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1
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Nishi H, Wang J, Onishi Y, Nangaku M. Infectious Risk and Variability of Hemoglobin Level in Patients Undergoing Hemodialysis. Kidney Int Rep 2023; 8:1752-1760. [PMID: 37705913 PMCID: PMC10496019 DOI: 10.1016/j.ekir.2023.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 05/29/2023] [Accepted: 06/05/2023] [Indexed: 09/15/2023] Open
Abstract
Introduction In the management of anemia in chronic kidney disease, hemoglobin levels often fall below or exceed target ranges. Past retrospective cohort studies of patients undergoing hemodialysis with conventional erythropoiesis stimulating agents (ESAs) found that hemoglobin level fluctuations predicted mortality and cardiovascular adverse events; long-acting agents were thereafter widely available. An updated validation by a prospective cohort study was needed. Methods Using Cox regression models, we evaluated associations between hemoglobin variability and all-cause death, hospitalization, and cardiovascular, thrombotic, or infectious adverse event outcomes in 3063 hemodialysis patients' data from the Japanese Dialysis Outcomes and Practice Patterns Study (J-DOPPS) from 2012 to 2018. Results During a median follow-up time of 2.5 years, all-cause mortality was lowest in the first quartile and tended to be higher in groups with greater hemoglobin variability (hazard ratio [HR]: 95% confidence interval for the fourth quartile of an absolute value of hemoglobin variability: 1.44 [0.99-2.08], P for trend = 0.056). Infectious event incidence in these patients was also lower in the first quartile than for the other quartiles (P for trend < 0.01). The association was more pronounced in patients with lower serum ferritin levels or iron supplementation. Cardiovascular and thrombotic event incidence was not associated with hemoglobin variability. Conclusions Maintenance hemodialysis patients on ESA treatment with higher hemoglobin variability are at higher risk for all-cause mortality and particularly infectious events.
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Affiliation(s)
- Hiroshi Nishi
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Jui Wang
- College of Public Health, National Taiwan University, Taipei, Taiwan
- Institute for Health Outcomes and Process Evaluation Research (iHope International), Kyoto, Japan
| | - Yoshihiro Onishi
- Institute for Health Outcomes and Process Evaluation Research (iHope International), Kyoto, Japan
| | - Masaomi Nangaku
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
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2
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López-Galán E, Vitón-Castillo AA, Carrazana-Escalona R, Planas-Rodriguez M, Fernández-García AA, Cutiño-Clavel I, Pascau-Simon A, Connes P, Sánchez-Hechavarría ME, Muñoz-Bustos GA. Autonomic and Vascular Responses during Reactive Hyperemia in Healthy Individuals and Patients with Sickle Cell Anemia. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1141. [PMID: 37374344 DOI: 10.3390/medicina59061141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 04/07/2023] [Accepted: 05/10/2023] [Indexed: 06/29/2023]
Abstract
Background and Objectives: To compare autonomic and vascular responses during reactive hyperemia (RH) between healthy individuals and patients with sickle cell anemia (SCA). Materials and Methods: Eighteen healthy subjects and 24 SCA patients were subjected to arterial occlusion for 3 min at the lower right limb level. The pulse rate variability (PRV) and pulse wave amplitude were measured through photoplethysmography using the Angiodin® PD 3000 device, which was placed on the first finger of the lower right limb 2 min before (Basal) and 2 min after the occlusion. Pulse peak intervals were analyzed using time-frequency (wavelet transform) methods for high-frequency (HF: 0.15-0.4) and low-frequency (LF: 0.04-0.15) bands, and the LF/HF ratio was calculated. Results: The pulse wave amplitude was higher in healthy subjects compared to SCA patients, at both baseline and post-occlusion (p < 0.05). Time-frequency analysis showed that the LF/HF peak in response to the post-occlusion RH test was reached earlier in healthy subjects compared to SCA patients. Conclusions: Vasodilatory function, as measured by PPG, was lower in SCA patients compared to healthy subjects. Moreover, a cardiovascular autonomic imbalance was present in SCA patients with high sympathetic and low parasympathetic activity in the basal state and a poor response of the sympathetic nervous system to RH. Early cardiovascular sympathetic activation (10 s) and vasodilatory function in response to RH were impaired in SCA patients.
