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Competing Interests: None declared.

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., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

The Pediatric Heart Network's Fontan Udenafil Exercise Longitudinal (FUEL) Trial (Mezzion Pharma Co. Ltd., NCT02741115) demonstrated improvements in some measures of exercise capacity and in the myocardial performance index following 6 months of treatment with udenafil (87.5 mg twice daily). In this post hoc analysis, we evaluate whether subgroups within the population experienced a differential effect on exercise performance in response to treatment. The effect of udenafil on exercise was evaluated within subgroups defined by baseline characteristics, including peak oxygen consumption (VO 2 ), serum brain-type natriuretic peptide level, weight, race, gender, and ventricular morphology. Differences among subgroups were evaluated using ANCOVA modeling with fixed factors for treatment arm and subgroup and the interaction between treatment arm and subgroup. Within-subgroup analyses demonstrated trends toward quantitative improvements in peak VO 2 , work rate at the ventilatory anaerobic threshold (VAT), VO 2 at VAT, and ventilatory efficiency (VE/VCO 2 ) for those randomized to udenafil compared to placebo in nearly all subgroups. There was no identified differential response to udenafil based on baseline peak VO 2 , baseline BNP level, weight, race and ethnicity, gender, or ventricular morphology, although participants in the lowest tertile of baseline peak VO 2 trended toward larger improvements. The absence of a differential response across subgroups in response to treatment with udenafil suggests that the treatment benefit may not be restricted to specific sub-populations. Further work is warranted to confirm the potential benefit of udenafil and to evaluate the long-term tolerability and safety of treatment and to determine the impact of udenafil on the development of other morbidities related to the Fontan circulation.Trial Registration NCT0274115., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: In the SVR trial (Single Ventricle Reconstruction), newborns with hypoplastic left heart syndrome were randomly assigned to receive a modified Blalock-Taussig-Thomas shunt (mBTTS) or a right ventricle-to-pulmonary artery shunt (RVPAS) at Norwood operation. Transplant-free survival was superior in the RVPAS group at 1 year, but no longer differed by treatment group at 6 years; both treatment groups had accumulated important morbidities. In the third follow-up of this cohort (SVRIII [Long-Term Outcomes of Children With Hypoplastic Left Heart Syndrome and the Impact of Norwood Shunt Type]), we measured longitudinal outcomes and their risk factors through 12 years of age., Methods: Annual medical history was collected through record review and telephone interviews. Cardiac magnetic resonance imaging (CMR), echocardiogram, and cycle ergometry cardiopulmonary exercise tests were performed at 10 through 14 years of age among participants with Fontan physiology. Differences in transplant-free survival and complication rates (eg, arrhythmias or protein-losing enteropathy) were identified through 12 years of age. The primary study outcome was right ventricular ejection fraction (RVEF) by CMR, and primary analyses were according to shunt type received. Multivariable linear and Cox regression models were created for RVEF by CMR and post-Fontan transplant-free survival., Results: Among 549 participants enrolled in SVR, 237 of 313 (76%; 60.7% male) transplant-free survivors (mBTTS, 105 of 147; RVPAS, 129 of 161; both, 3 of 5) participated in SVRIII. RVEF by CMR was similar in the shunt groups (RVPAS, 51±9.6 [n=90], and mBTTS, 52±7.4 [n=75]; P =0.43). The RVPAS and mBTTS groups did not differ in transplant-free survival by 12 years of age (163 of 277 [59%] versus 144 of 267 [54%], respectively; P =0.11), percentage predicted peak Vo 2 for age and sex (74±18% [n=91] versus 72±18% [n=84]; P =0.71), or percentage predicted work rate for size and sex (65±20% versus 64±19%; P =0.65). The RVPAS versus mBTTS group had a higher cumulative incidence of protein-losing enteropathy (5% versus 2%; P =0.04) and of catheter interventions (14 versus 10 per 100 patient-years; P =0.01), but had similar rates of other complications., Conclusions: By 12 years after the Norwood operation, shunt type has minimal association with RVEF, peak Vo 2 , complication rates, and transplant-free survival. RVEF is preserved among the subgroup of survivors who underwent CMR assessment. Low transplant-free survival, poor exercise performance, and accruing morbidities highlight the need for innovative strategies to improve long-term outcomes in patients with hypoplastic left heart syndrome., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT0245531., Competing Interests: Disclosures None.

