Sickle Cell Disease Subjects Have a Distinct Abnormal Autonomic Phenotype Characterized by Peripheral Vasoconstriction With Blunted Cardiac Response to Head-Up Tilt

In sickle cell disease (SCD), prolonged capillary transit times, resulting from reduced peripheral blood flow, increase the likelihood of rigid red cells entrapment in the microvasculature, predisposing to vaso-occlusive crisis. Since changes in peripheral flow are mediated by the autonomic nervous system (ANS), we tested the hypothesis that the cardiac and peripheral vascular responses to head-up tilt (HUT) are abnormal in SCD. Heart rate, respiration, non-invasive continuous blood pressure and finger photoplethysmogram (PPG) were monitored before, during, and after HUT in SCD, anemic controls and healthy subjects. Percent increase in heart rate from baseline was used to quantify cardiac ANS response, while percent decrease in PPG amplitude represented degree of peripheral vasoconstriction. After employing cluster analysis to determine threshold levels, the HUT responses were classified into four phenotypes: (CP) increased heart rate and peripheral vasoconstriction; (C) increased heart rate only; (P) peripheral vasoconstriction only; and (ST) subthreshold cardiac and peripheral vascular responses. Multinomial logistic regression (MLR) was used to relate these phenotypic responses to various parameters representing blood properties and baseline cardiovascular activity. The most common phenotypic response, CP, was found in 82% of non-SCD subjects, including those with chronic anemia. In contrast, 70% of SCD subjects responded abnormally to HUT: C-phenotype = 22%, P-phenotype = 37%, or ST-phenotype = 11%. MLR revealed that the HUT phenotypes were significantly associated with baseline cardiac parasympathetic activity, baseline peripheral vascular variability, hemoglobin level and SCD diagnosis. Low parasympathetic activity at baseline dramatically increased the probability of belonging to the P-phenotype in SCD subjects, even after adjusting for hemoglobin level, suggesting a characteristic autonomic dysfunction that is independent of anemia. Further analysis using a mathematical model of heart rate variability revealed that the low parasympathetic activity in P-phenotype SCD subjects was due to impaired respiratory-cardiac coupling rather than reduced cardiac baroreflex sensitivity. By having strong peripheral vasoconstriction without compensatory cardiac responses, P-phenotype subjects may be at increased risk for vaso-occlusive crisis. The classification of autonomic phenotypes based on HUT response may have potential use for guiding therapeutic interventions to alleviate the risk of adverse outcomes in SCD

Nitric oxide, vasodilation and the red blood cell

Since the identification of the elusive endothelium-derived relaxing factor as nitric oxide (NO), much attention has been devoted to understanding its physiological effects. NO is a free radical with many roles, and owing to its neutral charge and high diffusion capacity, it appears NO is involved in every mammalian biological system. Most attention has been focused on the NO generating pathways within the endothelium; however, the recent discovery of a NO synthase (NOS)-like enzyme residing in red blood cells (RBC) has increased our understanding of the blood flow and oxygen delivery modulation by RBC. In the present review, pathways of NO generation are summarized, with attention to those residing within RBC. While the bioactivity of RBC-derived NO is still debated due to its generation within proximity of NO scavengers, current theories for NO export from RBC are explored, which are supported by recent findings demonstrating an extracellular response to RBC-derived NO. The importance of NO in the active regulation of RBC deformability is discussed in the context of the subsequent effects on blood fluidity, and the complex interplay between blood rheology and NO are summarized. This review provides a summary of recent advances in understanding the role played by RBC in NO equilibrium and vascular regulation.No Full Tex

Blood Rheology and Hemodynamics: Still Illuminating after 20 Years

Interactions between the fluidity of blood and the function of the cardiovascular system are complex and intensely studied, and yet remain poorly understood beyond niche clusters of experts. In health, cardiovascular hemodynamics and the rheology of blood are critical to optimal performance and survival alike, and when perturbed underpin many pathologies. Indeed, various congenital and acquired heart diseases, and hematological disorders represent hallmarks of suboptimal hemodynamics and/or blood rheology, although clinical attention and therapeutics are typically narrowband. The seminal review published in the October 2003 issue of Seminars in Thrombosis and Hemostasis[1] presents an integration of topics that include fundamental rheology concepts, cardiovascular hemodynamics, and the intersection of the two.No Full Tex