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Affiliation(s)
- Erislandis López-Galán
- Departamento de Ciencias Básicas Biomédicas, Facultad de Medicina, Universidad de Ciencias Médicas de Santiago de Cuba, Santiago de Cuba 90100, Cuba
| | - Adrián Alejandro Vitón-Castillo
- Facultad de Ciencias Médicas "Dr. Ernesto Che Guevara de la Serna", Universidad de Ciencias Médicas de Pinar del Rio, Pinar del Rio 20100, Cuba
| | - Ramón Carrazana-Escalona
- Departamento de Ciencias Clínicas Básicas, Facultad de Medicina, Universidad Católica de la Santísima Concepción, Concepción 4090541, Chile
| | - Maylet Planas-Rodriguez
- Departamento de Ciencias Básicas Biomédicas, Facultad de Medicina, Universidad de Ciencias Médicas de Santiago de Cuba, Santiago de Cuba 90100, Cuba
| | | | - Ileana Cutiño-Clavel
- Departamento de Ciencias Básicas Biomédicas, Facultad de Medicina, Universidad de Ciencias Médicas de Santiago de Cuba, Santiago de Cuba 90100, Cuba
| | - Alexander Pascau-Simon
- Hospital General "Dr. Juan Bruno Zayas Alfonso", Laboratorio Vascular no Invasivo, Santiago de Cuba 90400, Cuba
| | - Philippe Connes
- LIBM Laboratory, Team "Vascular Biology and Red Blood Cell", Claude Bernard University Lyon 1, 69622 Lyon, France
| | - Miguel Enrique Sánchez-Hechavarría
- Grupo Bio-Bio Complejidad, Departamento de Ciencias Clínicas y Preclínicas, Facultad de Medicina, Universidad Católica de la Santísima Concepción, Concepción 4090541, Chile
- Núcleo Científico de Ciencias de la Salud, Facultad de Ciencias de la Salud, Universidad Adventista de Chile, Chillán 3780000, Chile
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Albohassan H, Ammen M, Alomran AA, Bu Shehab H, Al Sakkak H, Al Bohassan A. Impact of Hydroxyurea Therapy in Reducing Pain Crises, Hospital Admissions, and Length of Stay Among Sickle Cell Patients in the Eastern Region of Saudi Arabia. Cureus 2022; 14:e31527. [DOI: 10.7759/cureus.31527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/15/2022] [Indexed: 11/16/2022] Open
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4
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Linear heart rate variability measures in Sickle cell disease compared to the healthy control subjects: A systematic review and mete-analysis study. PHYSIOLOGY AND PHARMACOLOGY 2021. [DOI: 10.52547/phypha.26.2.10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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5
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Chalacheva P, Ji Y, Rosen CL, DeBaun MR, Khoo MCK, Coates TD. Nocturnal peripheral vasoconstriction predicts the frequency of severe acute pain episodes in children with sickle cell disease. Am J Hematol 2021; 96:60-68. [PMID: 33027545 DOI: 10.1002/ajh.26014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 10/01/2020] [Accepted: 10/05/2020] [Indexed: 01/27/2023]
Abstract
The basic model of SCD physiology states that vaso-occlusion occurs when hemoglobin S-containing red blood cells (RBC) undergo sickling before they escape the capillary into a larger vessel. We have shown that mental stress, pain and cold, and events reported by patients to trigger SCD vaso-occlusive crisis (VOC), cause rapid and significant decrease in blood flow, reducing the likelihood that RBC could transit the microvasculature before sickling occurs. However, the critical link between decrease in microvascular blood flow and the incidence of future sickle VOC has never been established experimentally in humans. Using data from centrally adjudicated, overnight polysomnograms (PSG), previously collected in a prospective multi-center cohort sleep study, we analyzed the beat-to-beat amplitudes of vasoconstriction reported by the fingertip photoplethysmogram in 212 children and adolescents with SCD and developed an algorithm that detects vasoconstriction events and quantifies the magnitude (Mvasoc ), duration, and frequency of vasoconstriction that reflect the individual's inherent peripheral vasoreactivity. The propensity to vasoconstrict, quantified by median Mvasoc , predicted the incidence rate of post-PSG severe acute vaso-occlusive pain events (P = .006) after accounting for age and hemoglobin. Indices of sleep-disordered breathing contributed to median Mvasoc but did not predict future pain rate. Median Mvasoc was not associated with vaso-occlusive pain events that occurred prior to each PSG. These results show that SCD individuals with high inherent propensity to vasoconstrict have more frequent severe acute pain events. Our empirical findings are consistent with the fundamental SCD hypothesis that decreased microvascular flow promotes microvascular occlusion.
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Affiliation(s)
| | - Yunhua Ji
- Department of Biomedical Engineering University of Southern California Los Angeles California
| | - Carol L. Rosen
- Department of Pediatrics, Division of Pediatric Pulmonary Allergy/Immunology and Sleep, University Hospitals‐Cleveland Medical Center, Rainbow Babies and Children's Hospitals Cleveland Ohio
| | - Michael R. DeBaun
- Division of Hematology‐Oncology, Department of Pediatrics Vanderbilt University School of Medicine Nashville Tennessee
| | - Michael C. K. Khoo
- Department of Biomedical Engineering University of Southern California Los Angeles California
| | - Thomas D. Coates
- Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Department of Pediatrics University of Southern California Keck School of Medicine Los Angeles California
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6
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Veluswamy S, Shah P, Khaleel M, Thuptimdang W, Chalacheva P, Sunwoo J, Denton CC, Kato R, Detterich J, Wood JC, Sposto R, Khoo MCK, Zeltzer L, Coates TD. Progressive vasoconstriction with sequential thermal stimulation indicates vascular dysautonomia in sickle cell disease. Blood 2020; 136:1191-1200. [PMID: 32518948 PMCID: PMC7472716 DOI: 10.1182/blood.2020005045] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 05/11/2020] [Indexed: 12/18/2022] Open
Abstract
Persons with sickle cell disease (SCD) exhibit subjective hypersensitivity to cold and heat perception in experimental settings, and triggers such as cold exposure are known to precipitate vaso-occlusive crises by still unclear mechanisms. Decreased microvascular blood flow (MBF) increases the likelihood of vaso-occlusion by increasing entrapment of sickled red blood cells in the microvasculature. Because those with SCD have dysautonomia, we anticipated that thermal exposure would induce autonomic hypersensitivity of their microvasculature with an increased propensity toward vasoconstriction. We exposed 17 patients with SCD and 16 control participants to a sequence of predetermined threshold temperatures for cold and heat detection and cold and heat pain via a thermode placed on the right hand. MBF was measured on the contralateral hand by photoplethysmography, and cardiac autonomic balance was assessed by determining heart rate variability. Thermal stimuli at both detection and pain thresholds caused a significant decrease in MBF in the contralateral hand within seconds of stimulus application, with patients with SCD showing significantly stronger vasoconstriction (P = .019). Furthermore, patients with SCD showed a greater progressive decrease in blood flow than did the controls, with poor recovery between episodes of thermal stimulation (P = .042). They had faster vasoconstriction than the controls (P = .033), especially with cold detection stimulus. Individuals with higher anxiety also experienced more rapid vasoconstriction (P = .007). Augmented vasoconstriction responses and progressive decreases in perfusion with repeated thermal stimulation in SCD are indicative of autonomic hypersensitivity in the microvasculature. These effects are likely to increase red cell entrapment in response to clinical triggers such as cold or stress, which have been associated with vaso-occlusive crises in SCD.
