Brandon Benefield

Association of Nonmyeloablative Hematopoietic Stem Cell Transplantation With Neurological Disability in Patients With Relapsing-Remitting Multiple Sclerosis

IMPORTANCE No current therapy for relapsing-remitting multiple sclerosis (MS) results in significant reversal of disability. OBJECTIVE To determine the association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability and other clinical outcomes in patients with MS. DESIGN, SETTING, AND PARTICIPANTS Case series of patients with relapsing-remitting MS (n = 123) or secondary-progressive MS (n = 28) (mean age, 36 years; range, 18-60 years; 85 women) treated at a single US institution between 2003 and 2014 and followed up for 5 years. Final follow-up was completed in June 2014. INTERVENTIONS Treatment with cyclophosphamide and alemtuzumab (22 patients) or cyclophosphamide and thymoglobulin (129 patients) followed by infusion of unmanipulated peripheral blood stem cells. MAIN OUTCOMES AND MEASURES Primary end point was reversal or progression of disability measured by change in the Expanded Disability Status Scale (EDSS) score of 1.0 or greater (score range, 0-10). Secondary outcomes included changes in the Neurologic Rating Scale (NRS) score of 10 or greater (score range, 0-100), Multiple Sclerosis Functional Composite (MSFC) score, quality-of-life Short Form 36 questionnaire scores, and T2 lesion volume on brain magnetic resonance imaging scan. RESULTS Outcome analysis was available for 145 patients with a median follow-up of 2 years and a mean of 2.5 years. Scores from the EDSS improved significantly from a pretransplant median of 4.0 to 3.0 (interquartile range [IQR], 1.5 to 4.0; n = 82) at 2 years and to 2.5 (IQR, 1.9 to 4.5; n = 36) at 4 years (P < .001 at each assessment). There was significant improvement in disability (decrease in EDSS score of ≥1.0) in 41 patients (50%; 95% CI, 39% to 61%) at 2 years and in 23 patients (64%; 95% CI, 46% to 79%) at 4 years. Four-year relapse-free survival was 80% and progression-free survival was 87%. The NRS scores improved significantly from a pretransplant median of 74 to 88.0 (IQR, 77.3 to 93.0; n = 78) at 2 years and to 87.5 (IQR, 75.0 to 93.8; n = 34) at 4 years (P < .001 at each assessment). The median MSFC scores were 0.38 (IQR, -0.01 to 0.64) at 2 years (P < .001) and 0.45 (0.04 to 0.60) at 4 years (P = .02). Total quality-of-life scores improved from a mean of 46 (95% CI, 43 to 49) pretransplant to 64 (95% CI, 61 to 68) at a median follow-up of 2 years posttransplant (n = 132) (P < .001). There was a decrease in T2 lesion volume from a pretransplant median of 8.57 cm3 (IQR, 2.78 to 22.08 cm3) to 5.74 cm3 (IQR, 1.88 to 14.45 cm3) (P < .001) at the last posttransplant assessment (mean follow-up, 27 months; n = 128). CONCLUSIONS AND RELEVANCE Among patients with relapsing-remitting MS, nonmyeloablative hematopoietic stem cell transplantation was associated with improvement in neurological disability and other clinical outcomes. These preliminary findings from this uncontrolled study require confirmation in randomized trials.

Autonomic Remodeling in the Left Atrium and Pulmonary Veins in Heart Failure – Creation of a Dynamic Substrate for Atrial Fibrillation

