Neonatal-Onset Multisystem Inflammatory Disease Responsive to Interleukin-1β Inhibition

Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. Many patients have mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, encoding cryopyrin, a protein that regulates inflammation

Acute Hemodynamic and Vascular Effects of Transfusion in Chronically Transfused Patients with Sickle Cell Anemia.

Abstract Abstract 1516 Poster Board I-539 Introduction Patients with sickle cell anemia (SCA) who are at risk for stroke or develop recurrent episodes of acute chest are often placed on chronic transfusion therapy. The acute hemodynamic and vascular consequences of transfusion are poorly characterized. In order to better characterize chronic changes in these patients, it is important to understand the acute changes involved with this intervention. Methods We enrolled SCA patients who are on chronic transfusion therapy in a prospective study to determine the cardiovascular effects of a single transfusion. The patients were older than 10 years of age, received chronic transfusions for greater than one year, and were crisis free for more than four weeks. All patients were studied immediately prior to transfusion and repeated within five days. Brachial artery relaxivity, laser doppler capillary blood flow monitoring, and near infrared spectroscopy of the hand was done in the setting of post occlusive reactive hyperemia. Studies included complete cardiac echocardiogram as well as laboratory markers of hemolysis, iron levels, blood count, viscosity and inflammation were obtained pre and post transfusion. Statistics utilized paired t-tests for paired data and for correlative data t-tests and chi square analysis was used. Results There are 15 patients enrolled in the study with an average age of 18.7yrs. There are 8 females and 7 males with average ages of 20.6 and 16.4 yrs respectively. With transfusion, hemoglobin increased from 9.4 g/dl to 11.6 g/dl post (p&amp;lt;0.0001), reticulocyte count decreased from 12.4% to 7.8% (p=0.0019) and HbS% decreased from 38.2% to 31.5% (p=0.0001). Markers of hemolysis (LDH, Plasma Free Hemoglobin, Arg/Orn Ratio) do not differ significantly pre and post transfusion. Cardiac index decreased from 5.4L/min/m2 to 4.1 L/min/m2 (p=0.0012), resulting from decreased stroke volume (70.8ml to 58.9ml, p=0.0119) and lower heart rate (84 to 78bpm, p=0.0098). Systolic and diastolic function metrics were unchanged, as was estimates of pulmonary artery pressure. Blood pressure was unchanged, indicating that the change in cardiac output was matched by parallel changes in total vascular resistance. Endothelial function and regional vascular reactivity assessed using laser Doppler capillary flow analysis demonstrated no significant change in hyperemic response pre and post transfusion. Blood viscosity increased with transfusion in a shear-rate dependent manner, for low shear rates the viscosity increased an average of 62% using fully oxygenated samples and at higher shear rates the viscosity increased an average of 25% using fully oxygenated samples. Discussion Transfusion therapy predictably increased oxygen carrying capacity, lowered reticulocyte count and %hemoglobin S. While these changes might improve tissue oxygen delivery, parallel changes in vascular resistance served to maintain relatively constant oxygen delivery. The rise in vascular resistance could result from increased blood viscosity or changes in vascular tone; we are currently conducting studies to try to separate these mechanisms. Despite the 24% reduction in cardiac index, no significant change was observed in microvascular perfusion or its response to forearm occlusion. The vascular system of SCA patients demonstrates chronic endothelial dysfunction but was not acutely influenced by transfusions, consistent with the lack of acute improvement in surrogates for hemolysis or nitric oxide metabolism. Further work is necessary to determine whether transfusion-mediated changes in tissue oxygen delivery vary among different organs and vascular beds. Disclosures Wood: Novartis: Research Funding. </jats:sec

Decrease in Microvascular Blood Flow in Sickle Cell Anemia Is Triggered by Autonomic Signals and Not Directly by Hypoxia: A New Hypothesis for Sickle Crisis.

Abstract Abstract 1523 Poster Board I-546 Sickle cell anemia (SCA) is a genetic disorder characterized by recurring episodes of vaso-occlusive crisis (VOC) that can lead to hospitalization or sudden death. Hypoxia is an accepted trigger of sickling and degrees of nighttime hypoxia correlate with strokes and frequency of VOC. To better understand the mechanism of events leading to VOC, we simulated the occurrence of nocturnal hypoxia in SCA patients by administration of five breaths of 100% nitrogen. Tidal volume (Vt), arterial oxygen saturation, electrocardiogram (ECG), and microvascular perfusion (PU) by Laser-Doppler were continuously recorded. We had anticipated a drop in PU after each controlled episode of hypoxia. However, we observed multiple prominent drops in PU in SCA subjects (n=8) that were not as clearly evident in controls (CTL; n=9), and found no direct relationship between hypoxia and change in PU (p = NS). As deep breaths or sighs can trigger reflex peripheral vasoconstriction, we examined Vt respiratory tracings obtained simultaneously and observed that PU drops frequently followed sighs (see Figure) in SCA subjects, but rarely in CTL. A statistical algorithm was used to find all sighs and vasoconstrictive events (PU drops) during each 40-minute experimental session. PU drops were associated with sighs in 7 of 8 SCA patients and in 4 of 9 CTL subjects (P &lt; 0.001, Poisson regression analysis). Five CTL and 1 SCA subjects had infrequent sighs and no association between sighs and PU drops. The likelihood ratio of sigh-associated PU drops was significantly higher in SCA than CTL subjects (median = 59.9 % vs. &lt; 1 % for SCA vs. CTL, P = 0.008, rank-sum test) whereas the frequency of sighs was not significantly different between the two groups (median = 2.2 % vs. 1.3 % for SCA vs. CTL, P = 0.16, rank-sum test), indicating that SCA patients are much more likely to have sigh-associated peripheral vasoconstriction. Since the sigh-vasoconstrictor response is controlled by the autonomic nervous system (ANS), we measured heart rate variability (HRV) which is an accepted index of sympathetic/parasympathetic balance. These studies showed substantial reduction of parasympathetic modulation of HRV during hypoxia in SCA but not in CTL subjects (p &lt; 0.01), indicating a marked abnormality of the ANS in SCA. In overview, the likelihood of coupling between spontaneous sighs and subsequent vasoconstrictive events (PU drops) is much higher in SCA patients than in CTL. Thus, we speculate that a drop in perfusion secondary to increased neural coupling between the lung and vasculature may be an initiating event in VOC. Hypoxia may secondarily promote VOC by altering ANS sensitivity and increasing the probability that a sigh will in turn lead to reflex peripheral vasoconstriction. In a background of HbS, transient decreases in perfusion may prolong red cell residence time in the microvasculature, leading to HbS polymerization, sickling and vascular occlusion. Disclosures No relevant conflicts of interest to declare. </jats:sec