Infantile hemangioma is the most common soft tissue tumor of infancy. Extensive organ involvement is rare. This report describes an infant with biopsy confirmed infantile hemangioma with diffuse organ involvement causing anemia and failure to thrive. Treatment was initiated with propranolol and led to initial improvement; however, course was complicated by several episodes of respiratory failure secondary to pulmonary edema. Propranolol therapy was interrupted for several months while patient was maintained on a diuretic regimen and treated with vincristine and high-dose corticosteroids. Patient was transitioned back to propranolol and is clinically thriving with objective improvement on radiographic imaging., (© 2022 Wiley Periodicals LLC.)

Sickle cell anemia (SCA) is characterized by decreased red blood cell (RBC) deformability due to polymerization of deoxygenated hemoglobin, leading to abnormal mechanical properties of RBC, increased cellular adhesion, and microcirculatory obstruction. Prior work has demonstrated that NO• influences RBC hydration and deformability and is produced at a basal rate that increases under shear stress in normal RBC. Nevertheless, the origin and physiological relevance of nitric oxide (NO•) production and scavenging in RBC remains unclear. We aimed to assess the basal and shear-mediated production of NO• in RBC from SCA patients and control (CTRL) subjects. RBCs loaded with a fluorescent NO• detector, DAF-FM (4-Amino-5-methylamino- 2',7'-difluorofluorescein diacetate), were imaged in microflow channels over 30-min without shear stress, followed by a 30-min period under 0.5Pa shear stress. We utilized non-specific nitric oxide synthase (NOS) blockade and carbon monoxide (CO) saturation of hemoglobin to assess the contribution of NOS and hemoglobin, respectively, to NO• production. Quantification of DAF-FM fluorescence intensity in individual RBC showed an increase in NO• in SCA RBC at the start of the basal period; however, both SCA and CTRL RBC increased NO• by a similar quantity under shear. A subpopulation of sickle-shaped RBC exhibited lower basal NO• production compared to discoid RBC from SCA group, and under shear became more circular in the direction of shear when compared to discoid RBC from SCA and CTRL, which elongated. Both CO and NOS inhibition caused a decrease in basal NO• production. Shear-mediated NO• production was decreased by CO in all RBC, but was decreased by NOS blockade only in SCA. In conclusion, total NO• production is increased and shear-mediated NO• production is preserved in SCA RBC in a NOS-dependent manner. Sickle shaped RBC with inclusions have higher NO• production and they become more circular rather than elongated with shear., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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 (R 2  = 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., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Alpha thalassemia is a hemoglobinopathy due to decreased production of the α-globin protein from loss of up to four α-globin genes, with one or two missing in the trait phenotype. Individuals with sickle cell disease who co-inherit the loss of one or two α-globin genes have been known to have reduced risk of morbid outcomes, but the underlying mechanism is unknown. While α-globin gene deletions affect sickle red cell deformability, the α-globin genes and protein are also present in the endothelial wall of human arterioles and participate in nitric oxide scavenging during vasoconstriction. Decreased production of α-globin due to α-thalassemia trait may thereby limit nitric oxide scavenging and promote vasodilation. To evaluate this potential mechanism, we performed flow-mediated dilation and microvascular post-occlusive reactive hyperemia in 27 human subjects (15 missing one or two α-globin genes and 12 healthy controls). Flow-mediated dilation was significantly higher in subjects with α-trait after controlling for age (P = .0357), but microvascular perfusion was not different between groups. As none of the subjects had anemia or hemolysis, the improvement in vascular function could be attributed to the difference in α-globin gene status. This may explain the beneficial effect of α-globin gene loss in sickle cell disease and suggests that α-globin gene status may play a role in other vascular diseases., (© 2020 Wiley Periodicals LLC.)

