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.
Subject(s)
Hypercapnia , Oxygen , Humans , Female , Adult , Middle Aged , Hypercapnia/diagnostic imaging , Hypercapnia/metabolism , Prospective Studies , Oxygen/metabolism , Hypoxia/metabolism , Magnetic Resonance Imaging/methods , Brain/diagnostic imaging , Brain/metabolism , Cerebrovascular Circulation , Oxygen ConsumptionABSTRACT
Fetal magnetic resonance imaging (MRI) is an important adjunct modality for the evaluation of fetal abnormalities. Recently, low-field MRI systems at 0.55 Tesla have become available which can produce images on par with 1.5 Tesla systems but with lower power deposition, acoustic noise, and artifact. In this article, we describe a technical innovation using low-field MRI to perform diagnostic quality fetal MRI.
Subject(s)
Fetus , Magnetic Resonance Imaging , Humans , Fetus/diagnostic imaging , Magnetic Resonance Imaging/methods , Acoustics , ArtifactsABSTRACT
Dilated cardiomyopathy (DCM) is an inevitable complication of Duchenne muscular dystrophy (DMD). Late gadolinium enhancement (LGE) demonstrated by cardiac MRI occurs in DMD-related DCM, indicating myocyte death and remodeling. We conducted a retrospective chart review identifying DMD patients in our center between January 2009 and July 2013. Subjects were cohorted by presence of LGE before age 14. We excluded patients in whom we could not determine LGE status prior to age 14. We reviewed comprehensive clinical data. Of the 41 subjects with complete data, 15 demonstrated LGE before age 14 ("early LGE") and 26 had no LGE by age 14 ("controls"). Those with early LGE exhibited a more rapid decline in LV fractional shortening (p = 0.028). Patients with early LGE were younger at age of initiation of ACE inhibition (p = 0.025), mineralocorticoid receptor antagonism (p = 0.0024), and beta-blockade (p = 0.0017), suggesting aggressive clinical management in response to abnormal MRI findings. There were no significant differences in LV dilation between the two groups (p = 0.1547). Early LGE was not associated with obesity (p = 0.32), age at loss of ambulation (p = 0.31), or heart rate (p-value > 0.8). Early onset of myocardial fibrosis as indicated by LGE on cardiac MRI is associated with earlier progression of cardiomyopathic changes despite earlier medication therapy. Identifying this risk factor, observed in 34% of our cohort during preadolescence, may guide medical therapy and early counseling about cardiomyopathy progression. We advocate for obtaining at least one MRI in patients with DMD prior to age 14 to risk stratify patients.
Subject(s)
Cardiomyopathies , Cardiomyopathy, Dilated , Muscular Dystrophy, Duchenne , Adolescent , Child , Humans , Cardiomyopathies/etiology , Cardiomyopathies/complications , Cardiomyopathy, Dilated/complications , Contrast Media , Gadolinium/pharmacology , Magnetic Resonance Imaging, Cine/adverse effects , Muscular Dystrophy, Duchenne/complications , Muscular Dystrophy, Duchenne/diagnostic imaging , Predictive Value of Tests , Prognosis , Retrospective StudiesABSTRACT
Habitual physical activity is beneficial for cerebrovascular health and cognitive function. Physical exercise therefore constitutes a clinically relevant cerebrovascular stimulus. This study demonstrates the feasibility of quantitative cerebral blood flow (CBF) measurements during supine bicycling exercise with pseudo-continuous arterial spin labeling (pCASL) magnetic resonance imaging (MRI) at 3 Tesla. Twelve healthy volunteers performed a steady-state exercise-recovery protocol on an MR-compatible bicycle ergometer, while dynamic pCASL data were acquired at rest, during moderate (60% of the age-predicted supine maximal heart rate (HRmax)) and vigorous (80% of supine HRmax) exercise, and subsequent recovery. These