Kidney Iron Deposition By R2* Is Associated with Hemolysis and Urinary Iron

Introduction Kidney iron deposition has been described in hemolytic disorders including mechanical valves, paroxysmal nocturnal hematuria, and sickle cell disease (Roberts &amp; Morrow, Circulation 1966; Leonardi &amp; Ruol, Blood 1960). Circulating plasma hemoglobin is filtered at the glomerulus and reabsorbed via the megalin cubulin system in the proximal and distal tubules (Gburek et al, J Am Soc Nephrol 2002). On MRI, this manifests as signal loss on gradient and spin echo sequences in the cortex of the kidney with complete sparing of the medulla (Jeong et al, Radiographics 2002). The signal darkening is quantified by the parameter R2*, which has been shown to be directly proportional to tissue iron in the liver and heart. Kidney R2* has previously been demonstrated to rise proportionally to lactate dehydrogenase (LDH) in chronically transfused sickle cell disease (SCD) patients (Wood et al, Br J Haematol 2016; Schein et al, J Magn Reson Imaging 2008), but LDH is not a specific marker of hemolysis, and chronically transfused patients could potentially deposit iron in the kidney through other mechanisms. Therefore, we characterized the relationship between kidney R2*, urinary iron and markers of hemolysis in non-transfused SCD patients. Methods Sixty-five non-transfused SCD patients were recruited to the study, which was approved by the Institutional Review Board of Children's Hospital Los Angeles. Following medical history and physical exam, subjects completed blood and urine testing, and then abdominal MRI for assessment of somatic iron stores. R2* measurements were collected using multiple gradient echo pulse sequences on 1.5 Tesla magnets. Statistical analysis was performed using JMP® Pro, Version 14.0.0 (SAS Institute Inc., Cary, NC, 2018). Results Subjects were generally adults with a mean age of 32 years. Nearly three quarters of subjects had homozygous sickle cell disease, while a quarter had SC disease or S-Beta thalassemia, and one subject had sickle cell trait. Most subjects were anemic, and all subjects had elevated markers of hemolysis. Fifty-four percent of subjects had an elevated kidney R2* level (≥34 Hz). On univariate analysis, kidney R2* was associated with urinary iron (R2=0.52, p&amp;lt;0.0001), LDH (R2=0.33, p&amp;lt;0.0001), plasma hemoglobin (R2=0.18, p=0.0007), and hemoglobin (R2=0.08, p=0.02), but it was not associated with reticulocyte count. On multivariate analysis, kidney R2* was associated with urinary iron and LDH (Figure 1). No association was found between R2* values of the kidney, liver, and pancreas. Discussion Our study supports previous findings that kidney R2* is associated with intravascular hemolysis, as measured by plasma hemoglobin and LDH, and inversely by hemoglobin (Kato et al, Blood 2006). The stronger association with urinary iron reinforces the concept that kidney R2* reflects filtered iron, which is insufficiently reabsorbed due to proximal and distal tubular injury in iron overload (van Raaij et al, Am J Physiol Renal Physiol 2019). Urinary iron is also elevated in diabetic nephropathy (Van et al, J Am Soc Nephrol 2017) and nephrotic syndrome (Niel et al, Blood 2011). These data raise important questions regarding the possible role of iron in sickle related renal disease. Disclosures Coates: apo pharma: Consultancy, Honoraria, Speakers Bureau; vifor: Consultancy, Honoraria; agios pharma: Consultancy, Honoraria; celgene: Consultancy, Honoraria, Other: steering committee of clinical study. Wood:National Institutes of Health: Research Funding; Philips Healthcare: Research Funding; BluebirdBio: Consultancy; Celgene: Consultancy; Apopharma: Consultancy; WorldcareClinical: Consultancy; BiomedInformatics: Consultancy; Imago Biosciences: Consultancy. </jats:sec