Objectives: We aimed to evaluate the effect of technical aspects of fetal aortic valvuloplasty (FAV) on procedural risks and pregnancy outcomes., Background: FAV is performed in cases of severe mid-gestation aortic stenosis with the goal of preventing hypoplastic left heart syndrome (HLHS)., Methods: The International Fetal Cardiac Intervention Registry was queried for fetuses who underwent FAV from 2002 to 2018, excluding one high-volume center., Results: The 108 fetuses had an attempted cardiac puncture (mean gestational age [GA] 26.1 ± 3.3 weeks). 83.3% of attempted interventions were technically successful (increased forward flow/new aortic insufficiency). The interventional cannula was larger than 19 g in 70.4%. More than one cardiac puncture was performed in 25.0%. Intraprocedural complications occurred in 48.1%, including bradycardia (34.1%), pericardial (22.2%) or pleural effusion (2.7%) requiring drainage, and balloon rupture (5.6%). Death within 48 hr occurred in 16.7% of fetuses. Of the 81 patients born alive, 59 were discharged home, 34 of whom had biventricular circulation. More than one cardiac puncture was associated with higher complication rates (p < .001). Larger cannula size was associated with higher pericardial effusion rates (p = .044). On multivariate analysis, technical success (odds ratio [OR] = 10.9, 95% confidence interval [CI] = 2.2-53.5, p = .003) and later GA at intervention (OR = 1.5, 95% CI = 1.2-1.9, p = .002) were associated with increased odds of live birth., Conclusions: FAV is an often successful but high-risk procedure. Multiple cardiac punctures are associated with increased complication and fetal mortality rates. Later GA at intervention and technical success were independently associated with increased odds of live birth. However, performing the procedure later in gestation may miss the window to prevent progression to HLHS., (© 2020 Wiley Periodicals, Inc.)

Sickle cell disease (SCD) is a monogenetic disease that results in the formation of hemoglobin S. Due to more rapid oxidation of hemoglobin S due to intracellular heme and adventitious iron in SCD, it has been thought that an inherent property of SCD red cells would be an imbalance in antioxidant defenses and oxidant production. Less deformable and fragile RBC in SCD results in intravascular hemolysis and release of free hemoglobin (PFHb) in the plasma, which might be expected to produce oxidative stress in the plasma. Thus, we aimed to characterize intracellular and vascular oxidative stress in whole blood and plasma samples from adult SCD patients and controls recruited into a large study of SCD at Children's Hospital of Los Angeles. We evaluated the cellular content of metHb and several components of the antioxidant system in RBC as well as oxidation of GSH and Prx-2 oxidation in RBC after challenge with hydroperoxides. Plasma markers included PFHb, low molecular weight protein bound heme (freed heme), hemopexin, isoprostanes, and protein carbonyls. While GSH was slightly lower in SCD RBC, protein carbonyls, NADH, NAD + and total NADP +  + NADPH were not different. Furthermore, GSH or Prx-2 oxidation was not different after oxidative challenge in SCD vs. Control. Elevated freed heme and PFHb had a significant negative, non-linear association with hemopexin. There appeared to be a threshold effect for hemopexin (200 μg/ml), under which the freed heme rose acutely. Plasma F 2 -isoprostanes were not significantly elevated in SCD. Despite significant release of Hb and elevation of freed heme in SCD when hemopexin was apparently saturated, there was no clear indication of uncompensated vascular oxidative stress. This somewhat surprising result, suggests that oxidative stress is well compensated in RBCs and plasma during a period of relative health., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We have previously demonstrated that sickle cell disease (SCD) patients maintain normal global systemic and cerebral oxygen delivery by increasing cardiac output. However, ischemic end-organ injury remains common suggesting that tissue oxygen delivery may be impaired by microvascular dysregulation or damage. To test this hypothesis, we performed fingertip laser Doppler flowmetry measurements at the base of the nailbed and regional oxygen saturation (rSO 2 ) on the dorsal surface of the same hand. This was done during flow mediated dilation (FMD) studies in 26 chronically transfused SCD, 75 non-transfused SCD, and 18 control subjects. Chronically transfused SCD patients were studied prior to and following a single transfusion and there was no acute change in rSO 2 or perfusion. Laser Doppler estimates of resting perfusion were 76% higher in non-transfused and 110% higher in transfused SCD patients, compared to control subjects. In contrast, rSO 2 was 12 saturation points lower in non-transfused SCD patients, but normal in the transfused SCD patients. During cuff occlusion, rSO 2 declined at the same rate in all subjects suggesting similar intrinsic oxygen consumption rates. Upon cuff release, laser doppler post occlusive hyperemia was blunted in SCD patients in proportion to their resting perfusion values. Transfusion therapy did not improve the hyperemia response. FMD was impaired in SCD subjects but partially ameliorated in transfused SCD subjects. Taken together, non-transfused SCD subjects demonstrate impaired conduit artery FMD, impaired microcirculatory post-occlusive hyperemia, and resting hypoxia in the hand despite compensated oxygen delivery, suggesting impaired oxygen supply-demand matching. Transfusion improves FMD and oxygen supply-demand matching but not microcirculation hyperemic response., (© 2019 Wiley Periodicals, Inc.)

