Mechanistic Insights Into Ventricular Arrhythmias Associated With Sickle Cell Disease: Role Of Abnormal Repolarization

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 980-980
Author(s):  
I D Greener ◽  
C A Rutledge ◽  
T Abassi ◽  
K Yadav ◽  
A B Desai ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Myocardial Fibrosis ◽  
Sickle Cell ◽  
Ventricular Arrhythmias ◽  
Normal Sinus Rhythm ◽  
Retrospective Chart Review ◽  
Left Ventricular ◽  
Cell Disease ◽  
Heart Rates

Abstract Introduction Sudden death, ventricular arrhythmias, prolonged QTc on ECG, and myocardial fibrosis have been documented independently in patients with sickle cell disease (SCD). We hypothesized that these electrical abnormalities are associated with myocardial fibrosis, ventricular arrhythmias, and death in SCD. Methods & Results A retrospective chart review of 195 SCD patients seen at the University of Illinois at Chicago was performed evaluating the association of ECG intervals with documented mortality and/or ventricular tachycardia (VT). Only ECGs demonstrating normal sinus rhythm and heart rates < 100 were included. Significant increases in PR (181 + 30 vs 162 + 26 ms, p=0.009), QRS (102 + 24 vs 89 + 11ms, p=0.0002), QTc (456 + 36 vs 441 + 25, p=0.02), and Tp-Te (duration between peak to end of T wave in lead V5, 114 + 46 vs 76 + 23, p=2.11X10-7) intervals were associated with a combined endpoint of all-cause mortality and VT (n=16 compared to n=179 SCD controls) with similar heart rates across both groups (78 + 14 vs. 77 + 11, p=0.72). To elucidate the mechanisms underlying this increased clinical risk in SCD patients, we investigated hearts from a mouse model of SCD. Cardiac electrical stimulation in vivo induced ventricular arrhythmias in 3/4 homozygous (-/-) SCD compared to only 1/5 wild-type (WT) hearts. Interestingly, Tp-Te– an established sudden cardiac death predictor- was significantly prolonged in -/- SCD vs. WT mice (5.6 + 0.29 vs. 4.1 + 0.37 msec ; p<0.05). Furthermore, left ventricular (LV) effective refractory periods (37+ 2.3 vs. 22 + 4.57 ms; p<0.05) and mid-anterior (LV) monophasic action potentials (MAPs) of -/- SCD mice, revealed increased duration compared to WT mice (53 + 2.3 vs. 33 + 6.9 ms; p<0.05). Conclusion In SCD patients, poor clinical outcomes are associated with abnormalities in depolarization and, prominently, repolarization. The SCD mouse exhibited arrhythmia vulnerability associated with repolarization abnormalities (Tp-Te, LV MAPs). The SCD mouse may represent a useful model for deciphering the mechanisms underlying the apparent increased arrhythmia burden in SCD patients. Disclosures: Hillery: Bayer: Consultancy; Biogen Idec: Consultancy.

scholarly journals Echocardiographic phenotypes of patients with sickle cell disease. An unsupervised analysis based on etendard cohort

2021 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
T D"humieres ◽  
J Inamo ◽  
S Deswarte ◽  
T Damy ◽  
G Loko ◽  
...  
Keyword(s):  
Cluster Analysis ◽  
Cardiac Output ◽  
Sickle Cell Disease ◽  
Diastolic Function ◽  
Sickle Cell ◽  
Left Ventricular ◽  
Integrative Approach ◽  
Cell Disease ◽  
Clinical Profiles ◽  
Cluster 2

