Changes in the incidence, patterns and outcomes of graft failure following hematopoietic stem cell transplantation for Hurler syndrome.

Hematopoietic stem cell transplantation (HSCT) is the standard of care in children with Hurler syndrome (HS) as it is the only therapy that can arrest disease progression. We examined the incidence, patterns and outcomes of graft failure in all HS children undergoing first HSCT at the Royal Manchester Children's Hospital or the University of Minnesota Children's Hospital from 1983 to 2016. Implementation of busulfan pharmacokinetic monitoring started in 2004 in both institutions. Two hundred and forty HS children were included in this analysis (historical era (pre-2004), n=131; current era (post 2004), n=109). The proportion of patients with graft failure was significantly lower in the current era compared with the historical era (37.2% vs 10.1%, respectively). Of 49 patients with graft failure in the historical era, 1 had aplasia and 48 had autologous reconstitution. All the 11 graft failures of the current era occurred in recipients of cord blood transplants (7 aplasia and 4 autologous reconstitution). The outcomes of second transplant in these patients has improved, with 89% of such patients alive and engrafted in the current era compared with 58% in the historical era. The pattern of graft failure has changed from autologous reconstitution, likely secondary to inadequate myelosuppression in the historical era, to aplasia in the current era, likely due to imperfect immunosuppression.

Non-myeloablative conditioning for second hematopoietic cell transplantation for graft failure in patients with non-malignant disorders: a prospective study and review of the literature.

Allogeneic hematopoietic cell transplantation (HCT) effectively treats several non-malignant disorders such as selected lysosomal disorders, cerebral adrenoleukodystrophy and hemoglobinopathies. However, rates of graft failure (GF) in non-malignant populations exceed those of patients with malignant indications for HCT. Salvage conditioning regimens and outcomes for second HCT for GF vary immensely in the literature. We report 17 consecutive pediatric patients with non-malignant disorders who underwent a second allogenic HCT for GF using a non-myeloablative, low-dose busulfan-based regimen. Graft sources for the second transplant included umbilical cord blood, unrelated bone marrow and unrelated PBSCs. Median age at time of second HCT was 6.6 years (1.1-14.6 years). Fourteen of seventeen patients (82%) achieved engraftment, with a 3-year overall survival of 82% (95% CI, 54-94%). Day 100 transplant-related mortality was 12% (95% CI, 0-27%). CMV and adenovirus reactivation occurred in 30% and fungal infections in 18%. The incidence of grade II-IV acute GvHD disease was 35% (95% CI, 13-58%) with only 6% grade III-IV (95% CI, 0-17%). In summary, we illustrate excellent overall survival and acceptable toxicity using a non-myeloablative conditioning regimen for second HCT as salvage therapy for first GF in patients with non-malignant conditions.

Ovarian function after hematopoietic cell transplantation: a descriptive study following the use of GnRH agonists for myeloablative conditioning and observation only for reduced-intensity conditioning.

Gonadal failure is a health and quality-of-life concern in hematopoietic cell transplant (HCT) survivors. While ovarian dysfunction is nearly universal following myeloablative (MA) conditioning, the risk is unclear after reduced-intensity conditioning (RIC). Gonadotropin-releasing hormone agonists decrease ovarian failure rates following conventional chemotherapy, but little is known about its effectiveness with HCT. We investigated the impact of leuprolide on ovarian function after MA conditioning and monitored ovarian function after RIC in this descriptive pilot study. Post-menarchal females <50 years undergoing HCT with adequate baseline ovarian function (follicle-stimulating hormone (FSH) level <40 mIU/mL and normal menstruation) were eligible. Prior to MA conditioning, leuprolide was administered. Those undergoing RIC were observed. FSH was measured at various time points. Seventeen women aged 12-45 years were evaluated (7 in the intervention group and 10 in the observation group). Compared to the historical high rate of ovarian failure after MA conditioning, 3 of 7 evaluable Lupron recipients had ovarian failure at a median of 703 days post transplant. Ovarian failure occurred in 1 of 10 recipients of RIC at a median follow-up of 901 days. In conclusion, leuprolide may protect ovarian function after MA conditioning. Additionally, RIC with cyclophosphamide, fludarabine and low-dose TBI has a low risk of ovarian failure.