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.

Background: Patients with pulmonary atresia with intact ventricular septum and critical pulmonary stenosis (PAIVS/CPS) have wide variation in right ventricle (RV) size, systolic function, and diastolic function at birth. Establishment of antegrade pulmonary blood flow creates the potential for RV dilation from chronic pulmonary insufficiency. Future surgical decisions are based on RV size and function, largely supported by longitudinal studies of patients with Tetralogy of Fallot (TOF). Given potential differences in RV physiology and lack of similar data in PAIVS/CPS, the objective of this study was to determine differences in RV size, systolic function, and diastolic function between patients with PAIVS/CPS versus TOF., Methods: We retrospectively collected cardiovascular magnetic resonance (CMR) data in 27 patients with PAIVS/CPS (ages 13.3 ± 8.8 years) and 78 with TOF (11.4 ± 5.4 years). RV volumes, ejection fraction (EF), regurgitant fraction, end-diastolic forward flow across the pulmonary valve, and right atrial cross-sectional area were calculated., Results: There was no difference between the groups in RV end-diastolic volume (RVEDVi), RVEF, or pulmonary regurgitation. RVEF tended to decrease in TOF when RVEDVi exceeded 164 ml/m 2 . In PAIVS/CPS, RVEDVi less frequently reached 164 ml/m 2 and was not associated with RVEF. There was worse RV diastolic dysfunction in PAIVS/CPS, with 1.5 times larger right atrial area and two times higher pulmonary end-diastolic forward flow (p < 0.0001)., Conclusions: Patients with PAIVS/CPS have similar RV size, systolic function, and pulmonary regurgitation as TOF. However, impaired RV diastolic function may limit extremes of RV dilatation and impact long-term management of PAIVS/CPS.

Background: Sickle cell disease (SCD) is a genetically inherited hemoglobinopathy in which deoxygenated hemoglobin S polymerizes, leading to stiff red blood cells (RBCs) and inefficient microcirculatory blood flow. Transfusion therapy acts as primary and secondary prevention of ischemic stroke in SCD. Whether blood transfusion alters the mechanical sensitivity (MS) of RBCs to prolonged subhemolytic shear stress (shear) is unknown. We hypothesized that individuals with SCD undergoing chronic blood transfusion would have improved sensitivity to shear, compared with patients not undergoing transfusion therapy., Study Design and Methods: Blood suspensions from individuals with SCD not receiving (n = 15) and receiving (n = 15) chronic simple transfusion were conditioned to shear (1, 4, 16, 32, and 64 Pa) for various durations (1, 4, 16, 32, and 64 sec), and then deformability of RBCs was immediately measured. Healthy young controls (n = 15) were included for reference. A surface mesh was interpolated using the data to determine the effect of blood transfusion on MS of RBCs., Results: There was impaired RBC deformability to prolonged supraphysiologic shear in both SCD groups; however, MS improved in transfused patients when exposed to prolonged physiologic shear. Furthermore, in the transfused patients with SCD, the threshold above which subhemolytic damage occurs was similar to controls., Conclusion: We found that chronic transfusion therapy normalizes the MS threshold above which RBC subhemolytic damage occurs after prolonged shear exposure in SCD. An important and novel finding in transfused patients with SCD was the improvement in RBC deformability in response to prolonged shear exposure over the physiologic range., (© 2018 AABB.)