Background—Atrial fibrillation (AF) is commonly associated with congestive heart failure (CHF). The autonomic nervous system is involved in the pathogenesis of both AF and CHF. We examined the role of autonomic remodeling in contributing to AF substrate in CHF. Methods and Results—Electrophysiological mapping was performed in the pulmonary veins and left atrium in 38 rapid ventricular–paced dogs (CHF group) and 39 control dogs under the following conditions: vagal stimulation, isoproterenol infusion, &bgr;-adrenergic blockade, acetylcholinesterase (AChE) inhibition (physostigmine), parasympathetic blockade, and double autonomic blockade. Explanted atria were examined for nerve density/distribution, muscarinic receptor and &bgr;-adrenergic receptor densities, and AChE activity. In CHF dogs, there was an increase in nerve bundle size, parasympathetic fibers/bundle, and density of sympathetic fibrils and cardiac ganglia, all preferentially in the posterior left atrium/pulmonary veins. Sympathetic hyperinnervation was accompanied by increases in &bgr;1-adrenergic receptor R density and in sympathetic effect on effective refractory periods and activation direction. &bgr;-Adrenergic blockade slowed AF dominant frequency. Parasympathetic remodeling was more complex, resulting in increased AChE activity, unchanged muscarinic receptor density, unchanged parasympathetic effect on activation direction and decreased effect of vagal stimulation on effective refractory period (restored by AChE inhibition). Parasympathetic blockade markedly decreased AF duration. Conclusions—In this heart failure model, autonomic and electrophysiological remodeling occurs, involving the posterior left atrium and pulmonary veins. Despite synaptic compensation, parasympathetic hyperinnervation contributes significantly to AF maintenance. Parasympathetic and/or sympathetic signaling may be possible therapeutic targets for AF in CHF.Background— Atrial fibrillation (AF) is commonly associated with congestive heart failure (CHF). The autonomic nervous system is involved in the pathogenesis of both AF and CHF. We examined the role of autonomic remodeling in contributing to AF substrate in CHF. Methods and Results— Electrophysiological mapping was performed in the pulmonary veins and left atrium in 38 rapid ventricular–paced dogs (CHF group) and 39 control dogs under the following conditions: vagal stimulation, isoproterenol infusion, β-adrenergic blockade, acetylcholinesterase (AChE) inhibition (physostigmine), parasympathetic blockade, and double autonomic blockade. Explanted atria were examined for nerve density/distribution, muscarinic receptor and β-adrenergic receptor densities, and AChE activity. In CHF dogs, there was an increase in nerve bundle size, parasympathetic fibers/bundle, and density of sympathetic fibrils and cardiac ganglia, all preferentially in the posterior left atrium/pulmonary veins. Sympathetic hyperinnervation was accompanied by increases in β1-adrenergic receptor R density and in sympathetic effect on effective refractory periods and activation direction. β-Adrenergic blockade slowed AF dominant frequency. Parasympathetic remodeling was more complex, resulting in increased AChE activity, unchanged muscarinic receptor density, unchanged parasympathetic effect on activation direction and decreased effect of vagal stimulation on effective refractory period (restored by AChE inhibition). Parasympathetic blockade markedly decreased AF duration. Conclusions— In this heart failure model, autonomic and electrophysiological remodeling occurs, involving the posterior left atrium and pulmonary veins. Despite synaptic compensation, parasympathetic hyperinnervation contributes significantly to AF maintenance. Parasympathetic and/or sympathetic signaling may be possible therapeutic targets for AF in CHF.

The Kinetics of Circulating Monocyte Subsets and Monocyte-Platelet Aggregates in the Acute Phase of ST-Elevation Myocardial Infarction: Associations with 2-Year Cardiovascular Events.

AbstractIn experimental myocardial infarction (MI), a rise in cell counts of circulating monocyte subsets contributes to impaired myocardial healing and to atherosclerotic plaque destabilization. In humans, the prognostic role of monocyte subsets in patients suffering ST-elevation MI (STEMI) is still unclear. In the present study, we aimed to determine the kinetics of the 3 monocyte subsets (classical CD14++CD16–, intermediate CD14++CD16+, and nonclassical CD14+CD16++ monocytes), as well as the subset-specific monocyte–platelet aggregates (MPA), in acute STEMI followed by primary percutaneous coronary intervention (PCI), and their relationships with cardiovascular outcomes during a 2-year follow-up.Monocyte subsets and MPA were measured in 100 STEMI patients receiving primary PCI on days 1, 2, 3, 5, and 7 of symptom onset, which were compared with 60 stable coronary heart disease patients and 35 healthy volunteers. From day 1 to day 7, significant increases in the counts of CD14++CD16+ monocytes and CD14++CD16+ MPA were observed, with peak levels on day 2. During a median follow-up of 2.0 years, 28 first cardiovascular events (defined as cardiovascular death, nonfatal ischemic stroke, recurrent MI, need for emergency or repeat revascularization, and rehospitalization for heart failure) were recorded. After adjustment for confounders, CD14++CD16+ monocytosis (day 1 [HR: 3.428; 95% CI: 1.597–7.358; P = 0.002], day 2 [HR: 4.835; 95% CI: 1.106–21.13; P = 0.04], day 3 [HR: 2.734; 95% CI: 1.138–6.564; P = 0.02], and day 7 [HR: 2.647; 95% CI: 1.196–5.861; P = 0.02]), as well as increased levels of CD14++CD16+ MPA measured on all time points (days 1, 2, 3, 5, and 7), had predictive values for adverse cardiovascular events.In conclusion, our data show the expansion of the CD14++CD16+ monocyte subset during acute phase of STEMI has predictive values for 2-year adverse cardiovascular outcomes in patients treated with primary PCI. Future studies will be warranted to elucidate whether CD14++CD16+ monocytes may become a target cell population for new therapeutic strategies after STEMI.