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Affiliation(s)
- Saranya Veluswamy
- Division of Hematology/Oncology, Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA
| | - Payal Shah
- Division of Hematology/Oncology, Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA
| | - Maha Khaleel
- Division of Hematology/Oncology, Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA
| | - Wanwara Thuptimdang
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA
| | - Patjanaporn Chalacheva
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA
| | - John Sunwoo
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA
| | - Christopher C Denton
- Division of Hematology/Oncology, Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA
| | | | | | | | - Richard Sposto
- Division of Preventive Medicine, Children's Hospital Los Angeles, Los Angeles, CA; and
| | - Michael C K Khoo
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA
| | - Lonnie Zeltzer
- Pediatric Pain Program, University of California, Los Angeles, CA
| | - Thomas D Coates
- Division of Hematology/Oncology, Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA
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7
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Abstract
Sickle cell disease (SCD) is one of the most common hereditary hemoglobinopathies worldwide. It is a multisystem disease that causes considerable patient morbidity. Despite advances in medical treatment, cardiopulmonary complications remain the most common cause of death in individuals with SCD. A growing body of evidence has shown that SCD results in a spectrum of cardiovascular complications through a variety of mechanisms, including chronic hemolysis, local tissue hypoxia, increased oxidative stress, and autonomic instability. Herein, we will examine the pathophysiology of sickle cell vasculopathy and discuss the spectrum of cardiovascular sequelae of the disease, while highlighting the impact of SCD on the cardiovascular health of the patients.
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8
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Autonomically-mediated decrease in microvascular blood flow due to mental stress and pain in sickle cell disease: A target for neuromodulatory interventions. Complement Ther Med 2020; 49:102334. [PMID: 32147052 DOI: 10.1016/j.ctim.2020.102334] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 01/29/2020] [Accepted: 01/30/2020] [Indexed: 11/20/2022] Open
Abstract
Pain and vaso-occlusive crises (VOC) are hallmark complications of sickle cell disease (SCD) and result in significant physical and psychosocial impairment. The variability in SCD pain frequency and triggers for the transition from steady state to VOC are not well understood. This paper summarizes the harmful physiological effects of pain and emotional stressors on autonomically-mediated vascular function in individuals with SCD and the effects of a cognitive, neuromodulatory intervention (i.e. hypnosis) on microvascular blood flow. We reviewed recent studies from the authors' vascular physiology laboratory that assessed microvascular responses to laboratory stressors in individuals with SCD. Results indicate that participants with SCD exhibit marked neurally mediated vascular reactivity in response to pain, pain-related fear, and mental stress. Further, pilot study results show that engagement in hypnosis may attenuate harmful microvascular responses to pain. The collective results demonstrate that autonomically-mediated vascular responses to pain and mental stress represent an important SCD intervention target. This ongoing work provides physiological justification for the inclusion of cognitive, neuromodulatory and complementary treatments in SCD disease management and may inform the development of targeted, integrative interventions that prevent the enhancement of autonomic vascular dysfunction in SCD.
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9
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Bokov P, El Jurdi H, Denjoy I, Peiffer C, Medjahdi N, Holvoet L, Benkerrou M, Delclaux C. Salbutamol Worsens the Autonomic Nervous System Dysfunction of Children With Sickle Cell Disease. Front Physiol 2020; 11:31. [PMID: 32174840 PMCID: PMC7054439 DOI: 10.3389/fphys.2020.00031] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 01/15/2020] [Indexed: 11/13/2022] Open
Abstract
Background Sickle cell disease (SCD) patients with asthma have an increased rate of vaso-occlusive crisis (VOC) and acute chest syndrome (ACS) episodes when compared to those without asthma. We hypothesized that either asthma diagnosis or bronchodilator treatment might aggravate SCD via their modulating effect on the autonomic nervous system (ANS). Methods Cross-sectional evaluation of heart rate variability (HRV) during pulmonary function tests, including salbutamol administration, in children with SCD receiving asthma treatment or not when compared to asthmatic children without SCD matched for ethnicity. Results SCD children with asthma (n = 30, median age of 12.9 years old) were characterized by a reduced FEV1/FVC ratio, an increased bronchodilator response, and a greater incidence of VOC and ACS when compared to SCD children without asthma (n = 30, 12.7 years). Children with asthma without SCD (n = 29, 11.4 years) were characterized by a higher exhaled NO fraction than SCD children. SCD children when compared to non-SCD children showed reduced HRV [total power, low (LF) and high (HF, vagal tone) frequencies], which was further worsened by salbutamol administration in all the groups: reduction in total power and HF with an increase in LF/HF ratio. After salbutamol, the LF/HF ratio of the SCD children was higher than that of the non-SCD children. The two groups of SCD children were similar, suggesting that asthma diagnosis per se did not modify ANS functions. Conclusion SCD children are characterized by impaired parasympathetic control and sympathetic overactivity that is worsened by salbutamol administration. Clinical Trial Registration www.ClinicalTrials.gov, identifier NCT04062409.