Sickle cell anemia is characterized by a mutation resulting in the formation of an abnormal beta-hemoglobin called hemoglobin S. Hemoglobin S polymerizes upon deoxygenation, causing impaired red blood cell deformability and increased blood viscosity at equivalent hematocrits. Thus, sickle cell disease is a hemorheologic disease that results in various pathologic processes involving multiple organ systems including the lungs, heart, kidneys and brain. Red blood cell mechanics and the perturbations on blood flow-endothelial interaction underlie much of the pathology found in sickle cell disease. Transfusion therapy is one of the few therapeutic options available to patients, acting as both primary and secondary prevention of stroke. Transfusion therapy, both simple and exchange, is also used for unremitting and frequent pain crises and pulmonary hypertension. Therefore, understanding basic rheologic changes following transfusion inform other therapeutic options that aim to mitigate this diffuse pathologic process. This review will aim to highlight transfusion effects on blood rheology.

Competing Interests: Conflict-of-interest disclosure: The author declares no competing financial interests.

Painful vaso-occlusive crisis (VOC), a complication of sickle cell disease (SCD), occurs when sickled red blood cells obstruct flow in the microvasculature. We postulated that exaggerated sympathetically mediated vasoconstriction, endothelial dysfunction and the synergistic interaction between these two factors act together to reduce microvascular flow, promoting regional vaso-occlusions, setting the stage for VOC. We previously found that SCD subjects had stronger vasoconstriction response to pulses of heat-induced pain compared to controls but the relative degrees to which autonomic dysregulation, peripheral vascular dysfunction and their interaction are present in SCD remain unknown. In the present study, we employed a mathematical model to decompose the total vasoconstriction response to pain into: 1) the neurogenic component, 2) the vascular response to blood pressure, 3) respiratory coupling and 4) neurogenic-vascular interaction. The model allowed us to quantify the contribution of each component to the total vasoconstriction response. The most salient features of the components were extracted to represent biophysical markers of autonomic and vascular impairment in SCD and controls. These markers provide a means of phenotyping severity of disease in sickle-cell anemia that is based more on underlying physiology than on genotype. The marker of the vascular component (BMv) showed stronger contribution to vasoconstriction in SCD than controls (p = 0.0409), suggesting a dominant myogenic response in the SCD subjects as a consequence of endothelial dysfunction. The marker of neurogenic-vascular interaction (BMn-v) revealed that the interaction reinforced vasoconstriction in SCD but produced vasodilatory response in controls (p = 0.0167). This marked difference in BMn-v suggests that it is the most sensitive marker for quantifying combined alterations in autonomic and vascular function in SCD in response to heat-induced pain.

After the Fontan procedure, patients with univentricular hearts can experience long-term complications due to chronic low-shear non-pulsatile pulmonary blood flow. We sought to evaluate hemorheology and its relationship to hemodynamics in children with univentricular hearts. We hypothesized that low-shear blood viscosity and red blood cell (RBC) aggregation would be associated with increased pulmonary vascular resistance (PVR) and decreased pulmonary blood flow (PBF). We performed a cross-sectional analysis of 62 children undergoing cardiac catheterization-20 with isolated atrial septal defect (ASD), 22 status post Glenn procedure (Glenn), and 20 status post Fontan procedure (Fontan). Shear-dependent blood viscosity, RBC aggregation and deformability, complete blood count, coagulation panel, metabolic panel, fibrinogen, and erythrocyte sedimentation rate were measured. PVR and PBF were calculated using the Fick equation. Group differences were analyzed by ANOVA and correlations by linear regression. Blood viscosity at all shear rates was higher in Glenn and Fontan, partially due to normocytic anemia in ASD. RBC aggregation and deformability were similar between all groups. Low-shear viscosity negatively correlated with PBF in Glenn and Fontan only (R (2) = 0.27, p < 0.001); it also negatively correlated with pulmonary artery pressure in Glenn (R (2) = 0.15, p = 0.01), and positively correlated with PVR in Fontan (R (2) = 0.28, p = 0.02). Our data demonstrate that elevated low-shear blood viscosity is associated with negative hemodynamic perturbations in a passive univentricular pulmonary circulation, but not in a pulsatile biventricular pulmonary circulation.