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): PHRC Backgroung Echocardiography is the cornerstone in the diagnosis of cardiopulmonary involvement in sickle cell disease (SCD). However, given the unique pathophysiology of SCD associating high cardiac output, and various degrees of peripheral vasculopathy, differentiate the pathological from the physiological using echocardiography can be particularly challenging. Purpose This study sought to link cardiac phenotypes in homozygous SCD patients with clinical profiles and outcomes using cluster analysis. Methods We analyzed data of 379 patients with a sufficient echographic dataset included in the French Etendard Cohort, a prospective cohort initially designed to assess the prevalence of pulmonary hypertension. A cluster analysis was performed on echocardiographic variables, and the association between clusters and clinical profiles and outcomes was assessed. Results Three clusters were identified. Cluster 1 (N = 122) patients had the lowest cardiac output, only mild left cavities remodeling, diastolic dysfunction, and high tricuspid regurgitation velocity (TRV). They were predominantly female, as old as cluster 2, and displayed the most severe functional limitation. Cluster 2 (N = 103) patients had the highest cardiac output, left ventricular mass and a severely dilated left atrium. Diastolic function and TRV were similar to cluster 1. These patients had a higher blood pressure and a severe hemolytic anemia. Cluster 3 (N = 154) patients had mild left cavities remodeling, the best diastolic function and the lowest TRV. They were younger patients with the highest hemoglobin and lowest hemolytic markers. Right heart catheterization was performed in 94 patients. Cluster 1 gathered the majority of precapillary PH while cluster 2 gathered postcapillary PH and no PH was found in cluster 3. After a follow-up of 9.9 years (IQR: 9.3 to 10.5 years) death occurred in 38 patients (10%). Clusters 2 had the worst prognosis with 18% mortality rate vs. 12% in cluster 2 and 5% in cluster 1 (P log-rank = 0,02). Results are summarized in the central illustration. Conclusions Cluster analysis of echocardiographic variables identified 3 phenotypes among SCD patients, each associated with different clinical features and outcome. These findings underlines the necessity to rethink echocardiographic evaluation of SCD patients, with an integrative approach based on simultaneous evaluation of TRV along with left cavities remodeling and diastolic parameters. Abstract Figure.

Abstract 65: Anemia-related Heart Failure in Sub-saharan African Sickle Cell Disease Patients

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Adebayo C Atanda ◽  
Yahya Aliyu ◽  
Oluwafunmilayo Atanda ◽  
Aliyu Babadoko ◽  
Aisha Suleiman ◽  
...  
Keyword(s):  
Heart Failure ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Hemoglobin Level ◽  
Sub Saharan Africa ◽  
Cell Disease ◽  
Jet Velocity ◽  
Sub Saharan

Introduction: Anemia has been implicated in heart failure. Existing literatures, involving predominantly African-Americans, suggests that Sickle Cell Disease (SCD) maybe linked to various cardiovascular complications including pulmonary hypertension and left venticular dysfunction. Peculiarly, our study involves exclusively Sub-Saharan population. Method: We conducted a cross sectional observational study of 208 hydroxyurea-naive consecutive SCD patients aged 10-52 years at steady state and 94 healthy non-matched controls who were studied in an out patient clinic in Sub-Saharan Africa. SCD patients were required to have electrophoretic or liquid chromatography documentation of major sickling phenotypes. Control group was required to have non-sickling phenotypes. Cardiac measurements were performed with TransThoracic Echo according to American Society of Echocardiography guidelines. Hemoglobin level was also obtained. Results: Hemoglobin level in SCD group (8.5+/- 1.5) was significant (P<0.001) compared to control (13.8+/- 1.7). Although SCD group had significantly higher values of left ventricular (LV) size, there was no qualitative evidence of LV dysfunction. SCD group had higher values of Ejection Fraction but not statistically significant. There was no evidence of LV wall stiffening to impair proper filling in SCD group, with the ratio of early to late ventricular filling velocities, E/A ratio elevated (1.7+/-0.4 compared to 1.6+/- 0.4; P=0.010). Right ventricular systolic pressure was determined using the formula of 4x Tricuspid Reugurgitant jet (TRV) square as an indirect measurement of Pulmonary arterial systolic pressure. SCD patients had significantly higher mean±SD values for tricuspid regurgitant jet velocity than did the controls (2.1±0.6 vs. 1.8±0.5; p= 0.001). Within the SCD group, there was no clear pattern of worsening diastolic function with increased TRV. Furthermore, E/A had a significant positive relationship with jet velocity in bivariate analysis (R=0.20; P=0.013). Conclusions: We were unable to demonstrate existence of anemia-associated left ventricular dysfunction in Sub-Saharan African with SCD. Further studies is required to highlight the reason behind this finding.

scholarly journals Engineering, Generation and Preliminary Characterization of a Humanized Porcine Sickle Cell Disease Animal Model

2020 ◽  
Author(s):  
Tobias M. Franks ◽  
Sharie J. Haugabook ◽  
Elizabeth A. Ottinger ◽  
Meghan S. Vermillion ◽  
Kevin M. Pawlik ◽  
...  
Keyword(s):  
Animal Model ◽  
Sickle Cell Disease ◽  
Mouse Models ◽  
Sickle Cell ◽  
Cell Model ◽  
Globin Genes ◽  
Cell Disease ◽  
Small Vessels