Childhood Cerebral Adrenoleukodystrophy: MR Perfusion Measurements and Their Use in Predicting Clinical Outcome after Hematopoietic Stem Cell Transplantation.

BACKGROUND AND PURPOSE: MR perfusion has shown abnormalities of affected WM in cerebral X-linked adrenoleukodystrophy, but serial data is needed to explore the import of such findings after hematopoietic stem cell transplantation. Our aim was to prospectively measure MR perfusion parameters in patients with cerebral adrenoleukodystrophy pre- and post-hematopoietic stem cell transplantation, and to correlate those measurements with clinical outcome. MATERIALS AND METHODS: Ten patients with cerebral adrenoleukodystrophy prospectively underwent DSC-MR perfusion imaging at <45 days pre- (baseline), 30-60 days post-, and 1 year post-hematopoietic stem cell transplantation. MR perfusion measurements in the 10 patients and 8 controls were obtained from the parieto-occipital WM, splenium of the corpus callosum, leading enhancing edge, and normal-appearing frontal white matter. MR imaging severity scores and clinical neurologic function and neurocognitive scores were also obtained. MR perfusion values were analyzed in the patients with cerebral adrenoleukodystrophy at each time point and compared with those in controls. Correlations were calculated between the pre-hematopoietic stem cell transplantation MR perfusion values and 1-year clinical scores, with P value adjustment for multiple comparisons. RESULTS: At baseline in patients with cerebral adrenoleukodystrophy, both relative CBV and relative CBF within the splenium of the corpus callosum and parieto-occipital WM significantly differed from those in controls (P = .005-.031) and remained so 1 year post-hematopoietic stem cell transplantation (P = .003-.005). Meanwhile, no MR perfusion parameter within the leading enhancing edge differed significantly from that in controls at baseline or at 1 year (P = .074-.999) or significantly changed by 1 year post-hematopoietic stem cell transplantation (P = .142-.887). Baseline Loes scores correlated with 1-year clinical neurologic function (r = 0.813, P < .0001), while splenium of the corpus callosum relative CBV also significantly correlated with 1-year neurologic function scale and the neurocognitive full-scale intelligence quotient and performance intelligence quotient scores (r = -0.730-0.815, P = .007-.038). CONCLUSIONS: Leading enhancing edge measurements likely remain normal post-hematopoietic stem cell transplantation in cerebral adrenoleukodystrophy, suggesting local disease stabilization. Meanwhile, parieto-occipital WM and splenium of the corpus callosum relative CBV and relative CBF values worsened; this change signified irreversible injury. Baseline splenium of the corpus callosum relative CBV may predict clinical outcomes following hematopoietic stem cell transplantation.

Intensity of MRI Gadolinium Enhancement in Cerebral Adrenoleukodystrophy: A Biomarker for Inflammation and Predictor of Outcome following Transplantation in Higher Risk Patients.

BACKGROUND AND PURPOSE: Outcomes following hematopoietic stem cell transplantation for higher risk childhood-onset cerebral adrenoleukodystrophy are variable. We explored whether a brain MR imaging gadolinium intensity scoring system improves prediction of neurologic outcome. MATERIALS AND METHODS: We developed a 4-point scale of gadolinium intensity relative to the choroid plexus: 0 = no enhancement; 1 = hypointense; 2 = isointense; 3 = hyperintense. The interobserver concordance of the scale was assessed on 30 randomly chosen studies. Scores were generated for 64 evaluable patients and compared with CSF chitotriosidase levels, a known inflammatory marker correlating with outcomes following transplantation. For 25 evaluable higher risk patients (Loes ≥10), the gadolinium intensity score was compared with longer term posttransplantation clinical change. RESULTS: The gadolinium intensity scoring system showed good interobserver reproducibility (κ = 0.72). Of 64 evaluable boys, the score positively correlated with average concomitant CSF chitotriosidase activity in nanograms/milliliter/hour: 0: 2717, n = 5; 1: 3218, n = 13; 2: 6497, n = 23; and 3: 12,030, n = 23 (P < .01). For 25 evaluable higher risk patients, more intense pretransplantation brain MR imaging gadolinium enhancement predicted greater average loss on the adrenoleukodystrophy neurologic function scale following transplantation: 0/1: adrenoleukodystrophy neurologic function scale score difference = 4.3, n = 7; 2/3: adrenoleukodystrophy neurologic function scale score difference = 10.4, n = 18 (P = .05). CONCLUSIONS: Gadolinium enhancement intensity on brain MR imaging can be scored simply and reproducibly for cerebral adrenoleukodystrophy. The enhancement score significantly correlates with chitotriosidase. In boys with higher risk cerebral disease (Loes ≥10), the enhancement score itself predicts neurologic outcome following treatment. Such data may help guide treatment decisions for clinicians and families.