Measurement of extracellular volume fraction by cardiac magnetic resonance imaging detects diffuse myocardial fibrosis in systemic sclerosis

Summary We measured extracellular volume fraction (Ve) from pre- and post-contrast T1 maps of the left ventricle in 13 patients with systemic sclerosis (SSc) and 13 agematched controls. SSc patients and controls were similar with regard to LV and RV mass, volumes, and function. However, Ve was significantly higher in SSc patients than in controls, even when patients with visible late gadolinium enhancement were excluded. Ve correlated with SSc severity as measured by the modified Rodnan Skin Score. Ve may be valuable for detection of myocardial involvement in SSc, even when conventional CMR appears normal. Background Primary cardiac involvement is common in systemic sclerosis (SSc) and responsible for 25% of deaths. Myocardial extracellular volume fraction (Ve), derived from cardiac magnetic resonance (CMR) T1 mapping of the myocardium, has been shown to quantify diffuse myocardial fibrosis (DMF) - but its utility in SSc has not been studied. We hypothesized that subjects with SSc have a higher Ve compared to controls and that patients with worse SSc severity have higher Ve. Methods CMR was performed in 13 SSc patients (5 diffuse and 8 limited cutaneous) and 13 age-matched controls. Cine, pre- and post- contrast T1 mapping, and late gadolinium enhanced (LGE) imaging was performed. LV mass index (LVMi), LV end-diastolic volume index (LVEDVi), LV ejection fraction (EF), RV mass index (RVMi), RV

Absolute quantification of myocardial blood flow with constrained estimation of the arterial input function.

To evaluate the performance of the constrained alternating minimization with model (CAMM) method for estimating the input function from the myocardial tissue curves.

CMR myocardial infarct evaluation in a canine model by three different contrast agents

We evaluated R1 curves, CNR and scar visualization and quantification in a dog model of myocardial infarction by CMR, using three different contrast agents: Gadopentate dimeglumine (Gd-DTPA, Magnevist), Gadobenate dimeglumine (Gd-BOPTA, MultiHance), and Gadofosveset (Ablavar). Gd-DTPA showed better characteristics for myocardial scar visualization and quantification. Gadofosveset demonstrated lower CNR and underestimation of infarct size when compared to Gd-DTPA.

A steady-state method for computation of myocardial blood volume with the intravascular contrast agent Ablavar

Our proof of principle results show the feasibility of quantifying myocardial blood volume (MBV) with the intravascular contrast agent MS-325. For severe stenoses in a canine model, stenosis zone MBV was higher than remote MBV at rest, and lower than remote during vasodilation.

Leakage and water exchange characterization of gadofosveset in the myocardium.

PURPOSE To determine the compartmentalization of the blood pool agent gadofosveset and the effect of its transient binding to albumin on the quantification of steady-state fractional myocardial blood volume (fMBV). METHODS Myocardial vascular fraction measurements were simulated assuming the limiting cases (slow or fast) of two-compartment water exchange for different contrast agent injection concentrations, binding fractions, bound and free relaxivities, and true cardiac vascular fractions. fMBV was measured in five healthy volunteers (4 males, 1 female, average age 33) at 1.5T after administration of five injections of gadofosveset. The measurements in the volunteers were retrospectively compared to measurements of fMBV after three serial injections of the ultra-small, paramagnetic iron oxide (USPIO) blood pool agent ferumoxytol in an experimental animal. The true fMBV and exchange rate of water protons in both human and animal data sets was determined by chi square minimization. RESULTS Simulations showed an error in the measurement of fMBV due to partial binding of gadofosveset of less than 30%. Measured fMBV values over-estimate simulation predictions, and approach cardiac extracellular volume (22%), which suggests that the intravascular assumption may not be appropriate for the myocardium, although it may apply to more distal perfusion beds. In comparison, fMBV measured with ferumoxytol (5%, with slow water proton exchange across vascular wall) agree with published values of myocardial vascular fraction. Further comparison between myocardium relaxation rates induced by gadofosveset and by other extracellular and intravascular contrast agents showed that gadofosveset behaves like an extracellular contrast agent. CONCLUSIONS The distribution of the volunteer data indicates that a three-compartment model, with slow water exchange of gadofosveset and water protons between the vascular and interstitial compartments, and fast water exchange between the interstitium and the myocytes, is appropriate. The ferumoxytol measurements indicate that this USPIO is an intravascular contrast agent that can be used to quantify myocardial blood volume, with the appropriate correction for water exchange using a two-compartment water exchange model.