Autonomic Response to Hypoxia and Isometric Exercise in Sickle Cell Trait Subjects

Abstract Abstract 3241 Loss of cardiac beat to beat variability reflected by high frequency power (HFP) is a strong predictor of death in patients with cardiovascular disease. Similar autonomic dysfunction is found in patients with Sickle Cell Anemia (SCA) and can be induced by a 30 second period of hypoxia during five breath nitrogen exposure (1,2). Some data suggest that Sickle Cell Trait (SCT) carriers also exhibit autonomic dysfunction. In light of the recent attention to sudden death in young athletes with SCT we examined the autonomic response to transient hypoxia and isometric exercise in subjects with SCT and matched controls. Autonomic responses to hypoxia induced by a five-breath nitrogen exposure and intense isometric exercise resulting from handgrip to exhaustion were measured. Autonomic parasympathetic tone and sympathetic-vagal balance were measured using respiratory-adjusted time-varying heart rate variability (HRV). High frequency power (HFP) reflects parasympathetic tone and low-high ratio (LHR), sympathetic-vagal balance (1,2). Ten African American SCT carriers (7 female, 35.7 yrs + 2.8) and 11 age, and ethnicity matched controls (CTRL, 8 female, 30.5 yrs + 2.8) were studied. No difference in resting heart rate (HR, SCT 67.1 + 5.1, CTRL 65.9 + 5.5), cardiac output (CO, SCT 6.17 + .57, CTRL 7.31 + .52), mean arterial pressure (MAP, SCT 101.49 + 4.61, CTRL 101.49 + 4.96) or LHR (SCT, 1.16 + .38, SCT 1.44 + .37) was observed. Five-breath nitrogen exposure produced nearly identical minimal arterial saturation (SaO2, SCT 84.1% ± 1.3%, CTRL 83.1% ± 1.3%) with compensatory tachycardia (DRRI, SCT −6.5% ± 1.2%, CTRL −4.79 ± 1.15%) and increased cardiac output (DCO, SCT 4.7% ± 1.7, CTRL 6.0% ± 1.6%). No change from baseline was observed in the population means of HFP or LHR for CTRLs or SCT subjects. Following ten minutes of recovery, handgrip to exhaustion was performed at 60% maximum voluntary contraction. No differences were observed in maximum handgrip or duration between SCT and CTRL. Men produced higher maximal response but women maintained contraction nearly twice as long, independent of diagnosis. Handgrip exercise increased heart rate, cardiac output (SCT +13.4% ± 5.4%, CTRL +13.9% ± 5.0%), mean arterial pressure (SCT +19.6% ± 2.5%, CTRL +16.0% ± 2.3%), systolic pressure (SCT +14.6% ± 2.2%, CTRL +10.7% ± 2.1%), and diastolic pressure (SCT +22.5% ± 2.9%, CTRL +18.5% ± 2.6%). No population differences were observed in these responses. LHR increased similarly in both populations as well (SCT +78.9% ± 35.7%, CTRL +68.5% ± 32.9%), but SCT carriers had a much larger drop in HFP that was significantly different from baseline and trended lower than the control population (SCT −58% ± 18%, CTRL −9% ± 17%, p&lt;.063). Our laboratory has previously demonstrated hyper-reflexic parasympathetic withdrawal in response to transient hypoxia in patients with SCA (1,2). SCT subjects did not demonstrate parasympathetic withdrawal to hypoxia. However, we found exaggerated parasympathetic withdrawal in response to handgrip exercise in SCT subject and not in matched controls. Even though the biophysical properties of the sickle trait red cell are not sufficient to result in major hemolysis or vaso-occlusion, they are sufficient to alter autonomic balance. It will be important to determine whether this response impacts the distribution of ventricular repolarization, potentially increasing risk of arrhythmia, or is reproduced in other autonomic axes such as mental stress. Figure 1: Cardiovascular and autonomic response to five breath nitrogen protocol. *statistically significant change from baseline (p&lt;.05). Figure 1:. Cardiovascular and autonomic response to five breath nitrogen protocol. *statistically significant change from baseline (p&lt;.05). Figure 2: Cardiovascular and autonomic response to handgrip exercise to exhaustion. *statistically significant change from baseline (p&lt;.05). Figure 2:. Cardiovascular and autonomic response to handgrip exercise to exhaustion. *statistically significant change from baseline (p&lt;.05). Disclosures: Coates: Apopharma: Consultancy; Novartis: Speakers Bureau. Wood:Novartis: Honoraria, Research Funding; Apotex: Consultancy, Honoraria; Shire: Consultancy; Ferrokin Biosciences: Consultancy. </jats:sec