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Affiliation(s)
- Plamen Bokov
- Service de Physiologie Pédiatrique, AP-HP, Hôpital Robert Debré, Paris, France.,UMR 1141, Equipe NeoPhen, INSERM co-tutelle, Université de Paris, Paris, France
| | - Houmam El Jurdi
- Service de Physiologie Pédiatrique, AP-HP, Hôpital Robert Debré, Paris, France
| | - Isabelle Denjoy
- Service de Physiologie Pédiatrique, AP-HP, Hôpital Robert Debré, Paris, France
| | - Claudine Peiffer
- Service de Physiologie Pédiatrique, AP-HP, Hôpital Robert Debré, Paris, France
| | - Noria Medjahdi
- Service de Physiologie Pédiatrique, AP-HP, Hôpital Robert Debré, Paris, France
| | - Laurent Holvoet
- Service d'Hématologie Pédiatrique, AP-HP, Hôpital Robert Debré, Paris, France
| | - Malika Benkerrou
- Service d'Hématologie Pédiatrique, AP-HP, Hôpital Robert Debré, Paris, France
| | - Christophe Delclaux
- Service de Physiologie Pédiatrique, AP-HP, Hôpital Robert Debré, Paris, France.,UMR 1141, Equipe NeoPhen, INSERM co-tutelle, Université de Paris, Paris, France
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10
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Association between long-term hemoglobin variability and mortality in Korean adults: a nationwide population-based cohort study. Sci Rep 2019; 9:17285. [PMID: 31754187 PMCID: PMC6872712 DOI: 10.1038/s41598-019-53709-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Accepted: 10/31/2019] [Indexed: 12/17/2022] Open
Abstract
Hemoglobin variability is known to be associated with mortality in patients with chronic renal failure and cardiovascular disease. However, the effect of hemoglobin variability on mortality in the general population has not yet been studied. We aimed to investigate the association between hemoglobin variability and mortality using Korean cohort from National Health Insurance Service-Health Screening 2002–2015 database. This study was conducted on 182,757 adults who underwent more than 4 health screenings from 2002 to 2009. Hemoglobin variability was assessed by 3 indices of coefficient of variation (CV), standard deviation (SD), and variability independent of the mean (VIM). Cox proportional hazard regression analysis was performed for each index of quartile groups (Q1–Q4). The hazard ratio and 95% confidence interval^l for all-cause mortality comparing Q2, Q3 and Q4 with Q1 of hemoglobin variability CV in the multivariable adjusted model were 1.07 [0.96–1.20], 1.18 [1.06–1.31] and 1.43 [1.29–1.58] respectively. As the 5% CV, SD, and VIM increased, the hazard ratio for mortality increased by 1.08 [1.06–1.10] in the multivariable adjusted model. Hemoglobin variability is not only important predictor in patients with chronic renal failure and cardiovascular disease but could also be considered as a useful predictor of mortality in the general population.
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11
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Veluswamy S, Shah P, Denton CC, Chalacheva P, Khoo MCK, Coates TD. Vaso-Occlusion in Sickle Cell Disease: Is Autonomic Dysregulation of the Microvasculature the Trigger? J Clin Med 2019; 8:jcm8101690. [PMID: 31618931 PMCID: PMC6832215 DOI: 10.3390/jcm8101690] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 10/11/2019] [Accepted: 10/11/2019] [Indexed: 02/02/2023] Open
Abstract
Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by polymerization of hemoglobin S upon deoxygenation that results in the formation of rigid sickled-shaped red blood cells that can occlude the microvasculature, which leads to sudden onsets of pain. The severity of vaso-occlusive crises (VOC) is quite variable among patients, which is not fully explained by their genetic and biological profiles. The mechanism that initiates the transition from steady state to VOC remains unknown, as is the role of clinically reported triggers such as stress, cold and pain. The rate of hemoglobin S polymerization after deoxygenation is an important determinant of vaso-occlusion. Similarly, the microvascular blood flow rate plays a critical role as fast-moving red blood cells are better able to escape the microvasculature before polymerization of deoxy-hemoglobin S causes the red cells to become rigid and lodge in small vessels. The role of the autonomic nervous system (ANS) activity in VOC initiation and propagation has been underestimated considering that the ANS is the major regulator of microvascular blood flow and that most triggers of VOC can alter the autonomic balance. Here, we will briefly review the evidence supporting the presence of ANS dysfunction in SCD, its implications in the onset of VOC, and how differences in autonomic vasoreactivity might potentially contribute to variability in VOC severity.
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Affiliation(s)
- Saranya Veluswamy
- Hematology Section, Children’s Center for Cancer and Blood Diseases, Children’s Hospital Los Angeles, 4650 Sunset boulevard, Los Angeles, CA 90027, USA; (S.V.); (P.S.); (C.C.D.)
| | - Payal Shah
- Hematology Section, Children’s Center for Cancer and Blood Diseases, Children’s Hospital Los Angeles, 4650 Sunset boulevard, Los Angeles, CA 90027, USA; (S.V.); (P.S.); (C.C.D.)
| | - Christopher C. Denton
- Hematology Section, Children’s Center for Cancer and Blood Diseases, Children’s Hospital Los Angeles, 4650 Sunset boulevard, Los Angeles, CA 90027, USA; (S.V.); (P.S.); (C.C.D.)
| | - Patjanaporn Chalacheva
- Department of Biomedical Engineering, University of Southern California, 1042 Downey Way, Los Angeles, CA 90089, USA; (P.C.)
| | - Michael C. K. Khoo
- Department of Biomedical Engineering, University of Southern California, 1042 Downey Way, Los Angeles, CA 90089, USA; (P.C.)
| | - Thomas D. Coates
- Hematology Section, Children’s Center for Cancer and Blood Diseases, Children’s Hospital Los Angeles, 4650 Sunset boulevard, Los Angeles, CA 90027, USA; (S.V.); (P.S.); (C.C.D.)
- Correspondence: ; Tel.: +1-323-361-2352
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12
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Akgul F, Batyraliev TA, Fettser DV, Seyfeli E, Arystan AG, Seydaliyeva T, Gali E, Yalcin F, Sidorenko BA. [Decreased Heart Rate Variability in Sickle Cell Anemia as Effect of Pulmonary Arterial Hypertension]. ACTA ACUST UNITED AC 2019; 59:39-44. [PMID: 31002038 DOI: 10.18087/cardio.2019.4.10237] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 04/17/2019] [Indexed: 11/18/2022]
Abstract
Decreased heart rate variability (HRV) is associated with increased mortality risk in various diseases. The objective of this investigation:to study HRV in patients with sickle cell anemia (SCA) and to assess the effect of pulmonary arterial hypertension (PAH) on HRV in these patients. Materials and methods. HRV registration and Doppler echocardiographic assessment of systolic pulmonary arterial pressure (PAP) was carried out in 61 stable patients with SCA and 24 healthy subjects. Results. Low frequency power (LFP) and high frequency power (HFP) were decreased in SCA patients compared to healthy subjects. Among SCA patients, PAH patients had lower LFP and HFP than patients without PAH. In SCA patients, systolic PAP showed significant negative correlation with LFP and HFP. Conclusion. HRV is significantly decreased in SCA patients, especially in those with PAH. HRV may be particularly useful in early detection of PAH patients who may have worse prognosis and higher mortality risk.