Tricuspid regurgitant (TR) jet velocity and its relationship to pulmonary hypertension has been controversial in sickle cell disease (SCD). Plasma free hemoglobin is elevated in SCD patients and acutely impairs systemic vascular reactivity. We postulated that plasma free hemoglobin would be negatively associated with both systemic and pulmonary endothelial function, assessed by flow-mediated dilation (FMD) of the brachial artery and TR jet velocity, respectively. Whole blood viscosity, plasma free hemoglobin, TR jet, and FMD were measured in chronically transfused SCD pre- and posttransfusion (N = 25), in nontransfused SCD (N = 26), and in ethnicity-matched control subjects (N = 10). We found increased TR jet velocity and decreased FMD in nontransfused SCD patients compared with the other 2 groups. TR jet velocity was inversely correlated with FMD. There was a striking nonlinear relationship between plasma free hemoglobin and both TR jet velocity and FMD. A single transfusion in the chronically transfused cohort improved FMD. In our patient sample, TR jet velocity and FMD were most strongly associated with plasma free hemoglobin and transfusion status (transfusions being protective), and thus consistent with the hypothesis that intravascular hemolysis and increased endogenous erythropoiesis damage vascular endothelia., (© 2015 by The American Society of Hematology.)

Sickle cell disease (SCD) is characterized by decreased erythrocyte deformability, microvessel occlusion and severe painful infarctions of different organs. Ektacytometry of SCD red blood cells (RBC) is made difficult by the presence of rigid, poorly-deformable irreversibly sickled cells (ISC) that do not align with the fluid shear field and distort the elliptical diffraction pattern seen with normal RBC. In operation, the computer software fits an outline to the diffraction pattern, then reports an elongation index (EI) at each shear stress based on the length and width of the fitted ellipse: EI=(length-width)/(length+width). Using a commercial ektacytometer (LORCA, Mechatronics Instruments, The Netherlands) we have approached the problem of ellipse fitting in two ways: (1) altering the height of the diffraction image on a computer monitor using an aperture within the camera lens; (2) altering the light intensity level (gray level) used by the software to fit the image to an elliptical shape. Neither of these methods affected deformability results (elongation index-shear stress relations) for normal RBC but did markedly affect results for SCD erythrocytes: (1) decreasing image height by 15% and 30% increased EI at moderate to high stresses; (2) progressively increasing the light level increased EI over a wide range of stresses. Fitting data obtained at different image heights using the Lineweaver-Burke routine yielded percentage ISC results in good agreement with microscopic cell counting. We suggest that these two relatively simple approaches allow minimizing artifacts due to the presence of rigid discs or ISC and also suggest the need for additional studies to evaluate the physiological relevance of deformability data obtained via these methods.

Consumption of red wine is associated with a decreased risk of several cardiovascular diseases (e.g., coronary artery disease, stroke), but unfortunately literature reports regarding ethanol's effects on hemorheological parameters are not concordant. In the present study, red blood cell (RBC) deformability was tested via laser ektacytometry (LORCA, 0.3-30 Pa) using two approaches: 1) addition of ethanol to whole blood at 0.25%-2% followed by incubation and testing in ethanol-free LORCA medium; 2) addition of ethanol to the LORCA medium at 0.25%-6% then testing untreated native RBC in these media. The effects of ethanol on deformability for oxidatively stressed RBC were investigated as were changes of RBC aggregation (Myrenne Aggregometer) for cells in autologous plasma or 3% 70 kDa dextran. Significant dose-related increases of RBC deformability were observed at 0.25% (p < 0.05) and higher concentrations only if ethanol was in the LORCA medium; no changes occurred for cells previously incubated with ethanol then tested in ethanol-free medium. The impaired deformability of cells pre-exposed to oxidative stress was improved only if ethanol was in the LORCA medium. RBC aggregation decreased with concentration at 0.25% and higher for cells in both autologous plasma and dextran 70. Our results indicate that ethanol reversibly improves erythrocyte deformability and irreversibly decreases erythrocyte aggregation; the relevance of these results to the health benefits of moderate wine consumption require further investigation.

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.