Change In Flow Mediated Dilation After Transfusion Is Dependent On BMI and Blood Age

Abstract Blood transfusions are given for acute and chronic illness including cardiothoracic surgery, acute stabilization, and chronic transfusion therapy (CTT) in patients with thalassemia and sickle cell disease (SCD). Increased age of stored red blood cells and the associated storage lesion has been implicated in poor cardiovascular outcomes, increased length of ICU stay, multiorgan failure and increased use of inotropes after cardiac surgery. Red cell aging, during storage, is thought to alter the metabolic profile of the red cell in a manner that causes decreased nitric oxide bioavailability. Aged red cells demonstrate vasoinhibitory activity of aortic ring preparations. S-nitrosohemoglobin is decreased in stored blood but when replete, tissue oxygen delivery and renal damage were ameliorated in an animal blood loss model. We aimed to determine whether the age of the stored blood relates to vascular function in-vivo, using a population of chronically transfused patients with SCD. We did prospective study to examine transfusion effects on vascular function, in which we enrolled 26 patients with SCD on CTT and tested flow mediated dilation (FMD) of the brachial artery, cardiac output and blood viscosity changes with transfusion. We measured both oxygenated and deoxygenated whole blood viscosity at shear rates from 1s-1 to 1000s-1 at native hematocrit using a Rheolog viscometer (Rheologics Co). We also obtained pre and post transfusion measures of cardiac output, flow mediated dilation of the brachial artery, blood counts, chemistry panels, markers of inflammation and hemolysis. 14 females and 12 males were enrolled. The ages and reasons for starting transfusions were similar for male and female patients. As expected, transfusion resulted in significant increases of hemoglobin and hematocrit (hct) with concomitant decrease of hemoglobin S% (HbS%) and reticulocyte count. Male patients had a significantly higher HbS%, reticulocyte count, plasma free hemoglobin and platelet count compared to females. Viscosity increased significantly across all shear rates with transfusion and with deoxygenation. There was no sex difference in viscosity. FMD was significantly improved following transfusion with an average increase of 1.4% (P=0.01). By univariate analysis, elevated body mass index (BMI), small change in hematocrit to viscosity ratio (HVR) at 2s-1 (low shear), and the lower age of the stored blood were significantly associated with improved FMD. By multivariate analysis, using only two variables at a time due to small sample size, elevated BMI was the best predictor of improved FMD. (Figure 1) There was a confounding effect between the age of the blood and BMI in our study; there was a negative correlation between age of the blood given and BMI, whereby smaller patients received older blood in our cohort.(R2 0.20, P=0.03). BMI did not correlate with pre-transfusion FMD. Most patients with SCD on CTT had improved FMD following transfusion and given the dependence of FMD on shear stress, changes in rheologic factors such as viscosity and hematocrit would be expected to cause significant changes in FMD. The increase in hct, and viscosity and the decrease in HbS% did not correlate with improvement in FMD. Decrease in low shear HVR did correlate with improved FMD, however, FMD is thought to correlate with higher shear rates, whereas the HVR at low shear rate would be found in the venous system. This could provide a link between endothelial function and the low shear venous system, particularly due to its FMD correlation with “deoxygenated” HVR. BMI and age of the stored red cells correlated whereby our smaller patients received older blood resulting in confounding between these variables. Despite the confounding effect, when blood age was locked in the model, BMI still exerts an independent effect on FMD. Whether the effect of BMI is chronic or acute could not be determined in our study; however, nutritional factors, adipose tissue and hormones might play a role in the set point of FMD via eNOS expression in the endothelium. Older blood age was associated with worsening FMD, which is consistent with decreased nitric oxide bioavailability as a piece of the red cell storage lesion puzzle. Future studies should attempt to control for BMI and blood age to minimize confounding effects. Disclosures: Coates: Novartis Inc.: Honoraria, Speakers Bureau; Apopharma: Honoraria, Speakers Bureau; Shire: Speakers Bureau. Wood:Shire: Consultancy, Research Funding; Apopharma: Honoraria, Patents &amp; Royalties; Novartis: Honoraria. </jats:sec