Cardiac QTc interval characteristics before and after hematopoietic stem cell transplantation: an analysis of 995 consecutive patients at a single center.

Hematopoietic stem cell transplantation (HSCT) treats disorders affecting patients of all ages. We studied the rate-corrected cardiac QT interval (QTc) in 995 consecutive children and adults undergoing HSCT at the University of Minnesota. We sought to (1) describe QTc before and after HSCT; (2) describe the change in QTc after HSCT; (3) identify factors affecting QTc and its change; and (4) scrutinize an 'at risk' sub-cohort with a long QTc before HSCT. Pre HSCT: 952 (96%) patients had an evaluable electrocardiography (ECG); median QTc was 426 ms and depended upon disease necessitating transplant. Post HSCT: 506 (51%) patients had an evaluable ECG; median QTc was 441 ms. Intrapatient QTc change: 490 (49%) evaluable patients showed median QTc change (pre to post HSCT) of +16 ms (P<0.0001). At risk group: 68 patients were 'at risk' (long pre-HSCT QTc). In some, 'at-risk' status trended toward predictive of post-transplant nonrelapse mortality. QTc interval prolongation is evident in a large, diverse cohort undergoing HSCT at our institution. Prospective studies of this patient population may be warranted, particularly for 'at-risk' patients who demonstrate significant QTc prolongation both pre and post HSCT.

Childhood cerebral X-linked adrenoleukodystrophy: diffusion tensor imaging measurements for prediction of clinical outcome after hematopoietic stem cell transplantation.

BACKGROUND AND PURPOSE: DTI in cerebral X-linked adrenoleukodystrophy may demonstrate abnormalities in both affected and nonaffected WM; these values have not been studied serially after hematopoietic stem cell transplantation. The purpose of this study was to study pretransplant and posttransplant DTI parameters serially and ultimately to determine the ability of pretransplant DTI parameters to predict clinical outcome after HSCT in children with ALD. MATERIALS AND METHODS: Eight patients with posterior-pattern cerebral ALD underwent DTI at 3T before HSCT (T0), at 30-60 days (T1), 90-120 days (T2), 180 days (T3), and 1 year (T4) after HSCT. FA and MD were serially measured in 19 regions, and these measurements were compared with those in control patients. MR imaging severity (Loes) scores were recorded. Correlations were performed between DTI parameters and Loes scores, neurologic function scores, and several neuropsychologic scores. RESULTS: Both FA and MD in subjects differed significantly from that in controls at nearly every time point within cerebellar WM, callosal splenium, and parieto-occipital WM; FA alone was significantly different at each time point within the optic radiations, lateral geniculate, and the Meyer loop (P < .05). Loes scores at T0 correlated strongly with each clinical score at T4 (r = 0.771-0.986, P < .05). The only significant DTI correlation at T0 with a clinical score at T4 was callosal body FA with adaptive function (r = 0.976, P < .001). Correlating the change in DTI values with change in NFS (change between T0 and T4) showed that only ΔMD within the optic radiations correlated strongly with ΔNFS (r = 0.903, P < .05). CONCLUSIONS: DTI values at T0 were generally poor predictors of outcome at 1 year, whereas Loes scores were generally good predictors. ΔMD within the optic radiations strongly correlates with ΔNFS over that year. In addition, certain normal-appearing regions, such as cerebellar WM, may have DTI abnormalities before HSCT that persist after HSCT.

Oxytetracycline Dynamics on Peach Leaves in Relation to Temperature, Sunlight, and Simulated Rain.