Background and Purpose: Abnormal cerebral microstructure has been documented in term neonates with congenital heart disease, portending risk for injury and poor neurodevelopmental outcome. Our hypothesis was that preterm neonates with congenital heart disease would demonstrate diffuse cerebral microstructural abnormalities when compared with critically ill neonates without congenital heart disease. A secondary aim was to identify any association between microstructural abnormalities, white matter injury (eg, punctate white matter lesions), and other clinical variables, including heart lesions., Materials and Methods: With the use of tract-based spatial statistics, an unbiased, voxelwise method for analyzing diffusion tensor imaging data, we compared 21 preterm neonates with congenital heart disease with 2 cohorts of neonates without congenital heart disease: 28 term and 27 preterm neonates, identified from the same neonatal intensive care unit., Results: Compared with term neonates without congenital heart disease, preterm neonates with congenital heart disease had microstructural abnormalities in widespread regions of the central white matter. However, 42% of the preterm neonates with congenital heart disease had punctate white matter lesions. When neonates with punctate white matter lesions were excluded, microstructural abnormalities remained only in the splenium. Preterm neonates with congenital heart disease had similar microstructure to preterm neonates without congenital heart disease., Conclusions: Diffuse microstructural abnormalities were observed in preterm neonates with congenital heart disease, strongly associated with punctate white matter lesions. Independently, regional vulnerability of the splenium, a structure associated with visual spatial function, was observed in all preterm neonates with congenital heart disease.

Background: Chronic transfusion therapy (CTT) is a mainstay for stroke prophylaxis in sickle cell anemia, but its effects on hemodynamics are poorly characterized. Transfusion improves oxygen-carrying capacity, reducing demands for high cardiac output, while decreasing hemoglobin (Hb)S%, reticulocyte count, and hemolysis. We hypothesized that transfusion would improve oxygen-carrying capacity, but that would be counteracted by a decrease in cardiac output due to increased hematocrit (Hct) and vascular resistance, leaving oxygen delivery unchanged., Study Design and Methods: To test this hypothesis, we examined patients on CTT immediately before transfusion and again 12 to 120 hours after transfusion, using echocardiography and near infrared spectroscopy., Results: Comparable increases in Hb and Hct and decreases in reticulocyte count and HbS with transfusion were observed in all patients, but males had a larger rebound of HbS%, reticulocyte count, and free Hb levels between transfusions. In males, transfusion decreased heart rate by 12%, stroke volume by 15%, and cardiac index by 24% while estimates for pulmonary and systemic vascular resistance increased, culminating in 6% decrease in oxygen delivery. In contrast, stroke volume and cardiac index and systemic and pulmonary vascular resistance did not change in women after transfusion, such that oxygen delivery improved 17%., Conclusion: In our sample population, males exhibit a paradoxical reduction in oxygen delivery in response to transfusion because the increase in vascular resistance is larger than the increase in oxygen capacity. This may result from an inability to adequately suppress their HbS% between transfusion cycles., (© 2012 American Association of Blood Banks.)

Fetal arrhythmias can be challenging to diagnose, even with the use of 2-dimensional, M-mode, and spectral Doppler sonography of myocardial or blood flow signals to determine the rate, synchrony, and timing. Color Doppler sonography combined with M-mode echocardiography uses the myocardium and blood flow to provide a robust evaluation of cardiac rhythm. Limited descriptions of color M-mode sonography have been published. This article describes the systematic application of the color M-mode technique using 4 specific clinical case examples and contrasts this technique with more conventional approaches to fetal arrhythmia diagnosis.