AbstractMouse models of sickle cell disease (SCD) that faithfully switch from fetal to adult hemoglobin (Hb) have been important research tools that accelerated advancement towards treatments and cures for SCD. Red blood cells (RBCs) in these animals sickled in vivo, occluded small vessels in many organs and resulted in severe anemia like in human patients. SCD mouse models have been valuable in advancing clinical translation of some therapeutics and providing a better understanding of the pathophysiology of SCD. However, mouse models vary greatly from humans in their anatomy and physiology and therefore have limited application for certain translational efforts to transition from the bench to bedside. These differences create the need for a higher order animal model to continue the advancement of efforts in not only understanding relevant underlying pathophysiology, but also the translational aspects necessary for the development of better therapeutics to treat or cure SCD. Here we describe the development of a humanized porcine sickle cell model that like the SCD mice, expresses human ɑ-, β− and γ-globin genes under the control of the respective endogenous porcine locus control regions (LCR). We also describe our initial characterization of the SCD pigs and plans to make this model available to the broader research community.

scholarly journals Reconstruction of Sickle Cell Disease with Circulating Sickling Red Blood Cells in Novel Humanized Cytokines and Liver Mistrg Mice

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-30
Author(s):  
Yuanbin Song ◽  
Rana Gbyli ◽  
Liang Shan ◽  
Wei Liu ◽  
Yimeng Gao ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Mouse Model ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Blood Cells ◽  
Red Cell ◽  
Cell Disease ◽  
Ineffective Erythropoiesis ◽  
Cd34 Cells

In vivo models of human erythropoiesis with generation of circulating mature human red blood cells (huRBC) have remained elusive, limiting studies of primary human red cell disorders. In our prior study, we have generated the first combined cytokine-liver humanized immunodeficient mouse model (huHepMISTRG-Fah) with fully mature, circulating huRBC when engrafted with human CD34+ hematopoietic stem and progenitor cells (HSPCs)1. Here we present for the first time a humanized mouse model of human sickle cell disease (SCD) which replicates the hallmark pathophysiologic finding of vaso-occlusion in mice engrafted with primary patient-derived SCD HSPCs. SCD is an inherited blood disorder caused by a single point mutation in the beta-globin gene. Murine models of SCD exclusively express human globins in mouse red blood cells in the background of murine globin knockouts2 which exclusively contain murine erythropoiesis and red cells and thus fail to capture the heterogeneity encountered in patients. To determine whether enhanced erythropoiesis and most importantly circulating huRBC in engrafted huHepMISTRG-Fah mice would be sufficient to replicate the pathophysiology of SCD, we engrafted it with adult SCD BM CD34+ cells as well as age-matched control BM CD34+ cells. Overall huCD45+ and erythroid engraftment in BM (Fig. a, b) and PB (Fig. c, d) were similar between control or SCD. Using multispectral imaging flow cytometry, we observed sickling huRBCs (7-11 sickling huRBCs/ 100 huRBCs) in the PB of SCD (Fig. e) but not in control CD34+ (Fig. f) engrafted mice. To determine whether circulating huRBC would result in vaso-occlusion and associated findings in SCD engrafted huHepMISTRG-Fah mice, we evaluated histological sections of lung, liver, spleen, and kidney from control and SCD CD34+ engrafted mice. SCD CD34+ engrafted mice lungs showed an increase in alveolar macrophages (arrowheads) associated with alveolar hemorrhage and thrombosis (arrows) but not observed control engrafted mice (Fig. g). Spleens of SCD engrafted mice showed erythroid precursor expansion, sickled erythrocytes in the sinusoids (arrowheads), and vascular occlusion and thrombosis (arrows) (Fig. h). Liver architecture was disrupted in SCD engrafted mice with RBCs in sinusoids and microvascular thromboses (Fig. i). Congestion of capillary loops and peritubular capillaries and glomeruli engorged with sickled RBCs was evident in kidneys (Fig. j) of SCD but not control CD34+ engrafted mice. SCD is characterized by ineffective erythropoiesis due to structural abnormalities in erythroid precursors3. As a functional structural unit, erythroblastic islands (EBIs) represent a specialized niche for erythropoiesis, where a central macrophage is surrounded by developing erythroblasts of varying differentiation states4. In our study, both SCD (Fig. k) and control (Fig. l) CD34+ engrafted mice exhibited EBIs with huCD169+ huCD14+ central macrophages surrounded by varying stages of huCD235a+ erythroid progenitors, including enucleated huRBCs (arrows). This implies that huHepMISTRG-Fah mice have the capability to generate human EBIs in vivo and thus represent a valuable tool to not only study the effects of mature RBC but also to elucidate mechanisms of ineffective erythropoiesis in SCD and other red cell disorders. In conclusion, we successfully engrafted adult SCD patient BM derived CD34+ cells in huHepMISTRG-Fah mice and detected circulating, sickling huRBCs in the mouse PB. We observed pathological changes in the lung, spleen, liver and kidney, which are comparable to what is seen in the established SCD mouse models and in patients. In addition, huHepMISTRG-Fah mice offer the opportunity to study the role of the central macrophage in human erythropoiesis in health and disease in an immunologically advantageous context. This novel mouse model could therefore serve to open novel avenues for therapeutic advances in SCD. Reference 1. Song Y, Shan L, Gybli R, et. al. In Vivo reconstruction of Human Erythropoiesis with Circulating Mature Human RBCs in Humanized Liver Mistrg Mice. Blood. 2019;134:338. 2. Ryan TM, Ciavatta DJ, Townes TM. Knockout-transgenic mouse model of sickle cell disease. Science. 1997;278(5339):873-876. 3. Blouin MJ, De Paepe ME, Trudel M. Altered hematopoiesis in murine sickle cell disease. Blood. 1999;94(4):1451-1459. 4. Manwani D, Bieker JJ. The erythroblastic island. Curr Top Dev Biol. 2008;82:23-53. Disclosures Xu: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Flavell:Zai labs: Consultancy; GSK: Consultancy.