Oxytetracycline (OTC), a member of the tetracycline antibiotics, is used as a foliar spray to control Xanthomonas arboricola pv. pruni on stone fruits and Erwinia amylovora on pome fruits. We studied the dynamics of OTC residues on attached peach (Prunus persica) leaves treated with 300 ppm active ingredient of an agricultural OTC in relation to temperature, natural sunlight, and simulated rain. We further evaluated the potential of three ultraviolet (UV) protectants (lignin, titanium dioxide, and oxybenzone) and one sticker-extender (Nu Film-17) to prolong OTC longevity on the leaf surface. OTC residue was determined by high-pressure liquid chromatography (HPLC)-UV (C18 reversed-phase column). In controlled conditions in darkness, constant temperatures up to 40°C did not affect OTC degradation on leaves. In contrast, OTC residue decreased rapidly in natural sunlight in the absence of rain, declining, on average, by 43.8, 77.8, and 92.1% within 1, 2, and 4 days after application, respectively; 7 days after application, OTC levels were near the detection limit. Use of shade fabric with 10 and 40% sunlight transmittance, simulating overcast sky, reduced OTC degradation significantly but did not extend OTC persistence beyond 7 days. Areas under the OTC residue curve, summarizing OTC dynamics during the 7-day exposure period, were negatively and significantly correlated with solar radiation and UV radiation variables, but not with temperature. UV protectants and Nu Film-17 were ineffective in improving OTC persistence in outdoor conditions. Simulated rain at 44 mm h-1 drastically (by 67.2%) lowered OTC residue after 2 min, and levels were near the detection limit after 60 min of continuous rain, regardless of whether plants were exposed to rainfall 1 or 24 h after OTC application. In artificial inoculation experiments with X. arboricola pv. pruni on attached peach leaves, OTC concentrations ≥50 ppm active ingredient (corresponding to ≥0.06 µg OTC cm-2 leaf surface) were sufficient to suppress bacterial spot development. By extrapolation from our outdoor exposure experiments, similar OTC residues following application of labeled OTC rates would be reached after less than 2 days under full sunlight, after 4 days under overcast sky, or after 2 min of a heavy rainstorm.

Expanded nonhuman primate tregs exhibit a unique gene expression signature and potently downregulate alloimmune responses.

We have established two complementary strategies for purifying naturally occurring regulatory T cells (Tregs) from rhesus macaques in quantities that would be sufficient for use as an in vivo cellular therapeutic. The first strategy identified Tregs based on their being CD4+/CD25(bright). The second incorporated CD127, and purified Tregs based on their expression of CD4 and CD25 and their low expression of CD127. Using these purification strategies, we were able to purify as many as 1x10(6) Tregs from 120 cc of peripheral blood. Cultures of these cells with anti-CD3, anti-CD28 and IL-2 over 21 days yielded as much as a 450-fold expansion, ultimately producing as many as 4.7x10(8) Tregs. Expanded Treg cultures potently inhibited alloimmune proliferation as measured by a carboxyfluorescein succinimidyl ester- mixed lymphocyte reaction (CFSE-MLR) assay even at a 1:100 ratio with responder T cells. Furthermore, both responder-specific and third-party Tregs downregulated alloproliferation similarly. Both freshly isolated and cultured Tregs had gene expression signatures distinguishable from concurrently isolated bulk CD4+ T-cell populations, as measured by singleplex reverse transcriptase-polymerase chain reaction (RT-PCR) and gene array. Moreover, an overlapping yet distinct gene expression signature seen in freshly isolated compared to expanded Tregs identifies a subset of Treg genes likely to be functionally significant.

Bermudagrass sod growth and metal uptake in coal combustion by-product-amended media.