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Affiliation(s)
- F Akgul
- Bulent Ecevit University, Zonguldak
| | | | | | | | - A G Arystan
- Medical Centre Hospital of President's Affairs Administration of the RK, Astana
| | | | - E Gali
- Antakya State Hospital, Antakya
| | - F Yalcin
- Mustafa Kemal University, Antakya
| | - B A Sidorenko
- Central State Medical Academy, President Management Department RF
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Chalacheva P, Kato RM, Shah P, Veluswamy S, Denton CC, Sunwoo J, Thuptimdang W, Wood JC, Detterich JA, Coates TD, Khoo MCK. Sickle Cell Disease Subjects Have a Distinct Abnormal Autonomic Phenotype Characterized by Peripheral Vasoconstriction With Blunted Cardiac Response to Head-Up Tilt. Front Physiol 2019; 10:381. [PMID: 31031633 PMCID: PMC6470196 DOI: 10.3389/fphys.2019.00381] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2019] [Accepted: 03/19/2019] [Indexed: 12/26/2022] Open
Abstract
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.
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Affiliation(s)
- Patjanaporn Chalacheva
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, United States
| | - Roberta M Kato
- Divisions of Pulmonology, Children's Hospital Los Angeles, Los Angeles, CA, United States
| | - Payal Shah
- Hematology Section, Children's Center for Cancer, Blood Disease and Bone Marrow Transplantation, Children's Hospital Los Angeles, Keck School of Medicine of University of Southern California, Los Angeles, CA, United States
| | - Saranya Veluswamy
- Hematology Section, Children's Center for Cancer, Blood Disease and Bone Marrow Transplantation, Children's Hospital Los Angeles, Keck School of Medicine of University of Southern California, Los Angeles, CA, United States
| | - Christopher C Denton
- Hematology Section, Children's Center for Cancer, Blood Disease and Bone Marrow Transplantation, Children's Hospital Los Angeles, Keck School of Medicine of University of Southern California, Los Angeles, CA, United States
| | - John Sunwoo
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, United States
| | - Wanwara Thuptimdang
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, United States
| | - John C Wood
- Divisions of Cardiology, Children's Hospital Los Angeles, Los Angeles, CA, United States
| | - Jon A Detterich
- Divisions of Cardiology, Children's Hospital Los Angeles, Los Angeles, CA, United States
| | - Thomas D Coates
- Hematology Section, Children's Center for Cancer, Blood Disease and Bone Marrow Transplantation, Children's Hospital Los Angeles, Keck School of Medicine of University of Southern California, Los Angeles, CA, United States
| | - Michael C K Khoo
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, United States
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14
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Zhao L, Hu C, Cheng J, Zhang P, Jiang H, Chen J. Haemoglobin variability and all-cause mortality in haemodialysis patients: A systematic review and meta-analysis. Nephrology (Carlton) 2019; 24:1265-1272. [PMID: 30644618 PMCID: PMC6899589 DOI: 10.1111/nep.13560] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/07/2019] [Indexed: 12/26/2022]
Abstract
Aim Haemoglobin (Hb) variability has been reported to be associated with mortality in dialysis patients in some but not all studies. We aimed to establish the prognostic significance of Hb variability with all‐cause mortality in haemodialysis patients through this meta‐analysis. Methods The Medline, Embase, Cochrane Library and Web of Science databases were searched for studies assessing the association between Hb variability and all‐cause mortality in haemodialysis patients after adjustment for other covariates. Results We included three studies of five cohorts with a total of 262 641 patients. Forest plots showed that the combined hazard ratio for all‐cause mortality was 1.09 (95% CI = 1.01–1.08; P = 0.03) per 1 g/dL increase in Hb variability. Conclusion Based on the current evidence, our meta‐analysis found an association between Hb variability and all‐cause mortality in patients receiving haemodialysis therapy. Three studies of five cohorts with a total of 262 641 patients showed a combined hazard ratio for all‐cause mortality in HD patients to be 1.09 (95% CI = 1.01–1.08; P = 0.03) per 1 g/dL increase in the haemoglobin level. A significant heterogeneity exists between the studies.
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Affiliation(s)
- Lingfei Zhao
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China.,National Key Clinical Department of Kidney Diseases, Institute of Nephrology, Zhejiang University, Hangzhou, China.,The Third Grade Laboratory under the National State, Administration of Traditional Chinese Medicine, Hangzhou, China
| | - Chenxia Hu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jun Cheng
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China.,National Key Clinical Department of Kidney Diseases, Institute of Nephrology, Zhejiang University, Hangzhou, China.,The Third Grade Laboratory under the National State, Administration of Traditional Chinese Medicine, Hangzhou, China
| | - Ping Zhang
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China.,National Key Clinical Department of Kidney Diseases, Institute of Nephrology, Zhejiang University, Hangzhou, China.,The Third Grade Laboratory under the National State, Administration of Traditional Chinese Medicine, Hangzhou, China
| | - Hua Jiang
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China.,National Key Clinical Department of Kidney Diseases, Institute of Nephrology, Zhejiang University, Hangzhou, China.,The Third Grade Laboratory under the National State, Administration of Traditional Chinese Medicine, Hangzhou, China
| | - Jianghua Chen
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China.,National Key Clinical Department of Kidney Diseases, Institute of Nephrology, Zhejiang University, Hangzhou, China.,The Third Grade Laboratory under the National State, Administration of Traditional Chinese Medicine, Hangzhou, China
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15
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Kim IJ, Yang PS, Kim TH, Uhm JS, Pak HN, Lee MH, Sung JH, Joung B. Relationship Between Anemia and the Risk of Sudden Cardiac Arrest - A Nationwide Cohort Study in South Korea. Circ J 2018; 82:2962-2969. [PMID: 30259899 DOI: 10.1253/circj.cj-18-0046] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/05/2024]
Abstract
BACKGROUND The relationship between anemia and sudden cardiac arrest (SCA) is unclear in the general population, so we assessed it in a nationwide cohort. METHODS AND RESULTS We studied 494,948 subjects (mean age, 47.8 years; 245,333 men [49.6%]) with national health check-up data from the Korean National Health Insurance Database Cohort. During a mean follow-up period of 5.4 years, SCA occurred in 616 participants (396 men, 220 women). The incidence rates of SCA increased across the 4 anemia groups in both men (0.3, 1.5, 5.3, and 4.5 per 1,000 person-years) and women (0.2, 0.5, 0.5, and 1.2 per 1,000 person-years). The SCA risk per 1-unit decrease in hemoglobin (Hb) increased by 21% and 24%, respectively, in multivariable models adjusted for cardiovascular factors, in men (95% confidence interval [CI], 13-29%; P<0.001) and women (95% CI, 13-37%; P<0.001). A negative correlation between QTc interval and Hb level was observed in men, and a trend was observed in women. CONCLUSIONS Anemia was associated with an increased risk of SCA even after accounting for concomitant conditions in a South Korean nationwide cohort. The correlation between anemia and SCA might be explained by an increase in arrhythmic risks, such as QTc prolongation.