CBF measurements were compared with 2D phase-contrast MRI measurements of blood flow through the carotid arteries. Procedures were repeated on a separate day for an assessment of measurement repeatability. Whole-brain (WB) CBF was 41.2 ± 6.9 mL/100 g/min at rest (heart rate 63 [57-71] beats/min), remained similar at moderate exercise (102 [97-107] beats/min), decreased by 10% to 37.1 ± 5.7 mL/100 g/min (p = 0.001) during vigorous exercise (139 [136-142] beats/min) and decreased further to 34.2 ± 6.0 mL/100 g/min (p < 0.001) during recovery. Hippocampus CBF decreased by 12% (p = 0.001) during moderate exercise, decreased further during vigorous exercise (-21%; p < 0.001) and was even lower during recovery (-31%; p < 0.001). In contrast, motor cortex CBF increased by 12% (p = 0.027) during moderate exercise, returned to resting-state values during vigorous exercise, and decreased by 17% (p = 0.006) during recovery. The inter-session repeatability coefficients for WB CBF were approximately 20% for all stages of the exercise-recovery protocol. Phase-contrast blood flow measurements through the common carotid arteries overestimated the WB CBF because of flow directed to the face and scalp. This bias increased with exercise. We have demonstrated the feasibility of dynamic pCASL-MRI of the human brain for a quantitative evaluation of cerebral perfusion during bicycling exercise. Our spatially resolved measurements revealed a differential response of CBF in the motor cortex as well as the hippocampus compared with the brain as a whole. Caution is warranted when using flow through the common carotid arteries as a surrogate measure for cerebral perfusion.
Subject(s)
Bicycling , Cerebrovascular Circulation/physiology , Magnetic Resonance Imaging/methods , Adult , Feasibility Studies , Female , Healthy Volunteers , Humans , Male , Spin LabelsABSTRACT
Persons with sickle cell disease (SCD) exhibit subjective hypersensitivity to cold and heat perception in experimental settings, and triggers such as cold exposure are known to precipitate vaso-occlusive crises by still unclear mechanisms. Decreased microvascular blood flow (MBF) increases the likelihood of vaso-occlusion by increasing entrapment of sickled red blood cells in the microvasculature. Because those with SCD have dysautonomia, we anticipated that thermal exposure would induce autonomic hypersensitivity of their microvasculature with an increased propensity toward vasoconstriction. We exposed 17 patients with SCD and 16 control participants to a sequence of predetermined threshold temperatures for cold and heat detection and cold and heat pain via a thermode placed on the right hand. MBF was measured on the contralateral hand by photoplethysmography, and cardiac autonomic balance was assessed by determining heart rate variability. Thermal stimuli at both detection and pain thresholds caused a significant decrease in MBF in the contralateral hand within seconds of stimulus application, with patients with SCD showing significantly stronger vasoconstriction (P = .019). Furthermore, patients with SCD showed a greater progressive decrease in blood flow than did the controls, with poor recovery between episodes of thermal stimulation (P = .042). They had faster vasoconstriction than the controls (P = .033), especially with cold detection stimulus. Individuals with higher anxiety also experienced more rapid vasoconstriction (P = .007). Augmented vasoconstriction responses and progressive decreases in perfusion with repeated thermal stimulation in SCD are indicative of autonomic hypersensitivity in the microvasculature. These effects are likely to increase red cell entrapment in response to clinical triggers such as cold or stress, which have been associated with vaso-occlusive crises in SCD.