The placental-umbilical unit in sickle cell disease pregnancy: A model for studying in vivo functional adjustments to hypoxia in humans

2004 ◽  
Vol 35 (11) ◽  
pp. 1353-1359 ◽  
Author(s):  
Paul Trampont ◽  
Martine Roudier ◽  
Anne-Marie Andrea ◽  
Nelly Nomal ◽  
Therese-Marie Mignot ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cell Disease

scholarly journals In vivo survival studies of 51Cr-labeled methyl acetimidate treated erythrocytes in patients with sickle cell disease

Blood ◽  
1980 ◽  
Vol 56 (6) ◽  
pp. 1041-1047 ◽  
Author(s):  
TG Gabuzda ◽  
TL Chao ◽  
MR Berenfeld ◽  
T Gelbart
Keyword(s):  
Sickle Cell Disease ◽  
Survival Time ◽  
Sickle Cell ◽  
Clinical Testing ◽  
Cell Disease ◽  
Show Evidence ◽  
Survival Studies ◽  
Circulating Antibody

Abstract Studies of the survival time of 51Cr labeled erythrocytes treated in vitro with methyl acetimidate (MAI) were conducted in 13 patients with sickle cell disease in order to assess the suitability of this antisickling agent for more extensive clinical testing. In comparison with previously measured control values (average t1/2 8.4 +/- 1.1 days a), the survival time of the treated erythrocytes in 10 of the patients who were not transfused was initially prolonged (average t1/2 24.4 +/- 4.6 days). However, 5 of the 13 patients studied developed circulating antibody against the MAI treated erythrocytes, markedly reducing the survival time of MAI treated erythrocytes in subsequent studies. Two patients, each challenged 3 times with infused MAI treated erythrocytes, failed to show evidence of antibody production, suggesting that not all subjects become immunized even after repeated exposure. In spite of many other promising properties of MAI as an antisickling agent of potential value, consideration of its use in further clinical testing must depend on successful avoidance of immunization in patients receiving infusions of treated erythrocytes.

Sialic acid in sickle cell disease.

1988 ◽  
Vol 34 (7) ◽  
pp. 1443-1446 ◽  
Author(s):  
G I Ekeke ◽  
G O Ibeh
Keyword(s):  
Sialic Acid ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Age Groups ◽  
Dependent Manner ◽  
Cell Disease ◽  
Concentration Dependent Manner ◽  
Sialic Acid Content ◽  
Age Range

Abstract Neuraminic (sialic) acid concentrations in serum from normal and sickle cell (HbSS) subjects were determined for discrete age groups from childhood through adolescence. Values in sickle cell disease were consistently lower over the entire age range. We further investigated the effect of exogenous sialic acid on the rate of sickling reversion of HbSS erythrocytes and demonstrated that this compound in millimole per liter concentrations could revert pre-sickled erythrocytes to their normal morphology in a concentration-dependent manner. When subjected to partial de-sialation with sialidase (EC 3.2.1.18), the HbSS erythrocytes not only sickled faster upon deoxygenation, they also reverted more slowly on treatment with phenylalanine (a more efficient anti-sickling agent than sialic acid) than did untreated cells. We conclude that, in sickle cell disease, erythrocyte sialic acid content could play a significant role, not only in the control of the sickling rate in vivo, but also, after sickling has occurred, in the rate of recovery from a sickling crisis.

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