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Affiliation(s)
- In-Jung Kim
- Division of Cardiology, Department of Internal Medicine, Severance Cardiovascular Hospital, Yonsei University College of Medicine
| | - Pil-Sung Yang
- Department of Cardiology, CHA Bundang Medical Center, CHA University
| | - Tae-Hoon Kim
- Division of Cardiology, Department of Internal Medicine, Severance Cardiovascular Hospital, Yonsei University College of Medicine
| | - Jae-Sun Uhm
- Division of Cardiology, Department of Internal Medicine, Severance Cardiovascular Hospital, Yonsei University College of Medicine
| | - Hui-Nam Pak
- Division of Cardiology, Department of Internal Medicine, Severance Cardiovascular Hospital, Yonsei University College of Medicine
| | - Moon-Hyoung Lee
- Division of Cardiology, Department of Internal Medicine, Severance Cardiovascular Hospital, Yonsei University College of Medicine
| | - Jung-Hoon Sung
- Department of Cardiology, CHA Bundang Medical Center, CHA University
| | - Boyoung Joung
- Division of Cardiology, Department of Internal Medicine, Severance Cardiovascular Hospital, Yonsei University College of Medicine
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16
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Coates TD, Chalacheva P, Zeltzer L, Khoo MC. Autonomic nervous system involvement in sickle cell disease. Clin Hemorheol Microcirc 2018; 68:251-262. [DOI: 10.3233/ch-189011] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Affiliation(s)
- Thomas D. Coates
- Section of Hematology, Children’s Center for Cancer and Blood Diseases, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Patjanaporn Chalacheva
- Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, USA
| | - Lonnie Zeltzer
- Department of Pediatrics, Pediatric Pain and Palliative Care Program Division of Hematology-Oncology, Department of Pediatrics, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA, USA
| | - Michael C.K. Khoo
- Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, USA
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17
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Saunthararajah Y, Vichinsky EP. Sickle Cell Disease. Hematology 2018. [DOI: 10.1016/b978-0-323-35762-3.00042-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
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18
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Khaleel M, Puliyel M, Shah P, Sunwoo J, Kato RM, Chalacheva P, Thuptimdang W, Detterich J, Wood JC, Tsao J, Zeltzer L, Sposto R, Khoo MCK, Coates TD. Individuals with sickle cell disease have a significantly greater vasoconstriction response to thermal pain than controls and have significant vasoconstriction in response to anticipation of pain. Am J Hematol 2017; 92:1137-1145. [PMID: 28707371 DOI: 10.1002/ajh.24858] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 07/07/2017] [Accepted: 07/10/2017] [Indexed: 12/17/2022]
Abstract
The painful vaso-occlusive crises (VOC) that characterize sickle cell disease (SCD) progress over hours from the asymptomatic steady-state. SCD patients report that VOC can be triggered by stress, cold exposure, and, pain itself. We anticipated that pain could cause neural-mediated vasoconstriction, decreasing regional blood flow and promoting entrapment of sickle cells in the microvasculature. Therefore, we measured microvascular blood flow in the fingers of both hands using plethysmography and laser-Doppler flowmetry while applying a series of painful thermal stimuli on the right forearm in 23 SCD patients and 25 controls. Heat pain applied to one arm caused bilateral decrease in microvascular perfusion. The vasoconstriction response started before administration of the thermal pain stimulus in all subjects, suggesting that pain anticipation also causes significant vasoconstriction. The time delay between thermal pain application and global vasoconstriction ranged from 5 to 15.5 seconds and increased with age (P < .01). Although subjective measures, pain threshold and pain tolerance were not different between SCD subjects and controls, but the vaso-reactivity index characterizing the microvascular blood flow response to painful stimuli was significantly higher in SCD patients (P = .0028). This global vasoconstriction increases microvascular transit time, and may promote entrapment of sickle cells in the microvasculature, making vaso-occlusion more likely. The rapidity of the global vasoconstriction response indicates a neural origin that may play a part in the transition from steady-state to VOC, and may also contribute to the variability in VOC frequency observed in SCD patients.