A pilot study of leakage and compartmentalization of the contrast agent Ablavar

Methods Simulation study: In vitro studies have shown Ablavar to be 80-90% bound to albumin, with up to 10 fold relaxivity difference between bound and free fractions. We performed simulations to assess the effect of extravasation of the free fraction on signal. Vascular fraction measurements were simulated assuming slow two-compartment exchange for different contrast agent injection concentrations, binding fractions, bound and free relaxivity, and true vascular fractions. Volunteer study: five healthy volunteers (4 males, average age 33) underwent T1 measurement pre and 2 minutes post administration of five injections of 0.006 mmol/kg (a fifth of a single dose) Ablavar. Steady-state T1 was mapped using a cardiac gated Modified Look Locker Inversion Recovery (MOLLI) pulse sequence (slice thickness 8 mm, FOV 300 x 400 mm, matrix 256 x 172, effective TI 100 ms). Image Processing: Maps of vascular fraction were calculated from signal difference maps, according to a slow water exchange model. Fv was measured in the myocardium, dome of the liver, and skeletal muscle visible on the short axis MOLLI images, and was corrected for Ablavar extravasation based on the leakage study. The true fv and exchange rate of water protons was determined by chi square minimization between data and simulations of the effect of water exchange on fv according to the two compartment water exchange model presented by Donahue et al. (1996).

Diffuse cardiac fibrosis quantification in early systemic sclerosis by magnetic resonance imaging and correlation with skin fibrosis

Purpose: To evaluate the utility of cardiac magnetic resonance T1 mapping in early systemic sclerosis and its association with skin score. Methods: In total, 24 consecutive patients with early systemic sclerosis referred for cardiovascular evaluation and 12 controls without systemic sclerosis were evaluated. All patients underwent cine, T1 mapping, and late gadolinium–enhanced cardiac magnetic resonance imaging. T1 mapping indices were compared between systemic sclerosis patients and controls (extracellular volume fraction, gadolinium partition coefficient (λ), pre-contrast T1, and post-contrast T1). The association between T1 mapping parameters and the modified Rodnan skin score was determined. Results: There were no significant differences in cardiac structure/function between systemic sclerosis patients and controls on cine imaging, and 8 of 24 (33%) systemic sclerosis patients had evidence of late gadolinium–enhanced cardiac magnetic resonance imaging (i.e. focal myocardial fibrosis). Of the T1 mapping parameters (indices indicative of diffuse myocardial fibrosis), extracellular volume fraction differentiated systemic sclerosis patients from controls the best, followed by λ, even when the eight systemic sclerosis patients with late gadolinium–enhanced cardiac magnetic resonance imaging were excluded. Extracellular volume fraction had a sensitivity and specificity of 75% and 75% for diffuse myocardial fibrosis (optimal abnormal cutoff value of >27% (area under receiver operating characteristic curve = 0.85)). In the 16 patients without evidence of late gadolinium–enhanced cardiac magnetic resonance imaging, each of the four cardiac magnetic resonance T1 mapping parameters (extracellular volume fraction, λ, Pre-T1 and Post-T1) correlated with modified Rodnan skin score (R = 0.51–0.65, p = 0.007–0.043), indicating a correlation between systemic sclerosis cardiac and skin fibrosis. Conclusion: The four T1 mapping indices are significantly correlated with modified Rodnan skin score in patients with early systemic sclerosis. Quantification of diffuse myocardial fibrosis using extracellular volume fraction should be considered as a marker for cardiac involvement in systemic sclerosis clinical studies.