Coal combustion by-products (CCB) include fly ash and bottom ash and are generated nationally at rates of 10(8) Mg yr(-1). Land applications of CCB have improved physicochemical properties of soil, yet inherent bulkiness and trace metal content of CCB often limit their use. Likewise, utilization of biosolids and manure as fertilizer can be problematic due to unfavorable nutrient ratios. A 2-yr field study evaluated environmental and technical parameters associated with CCB-organic waste utilization as growth media in turfgrass sod production. Experimental growth media formulated with CCB and organic waste and a sand-compost control mixture were uniformly spread at rates from 200 to 400 m3 ha(-1) and sprigged with hybrid bermudagrass [Cynodon dactylon (L.) Pers. x C. transvaalensis Burtt-Davy]. Leaf clippings were collected and analyzed for total elemental content each year. In Year 2, growth media samples were collected during establishment 47 and 84 days after planting (DAP) and viable Escherichia coli organisms were quantified. At harvest (99 or 114 DAP), sod biomass and physicochemical properties of the growth media were measured. During sod propagation, micronutrient and metal content in leaf clippings varied by growth media and time. After 47 d of typical sod field management, viable E. coli pathogens were detected in only one biosolids-amended plot. No viable E. coli were measured at 84 DAP. In both years, sod biomass was greatest in media containing biosolids and fly ash. Following installation of sod, evaluations did not reveal differences by media type or application volume. Using CCB-organic waste mixes at the rates described herein is a rapid and environmentally safe method of bermudagrass sod production.

Accumulation of potentially toxic elements in plants and their transfer to human food chain.

Contaminated soils can be a source for crop plants of such elements like As, Cd, Cr, Cu, Ni, Pb, and Zn. The excessive transfer of As, Cu, Ni, and Zn to the food chain is controlled by a "soil-plant barrier"; however, for some elements, including Cd, the soil-plant barrier fails. The level of Cd ingested by average person in USA is about 12 micrograms/day, which is relatively low comparing to Risk Reference Dose (70 micrograms Cd/day) established by USEPA. Food of plant origin is a main source of Cd intake by modern society. Fish and shellfish may be a dominant dietary sources of Hg for some human populations. About half of human Pb intake is through food, of which more than half originates from plants. Dietary intake of Cd and Pb may be increased by application of sludges on cropland with already high levels of these metals. Soils amended with sludges in the USA will be permitted (by USEPA-503 regulations) to accumulate Cr, Cd, Cu, Pb, Hg, Ni, and Se, and Zn to levels from 10 to 100 times the present baseline concentrations. These levels are very permissive by international standards. Because of the limited supply of toxicity data obtained from metals applied in sewage sludge, predictions as to the new regulations will protect crop plants from metal toxicities, and food chain from contamination, are difficult to make.

Incorporation of the troponin regulatory complex of post-ischemic stunned porcine myocardium reduces myofilament calcium sensitivity in rabbit psoas skeletal muscle fibers.

Decreased calcium sensitivity of tension in post-ischemic myocardium is thought to be a mechanism of depressed function in stunning. The purpose of this study was to determine if the decrease in calcium sensitivity of tension results from ischemia and/or reperfusion-induced alterations in the thin filament regulatory troponin. The experiments utilized an open-chest porcine model of regional LAD myocardial stunning that has previously been shown to cause a decrease in calcium sensitivity of tension in permeabilized myocytes. Stunning was induced by 45 min of low-flow ischemia to the left anterior descending (LAD) coronary artery perfusion bed, which was followed by 30 min of reperfusion. Regional LAD function after reperfusion was 0.5+/-2.8%, as assessed by systolic wall thickening (v 23.9+/-4.1% thickening in control, P<0.001). Core biopsy samples from control circumflex and stunned LAD myocardium were acquired from each heart (n=9) after LAD reperfusion, and were used to obtain purified troponin complexes. Isometric tension-pCa relationships were measured in permeabilized psoas skeletal fibers before and after partial exchange of cardiac troponin from either control circumflex (n=6) or stunned LAD (n=8) myocardium for endogenous skeletal troponin. Calcium sensitivity of tension as assessed by pCa50 (i.e. pCa for half-maximal tension) was unchanged after exchange of troponin from control circumflex myocardium (pCa50=5. 98+/-0.02 v 5.96+/-0.06), but there was a significant decrease in calcium sensitivity of tension after exchange of troponin from stunned LAD myocardium (pCa50=5.97+/-0.07 v 5.82+/-0.05, P<0.05). We conclude that the decrease in calcium sensitivity of tension in postischemic stunned myocardium is, in part, due to ischemia and/or reperfusion-induced alterations in the cardiac troponin regulatory complex.