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Affiliation(s)
- Maha Khaleel
- Section of Hematology; Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Keck School of Medicine; Los Angeles California
| | - Mammen Puliyel
- Section of Hematology; Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Keck School of Medicine; Los Angeles California
| | - Payal Shah
- Section of Hematology; Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Keck School of Medicine; Los Angeles California
| | - John Sunwoo
- Biomedical engineering; Viterbi School of Engineering; Los Angeles California
| | - Roberta M. Kato
- Division of Pulmonology; Children's Hospital Los Angeles, Keck School of Medicine; Los Angeles California
| | | | - Wanwara Thuptimdang
- Biomedical engineering; Viterbi School of Engineering; Los Angeles California
| | - Jon Detterich
- Division of Cardiology; Children's Hospital Los Angeles, Keck School of Medicine; Los Angeles California
| | - John C. Wood
- Biomedical engineering; Viterbi School of Engineering; Los Angeles California
- Division of Cardiology; Children's Hospital Los Angeles, Keck School of Medicine; Los Angeles California
| | - Jennie Tsao
- Pediatric Pain Program, University of California Los Angeles; Los Angeles California
| | - Lonnie Zeltzer
- Pediatric Pain Program, University of California Los Angeles; Los Angeles California
| | - Richard Sposto
- Section of Hematology; Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Keck School of Medicine; Los Angeles California
- Department of Preventive Medicine, Keck School of Medicine; University of Southern California; Los Angeles California
| | - Michael C. K. Khoo
- Biomedical engineering; Viterbi School of Engineering; Los Angeles California
| | - Thomas D. Coates
- Section of Hematology; Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Keck School of Medicine; Los Angeles California
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19
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Coloigner J, Kim Y, Bush A, Choi S, Balderrama MC, Coates TD, O’Neil SH, Lepore N, Wood JC. Contrasting resting-state fMRI abnormalities from sickle and non-sickle anemia. PLoS One 2017; 12:e0184860. [PMID: 28981541 PMCID: PMC5628803 DOI: 10.1371/journal.pone.0184860] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 08/31/2017] [Indexed: 11/20/2022] Open
Abstract
Sickle cell disease (SCD) is a chronic blood disorder that is often associated with acute and chronic cerebrovascular complications, including strokes and impaired cognition. Using functional resting state magnetic resonance images, we performed whole-brain analysis of the amplitude of low frequency fluctuations (ALFF), to detect areas of spontaneous blood oxygenation level dependent signal across brain regions. We compared the ALFF of 20 SCD patients to that observed in 19 healthy, age and ethnicity-matched, control subjects. Significant differences were found in several brain regions, including the insula, precuneus, anterior cingulate cortex and medial superior frontal gyrus. To identify the ALFF differences resulting from anemia alone, we also compared the ALFF of SCD patients to that observed in 12 patients having comparable hemoglobin levels but lacking sickle hemoglobin. Increased ALFF in the orbitofrontal cortex and the anterior and posterior cingulate cortex and decreased ALFF in the frontal pole, cerebellum and medial superior frontal gyrus persisted after accounting for the effect of anemia. The presence of white matter hyperintensities was associated with depressed frontal and medial superior frontal gyri activity in the SCD subjects. Decreased ALFF in the frontal lobe was correlated with decreased verbal fluency and cognitive flexibility. These findings may lead to a better understanding of the pathophysiology of SCD.
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Affiliation(s)
- Julie Coloigner
- CIBORG laboratory, Division of Radiology, Children’s Hospital, Los Angeles, California, United States of America
| | - Yeun Kim
- CIBORG laboratory, Division of Radiology, Children’s Hospital, Los Angeles, California, United States of America
| | - Adam Bush
- Department of Biomedical Engineering, University of Southern California, Los Angeles, California, United States of America
| | - Soyoung Choi
- Neuroscience Graduate Program, University of Southern California, Los Angeles, California, United States of America
| | - Melissa C. Balderrama
- Division of Hematology, Oncology and Blood and Marrow Transplantation, Children’s Hospital, Los Angeles, California, United States of America
- Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Thomas D. Coates
- Division of Hematology, Oncology and Blood and Marrow Transplantation, Children’s Hospital, Los Angeles, California, United States of America
- Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Sharon H. O’Neil
- Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
- Division of Neurology, Children’s Hospital, Los Angeles, California, United States of America
- The Saban Research Institute, Children’s Hospital, Los Angeles, California, United States of America
| | - Natasha Lepore
- CIBORG laboratory, Division of Radiology, Children’s Hospital, Los Angeles, California, United States of America
| | - John C. Wood
- Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
- Division of Cardiology, Children’s Hospital, Los Angeles, California, United States of America
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20
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Bailey K, Wesley J, Adeyinka A, Pierre L. Integrating Fat Embolism Syndrome Scoring Indices in Sickle Cell Disease: A Practice Management Review. J Intensive Care Med 2017; 34:797-804. [DOI: 10.1177/0885066617712676] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Fat embolism syndrome (FES) has been described in the literature as a rare complication of sickle cell disease (SCD). A review article published in 2005 reported 24 cases of FES associated with SCD. In many cases, a definitive diagnosis of FES in SCD is made on autopsy because of the lack of early recognition and the paucity of sensitive and specific testing for this syndrome. Patients with FES usually have a fulminant, rapidly deteriorating clinical course with mortality occurring within the first 24 hours. We postulate that FES is not well recognized in SCD and that FES scores are useful diagnostic tools in patients with SCD. We queried the electronic medical records with the diagnostic codes for SCD with acute chest syndrome (ACS), pulmonary embolism, or acute respiratory distress syndrome admitted to our hospital from 2008 to 2016 to identify patients suspected of having FES. In addition, we performed an extensive literature review to evaluate the management practice of pediatric patients with FES and SCD from 1966 to 2016. Six patients met our selection criteria from the hospital records, and 4 case reports from the literature search were also included. We applied the Gurd and Wilson criteria and the Schonfeld Fat Embolism Index to identify patients who met the criteria for FES. Nine patients fulfilled Gurd and Wilson criteria, and 9 patients who were evaluable met the Schonfeld criteria for FES. A rapidly deteriorating clinical course in a patient with SCD presenting with ACS or severe vaso-occlusive crisis should trigger a high index of suspicion for FES. Gurd and Wilson criteria or the Schonfeld Fat Embolism Index are useful diagnostic tools for FES in SCD.