Background: Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening disease manifested by progressive pulmonary vascular remodeling, compromised pulmonary blood flow and right heart failure. Most studies have explored how pulmonary endothelial function modulates disease pathogenesis. We hypothesize that IPAH is a progressive panvasculopathy, affecting both pulmonary and systemic vascular beds, and that systemic endothelial dysfunction correlates with disease severity. Recent studies have demonstrated systemic endothelial dysfunction in adults with pulmonary hypertension; however, adults often have additional comorbidities affecting endothelial function. Systemic endothelial function has not been explored in children with IPAH., Methods: In this single-center, prospective, cross-sectional study we examined brachial artery flow-mediated dilation (FMD), a nitric oxide-mediated, endothelial-dependent response, in children with IPAH and matched controls. FMD measurements were compared with clinical and echocardiographic measures of IPAH severity., Results: Thirteen patients and 13 controls were studied, ranging in age from 6 to 20 years. FMD was decreased in IPAH subjects compared with controls (5.1 ± 2.1% vs 9.7 ± 2.0%; p < 0.0001). In IPAH subjects, FMD correlated directly with cardiac index (R(2) = 0.34, p = 0.035), and inversely with tricuspid regurgitation velocity (R(2) = 0.57, p = 0.019) and right ventricular myocardial performance index (R(2) = 0.44, p = 0.028)., Conclusions: The presence of systemic endothelial dysfunction in children with IPAH and its strong association with IPAH severity demonstrate that IPAH is a global vasculopathy. Although morbidity in IPAH is typically associated with pulmonary vascular disease, systemic vascular changes may also relate to disease pathogenesis and progression. Further study into shared mechanisms of systemic and pulmonary endothelial dysfunction may contribute to future therapies for IPAH., (Copyright © 2012 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Ektacytometry measures the shape of red blood cells under shear stress by analyzing the diffraction pattern of laser light passing through a thin layer of suspended cells. Here we model the diffraction pattern using a combination of Bessel and anomalous scattering functions, and employ a global pattern-fitting technique over nine different shear stresses to determine the separate mechanical properties of normal and non-deformable cells. This technique is capable of yielding the correct elongation index of the normal cells over a range of shear stresses even when they are mixed with as much as 50% non-deformable cells. Additionally, the relative concentrations of normal and non-deformable cells can be determined.

Rationale: Sickle cell disease is an inherited blood disorder characterized by vasoocclusive crises. Although hypoxia and pulmonary disease are known risk factors for these crises, the mechanisms that initiate vasoocclusive events are not well known., Objectives: To study the relationship between transient hypoxia, respiration, and microvascular blood flow in patients with sickle cell., Methods: We established a protocol that mimics nighttime hypoxic episodes and measured microvascular blood flow to determine if transient hypoxia causes a decrease in microvascular blood flow. Significant desaturations were induced safely by five breaths of 100% nitrogen., Measurements and Main Results: Desaturation did not induce change in microvascular perfusion; however, it induced substantial transient parasympathetic activity withdrawal in patients with sickle cell disease, but not controls subjects. Marked periodic drops in peripheral microvascular perfusion, unrelated to hypoxia, were triggered by sighs in 11 of 11 patients with sickle cell and 8 of 11 control subjects. Although the sigh frequency was the same in both groups, the probability of a sigh inducing a perfusion drop was 78% in patients with sickle cell and 17% in control subjects (P < 0.001). Evidence for sigh-induced sympathetic nervous system dominance was seen in patients with sickle cell (P < 0.05), but was not significant in control subjects., Conclusions: These data demonstrate significant disruption of autonomic nervous system balance, with marked parasympathetic withdrawal in response to transient hypoxia. They draw attention to an enhanced autonomic nervous system–mediated sigh–vasoconstrictor response in patients with sickle cell that could increase red cell retention in the microvasculature, promoting vasoocclusion.

Sickle cell anemia (SCA) is a genetic disease which is characterized by painful episodes of vascular occlusions. In the present study, we investigated a potential contribution of the autonomic nervous system (ANS) in initiating such episodes. We observed prominent decreases in microvascular perfusion in response to spontaneous sighs, which may increase the likelihood of red blood cell polymerization followed by vascular occlusions in SCA patients. Time-varying spectral analysis of heart rate variability (HRV), based on recursive least squares estimation, was employed to study the modulation of the ANS in response to sighs. To improve robustness of the spectral estimation while retaining its ability to track rapid changes, we propose a time-varying parameter estimate variability reduction (TV-PEVR) technique. Because respiration patterns can vary considerably across subjects, we employed a time-varying autoregressive with exogenous input (TV-ARX) model to adjust for the effect of respiration patterns on the HRV indices. Results from 8 SCA subjects and 9 normal controls suggested that the cardiac ANS responses to sighs are not different between the two groups, after adjusting for the effect of post-sigh respiration. However, the peripheral sympathetic response in SCA appeared to be enhanced in this group relative to normals, and sighs may play a role in initiation of vaso-occlusive events in this group of patients.