The effect of variation of the lingual shape of mandibular complete dentures on lingual resistance to lifting forces.

UNLABELLED: Increasing life expectancy, age related reduction in adaptability and progressive severe mandibular resorption all add to the importance of any factor improving the prosthetic success. OBJECTIVE: To investigate the effect of two different lingual shapes of lower dentures on patients' ability to resist lifting forces. DESIGN: Tongue pressures on the lingual surface of complete mandibular experimental dentures were recorded from mid-line, premolar and molar transducers. Two experimental prostheses were fabricated for each subject: one conventionally contoured, the other formed by piezography. SETTING: A clinical research laboratory. SUBJECTS: Five experienced complete denture wearers between age 64 and 82 years. INTERVENTION: Lifting forces were applied at the midline, left and right premolar sites in random order. MAIN OUTCOME MEASURES: Peak resistance to lifting forces and lingual pressures used during these tests. RESULTS: Lingual pressures exerted anteriorly were dramatically higher than those on premolar and molar surfaces. Significantly higher pressures were used to resist lifting forces applied to piezographically than conventionally formed contours; correspondingly, significantly higher lifting peak forces were, on average, resisted. CONCLUSIONS: Providing a lower denture with a piezographically produced lingual surface was shown, in this preliminary study, to enhance tongue retentive ability over a conventional design. It seems reasonable to maximise retentive potential with oblique sublingual polished surfaces and minimise the adaptive demand, particularly for older patients, by using a piezographic technique which "customises" the contour and precludes over-extension.

Onset of reduced Ca2+ sensitivity of tension during stunning in porcine myocardium.

Recent data suggest that reduced Ca2+ sensitivity of tension is a mechanism of the post-ischemic myocardial dysfunction, termed stunning. The purpose of the present study was to determine whether the decrease in myofilament Ca2+ sensitivity occurs during ischemia or during the subsequent period of reperfusion. Serial biopsies from an in vivo open-chest porcine model of regional LAD myocardial stunning (n = 6) were used to obtain in vitro measurements of Ca2+ sensitivity of tension in myocardium from the LAD bed. Regional ventricular myocardial function was assessed from percentage systolic myocardial wall thickening (%Th) and the load-independent end-systolic pressure wall thickness relation (ESPTR). Stunning was induced by 45 min of low flow LAD ischemia (43 +/- 4 ml/min/100 gm) followed by 30 min of reperfusion with control aerobic flow (117 +/- 7 ml/min/100 g). Endocardial biopsies were obtained from the LAD bed during pre-ischemia, ischemia (immediately prior to reperfusion), and post-ischemia (after 30 min of reperfusion). Biopsies were mechanically disrupted and single cell-sized preparations of permeabilized myocardium were attached to a force transducer to measure directly steady-state tension-pCa relationships. The % decreased to 7 +/- 11% of control during ischemia (P < 0.001) and returned to 30 +/- 11% of control in the post-ischemic stunned state (P < 0.001). Stunning resulted in a significant leftward shift of the ESPTR as compared to control, indicating depressed regional myocardial function. The pCa (-log[Ca2+]) for half maximal activation of tension, i.e. pCa50, was 5.96 +/- 0.04 in control myocardium and was unchanged during ischemia (5.95 +/- 0.03), but significantly decreased to 5.82 +/- 0.04 upon reperfusion (P < 0.05). These data show that the decrease in Ca2+ sensitivity of tension associated with stunning occurs during reperfusion, and supports the idea that reperfusion injury is a mechanism of myocardial stunning.

Isometric and dynamic contractile properties of porcine skinned cardiac myocytes after stunning.