Subject(s)
Anemia, Sickle Cell/complications , Microvessels/physiopathology , Primary Dysautonomias/pathology , Temperature , Vascular Diseases/pathology , Vasoconstriction , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Primary Dysautonomias/etiology , Vascular Diseases/etiologyABSTRACT
Silent cerebral infarcts (SCI) are common in patients with sickle cell disease (SCD) and are thought to be caused by a mismatch between oxygen delivery and consumption. Functional cerebrovascular shunting is defined as reduced oxygen offloading due to the rapid transit of blood through the capillaries caused by increased flow and has been suggested as a potential mechanism underlying reduced oxygenation and SCI. We investigated the venous arterial spin labeling signal (VS) in the sagittal sinus as a proxy biomarker of cerebral functional shunting, and its association with hemodynamic imaging and hematological laboratory parameters. We included 28 children and 38 adults with SCD, and ten healthy racematched adult controls. VS, cerebral blood flow (CBF), velocity in the brain feeding arteries, oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) were measured before and after acetazolamide administration. VS was higher in patients with SCD compared to controls (P<0.01) and was increased after acetazolamide administration in all groups (P<0.01). VS was primarily predicted by CBF (P<0.01), but CBF-corrected VS was also associated with decreased CMRO2 (P<0.01). Additionally, higher disease severity defined by low hemoglobin and increased hemolysis was associated with higher CBF-corrected VS. Finally, CMRO2 was negatively correlated with fetal hemoglobin, and positively correlated with lactate dehydrogenase, which could be explained by changes in oxygen affinity. These findings provide evidence for cerebral functional shunting and encourage future studies investigating the potential link to aberrant capillary exchange in SCD.
Subject(s)
Anemia, Sickle Cell , Magnetic Resonance Imaging , Adult , Child , Humans , Magnetic Resonance Imaging/methods , Acetazolamide , Brain/blood supply , Brain/metabolism , Oxygen/metabolism , Cerebral Infarction , Oxygen Consumption/physiologyABSTRACT
BACKGROUND: Liver iron concentration (LIC) measured by MRI has become the clinical reference standard for managing iron overload in chronically transfused patients. Transverse relaxivity (R2 or R2* ) measurements are converted to LIC units using empirically derived calibration curves. HYPOTHESIS: That flip angle (FA) error due to B1+ spatial heterogeneity causes significant LIC quantitation error. B1+ scale (b1 , [FAactual /FAspecified ]) variation is a major problem at 3 T which could reduce the accuracy of transverse relaxivity measurements. STUDY TYPE: Prospective. POPULATION: Forty-seven subjects with chronic transfusional iron overload undergoing clinically indicated LIC assessment. FIELD STRENGTH/SEQUENCE: 5 T/3 T dual-repetition time B1+ mapping sequence ASSESSMENT: We quantified the average/standard deviation b1 in the right and left lobes of the liver from B1+ maps acquired at 1.5 T and 3 T. The impact of b1 variation on spin echo LIC estimates was determined using a Monte Carlo model. STATISTICAL TESTS: Mean, median, and standard deviation in whole liver and right and left lobes; two-sided t-test between whole-liver b1 means. RESULTS: Average b1 within the liver was 99.3% ± 12.3% at 1.5 T versus 69.6% ± 14.6% at 3 T and was independent of iron burden (P < 0.05). Monte Carlo simulations demonstrated that b1 systematically increased R2 estimates at lower LIC (<~25 mg/g at 1.5 T, <~15 mg/g at 3 T) but flattened or even inverted the R2 -LIC relationship at higher LIC (≥~25 mg/g to 1.5 T, ≥~15 mg/g to 3 T); changes in the R2 -LIC relationship were symmetric with respect to over and under excitation and were similar at 1.5 T and 3 T (for the same R2 value). The R2* -LIC relationship was independent of b1 . CONCLUSION: Spin echo R2 measurement of LIC at 3 T is error-prone without correction for b1 errors. The impact of b1 error on current 1.5 T spin echo-based techniques for LIC quantification is large enough to introduce measurable intersubject variability but the in vivo effect size needs a dedicated validation study. TECHNICAL EFFICACY STAGE: 2.
Subject(s)
Iron Overload , Iron , Humans , Iron Overload/diagnostic imaging , Liver/diagnostic imaging , Magnetic Resonance Imaging/methods , Prospective StudiesABSTRACT
Kidney iron deposition measured by R2* (magnetic resonance imaging) MRI is posited to result from tubular reabsorption of filtered haemoglobin due to intravascular haemolysis. In chronically transfused sickle cell disease (SCD), R2* is elevated and positively correlated with lactate dehydrogenase (LDH). To account for contributions to renal iron from systemic iron overload, we evaluated kidney R2*, urinary iron and haemolysis markers in 62 non-transfused SCD patients. On multivariate analysis, kidney R2* was associated with urinary iron and LDH (R2 = 0·55, P < 0·0001). Our study confirms that kidney R2* is associated with intravascular haemolysis and raises important questions regarding the role of iron in SCD nephropathy.