The purpose of this study was to investigate myofibrillar mechanisms of depressed contractile function associated with myocardial stunning. We first tested whether the degree of stunning was directly related to changes in myofilament Ca2+ sensitivity. Variable degrees and durations of low-flow ischemia were followed by 30 minutes of reperfusion in an open-chest porcine model of regional myocardial stunning (n = 27). Ca2+ sensitivity of isometric tension was measured in skinned myocytes obtained from endocardial biopsies taken during control aerobic flow and after 30 minutes of reperfusion. The degree of stunning, as assessed by percent systolic wall thickening, ranged from -3% to 75% of control but did not correlate (r = .11) with changes in pCa50, ie, pCa for half-maximal tension. Only in the group (n = 10) with the most severe level of ischemia was there a significant decrease in pCa50 (from 5.97 +/- 0.06 in the control condition to 5.86 +/- 0.07 after ischemia, P < .05). Less severe levels of ischemia (n = 17) resulted in significant stunning (percent systolic wall thickening, 38 +/- 4% of control) but no change in pCa50. To investigate the possibility that alterations in myofibrillar cross-bridge kinetics contribute to depressed function in stunning, maximum velocity of shortening (Vo) was measured in postischemic myocytes. Vo in postischemic myocytes was reduced to 56 +/- 4% of Vo in control myocytes and was independent both of the degree of stunning (r = .26) and changes in Ca2+ sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of altered contractility on the linearity of regional left ventricular end-systolic relations in intact hearts.

The purpose of these studies was to determine the effect of altered regional contractility on the linearity of regional left ventricular end-systolic relations. Significant change in the shape of these relations would limit their application as load-independent indices of regional contractility. In a paced, open-chest pig heart preparation (n = 7), the left ventricular end-systolic pressure-segment length relation (ESPLR) and pressure-wall thickness relation (ESPTR) were obtained over a wide range of end-systolic pressures (134 +/- 9 to 70 +/- 6 mm Hg). Regional inotropic state was varied with intracoronary calcium and verapamil. The shapes of the ESPLR and ESPTR were characterized by using linear and quadratic models. Both provided a good fit, although the quadratic model showed a slight concavity to the segment length and thickness axes (second-order coefficient < 0). In the linear model, calcium increased the slope of the ESPLR by 111% (p < 0.01) and the slope of the ESPTR by 170% (p < 0.01). At a pressure of 100 mm Hg, end-systolic segment length (L100) shifted to the left (p < 0.05) and end-systolic wall thickness (T100) to the right (p < 0.025). Verapamil decreased the slope of the ESPLR by 45% (p < 0.01) and of the ESPTR by 33% (p not significant) and produced significant shifts in L100 (p < 0.001) and T100 (p < 0.025). The values of L100 and T100 determined by the quadratic fit were nearly identical to those for the linear fit, and both showed similar significant shifts with altered contractility. There was no significant change in the shape of the quadratic fit (as assessed by the second-order coefficient) with different contractile states. It is concluded that the curvilinearity of the ESPLR and ESPTR under physiologic conditions is slight and appears to be independent of the contractile state. Furthermore, a linear model of regional end-systolic relations can be used to assess regional left ventricular function in intact hearts.

Improved densitometric measurement of left ventricular ejection fraction using dual-energy digital subtraction angiography.

The effects of misregistration artifacts and background corrections on the densitometric measurement of left ventricular ejection fraction (EF) from digital subtraction angiography (DSA) images were studied in 20 patients. Densitometric ejection fraction measurements were performed on both conventional time subtraction images and on dual-energy subtraction images. Dual-energy subtraction is not sensitive to the motion induced artifacts which often mar time subtraction images. While the time subtraction images had varying degrees of misregistration artifacts, none of the dual-energy studies contained significant misregistration artifacts. Densitometrically determined ejection fractions measured with and without correction for background signals were compared. Poor agreement between time subtraction ejection fractions determined with and without background correction (EFNO-BKG = 0.88 EFBKG - 6.0%, SEE = 8.1%, r = 0.83) demonstrated the sensitivity of time subtraction EFs to the performance of a background correction procedure. Conversely, densitometric measurement of ejection fraction using dual-energy subtraction was significantly less sensitive to the performance of a background correction (EFNO-BKG = 0.99 EFBKG - 5.3%, SEE = 4.3%, r = 0.96). Since background correction requires accurate definition of ventricular borders, but motion artifacts often preclude accurate border definition, it is concluded that dual-energy subtraction is a significantly more robust method for measuring left ventricular ejection fraction using densitometry. It is further concluded that identification of the systolic endocardial border is not required when performing densitometric EF measurements on dual-energy images. Drawing of the end-diastolic border alone is sufficient to produce an accurate ejection fraction measurement.