Subject(s)
Anemia, Sickle Cell , Hemolysis , Iron/urine , Kidney Diseases , Kidney , Magnetic Resonance Imaging , Adolescent , Adult , Aged , Anemia, Sickle Cell/diagnostic imaging , Anemia, Sickle Cell/urine , Biomarkers/urine , Child , Female , Humans , Kidney/diagnostic imaging , Kidney/metabolism , Kidney Diseases/diagnostic imaging , Kidney Diseases/urine , Male , Middle AgedABSTRACT
PURPOSE: Gadolinium-based dynamic susceptibility contrast (DSC) is commonly used to characterize blood flow in patients with stroke and brain tumors. Unfortunately, gadolinium contrast administration has been associated with adverse reactions and long-term accumulation in tissues. In this work, we propose an alternative deoxygenation-based DSC (dDSC) method that uses a transient hypoxia gas paradigm to deliver a bolus of paramagnetic deoxygenated hemoglobin to the cerebral vasculature for perfusion imaging. METHODS: Through traditional DSC tracer kinetic modeling, the MR signal change induced by this hypoxic bolus can be used to generate regional perfusion maps of cerebral blood flow, cerebral blood volume, and mean transit time. This gas paradigm and blood-oxygen-level-dependent (BOLD)-MRI were performed concurrently on a cohort of 66 healthy and chronically anemic subjects (age 23.5 ± 9.7, female 64%). RESULTS: Our results showed reasonable global and regional agreement between dDSC and other flow techniques, such as phase contrast and arterial spin labeling. CONCLUSION: In this proof-of-concept study, we demonstrated the feasibility of using transient hypoxia to generate a contrast bolus that mimics the effect of gadolinium and yields reasonable perfusion estimates. Looking forward, optimization of the hypoxia boluses and measurement of the arterial-input function is necessary to improve the accuracy of dDSC. Additionally, a cross-validation study of dDSC and DSC in brain tumor and ischemic stroke subjects is warranted to evaluate the clinical diagnostic utility of this approach.
Subject(s)
Contrast Media , Magnetic Resonance Imaging , Adolescent , Adult , Cerebrovascular Circulation , Female , Humans , Hypoxia , Perfusion , Spin Labels , Young AdultABSTRACT
PURPOSE: CPMG spin echo acquisitions are attractive for diagnosing and monitoring liver iron concentration in iron overload disorders due to their time efficiency and potential to reveal unique information about tissue iron distribution. Clinical adoption remains low due to the insensitivity of CPMG-based R 2 estimates to liver iron concentration (LIC) when common fitting techniques are applied. In this work, we demonstrate that the inclusion of a proton density estimator (PDE) derived from the CPMG acquisition increase the sensitivity of CPMG R 2 estimates to LIC in both simulated and in-vivo human data. THEORY AND METHODS: CPMG R 2 acquisitions from 50 clinically indicated MRI studies in patients with iron overload were analyzed with and without PDE constraints. Liver regions of interest were fit to monoexpontial and nonexponential signal decay equations. LIC by R 2 ∗ served as the reference standard. The observed calibration between CPMG R 2 values and LIC were compared to results predicted from a previously validated Monte Carlo model. RESULTS: The sensitivity of CPMG-derived R 2 triples when a proton density constraint is applied. When compared with R 2 ∗ -LIC estimates, both monoexponential and nonexponential models were unbiased but demonstrated broad 95% confidence intervals particularly for LIC values below 12 mg/g. Absolute error did not increase with LIC. CONCLUSION: A proton density constraint can increase the sensitivity of CPMG-based models to iron. CPMG acquisitions are time-efficient and could potentially improve the dynamic range of single spin echo techniques as well as providing insight into tissue iron distribution.