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Affiliation(s)
- Keneisha Bailey
- Department of Pediatrics, The Brooklyn Hospital Center, Brooklyn, NY, USA
| | - Jagila Wesley
- Department of Pediatrics, The Brooklyn Hospital Center, Brooklyn, NY, USA
| | - Adebayo Adeyinka
- Department of Pediatrics, The Brooklyn Hospital Center, Brooklyn, NY, USA
| | - Louisdon Pierre
- Department of Pediatrics, The Brooklyn Hospital Center, Brooklyn, NY, USA
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21
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Chalacheva P, Khaleel M, Sunwoo J, Shah P, Detterich JA, Kato RM, Thuptimdang W, Meiselman HJ, Sposto R, Tsao J, Wood JC, Zeltzer L, Coates TD, Khoo MCK. Biophysical markers of the peripheral vasoconstriction response to pain in sickle cell disease. PLoS One 2017; 12:e0178353. [PMID: 28542469 PMCID: PMC5443571 DOI: 10.1371/journal.pone.0178353] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Accepted: 05/11/2017] [Indexed: 02/07/2023] Open
Abstract
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.
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Affiliation(s)
- Patjanaporn Chalacheva
- Department of Biomedical Engineering, University of Southern California, Los Angeles, California, United States of America
- * E-mail:
| | - Maha Khaleel
- Division of Hematology, Oncology and Blood & Marrow Transplantation, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, California, United States of America
| | - John Sunwoo
- Department of Biomedical Engineering, University of Southern California, Los Angeles, California, United States of America
| | - Payal Shah
- Division of Hematology, Oncology and Blood & Marrow Transplantation, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, California, United States of America
| | - Jon A. Detterich
- Division of Cardiology, Children’s Hospital Los Angeles, Los Angeles, California, United States of America
- Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Roberta M. Kato
- Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
- Division of Pulmonology, Children’s Hospital Los Angeles, Los Angeles, California, United States of America
| | - Wanwara Thuptimdang
- Department of Biomedical Engineering, University of Southern California, Los Angeles, California, United States of America
| | - Herbert J. Meiselman
- Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Richard Sposto
- Division of Hematology, Oncology and Blood & Marrow Transplantation, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, California, United States of America
- Department of Preventative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Jennie Tsao
- Pediatric Pain Program, David Geffen School of Medicine, University of California at Los Angeles, California, United States of America
| | - John C. Wood
- Department of Biomedical Engineering, University of Southern California, Los Angeles, California, United States of America
- Division of Cardiology, Children’s Hospital Los Angeles, Los Angeles, California, United States of America
| | - Lonnie Zeltzer
- Pediatric Pain Program, David Geffen School of Medicine, University of California at Los Angeles, California, United States of America
| | - Thomas D. Coates
- Division of Hematology, Oncology and Blood & Marrow Transplantation, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, California, United States of America
- Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Michael C. K. Khoo
- Department of Biomedical Engineering, University of Southern California, Los Angeles, California, United States of America
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22
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Bakeer N, James J, Roy S, Wansapura J, Shanmukhappa SK, Lorenz JN, Osinska H, Backer K, Huby AC, Shrestha A, Niss O, Fleck R, Quinn CT, Taylor MD, Purevjav E, Aronow BJ, Towbin JA, Malik P. Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology. Proc Natl Acad Sci U S A 2016; 113:E5182-E5191. [PMID: 27503873 PMCID: PMC5024607 DOI: 10.1073/pnas.1600311113] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Cardiopulmonary complications are the leading cause of mortality in sickle cell anemia (SCA). Elevated tricuspid regurgitant jet velocity, pulmonary hypertension, diastolic, and autonomic dysfunction have all been described, but a unifying pathophysiology and mechanism explaining the poor prognosis and propensity to sudden death has been elusive. Herein, SCA mice underwent a longitudinal comprehensive cardiac analysis, combining state-of-the-art cardiac imaging with electrocardiography, histopathology, and molecular analysis to determine the basis of cardiac dysfunction. We show that in SCA mice, anemia-induced hyperdynamic physiology was gradually superimposed with restrictive physiology, characterized by progressive left atrial enlargement and diastolic dysfunction with preserved systolic function. This phenomenon was absent in WT mice with experimentally induced chronic anemia of similar degree and duration. Restrictive physiology was associated with microscopic cardiomyocyte loss and secondary fibrosis detectable as increased extracellular volume by cardiac-MRI. Ultrastructural mitochondrial changes were consistent with severe chronic hypoxia/ischemia and sarcomere diastolic-length was shortened. Transcriptome analysis revealed up-regulation of genes involving angiogenesis, extracellular-matrix, circadian-rhythm, oxidative stress, and hypoxia, whereas ion-channel transport and cardiac conduction were down-regulated. Indeed, progressive corrected QT prolongation, arrhythmias, and ischemic changes were noted in SCA mice before sudden death. Sudden cardiac death is common in humans with restrictive cardiomyopathies and long QT syndromes. Our findings may thus provide a unifying cardiac pathophysiology that explains the reported cardiac abnormalities and sudden death seen in humans with SCA.
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MESH Headings
- Anemia, Sickle Cell/complications
- Anemia, Sickle Cell/physiopathology
- Animals
- Arrhythmias, Cardiac/etiology
- Arrhythmias, Cardiac/genetics
- Arrhythmias, Cardiac/physiopathology
- Cardiomyopathies/etiology
- Cardiomyopathies/genetics
- Cardiomyopathies/physiopathology
- Death, Sudden, Cardiac/etiology
- Disease Models, Animal
- Electrocardiography/methods
- Gene Expression Profiling
- Heart Failure, Diastolic/etiology
- Heart Failure, Diastolic/genetics
- Heart Failure, Diastolic/physiopathology
- Humans
- Hypertension, Pulmonary/etiology
- Hypertension, Pulmonary/genetics
- Hypertension, Pulmonary/physiopathology
- Mice, Inbred C57BL
- Mice, Knockout
- Mice, Transgenic
- Myocardium/metabolism
- Myocardium/pathology
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Affiliation(s)
- Nihal Bakeer
- Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
| | - Jeanne James
- Division of Cardiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
| | - Swarnava Roy
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
| | - Janaka Wansapura
- Imaging Research Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Department of Physics, University of Colombo, Colombo 03, Sri Lanka
| | | | - John N Lorenz
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, OH 45267
| | - Hanna Osinska
- Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
| | - Kurt Backer
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
| | - Anne-Cecile Huby
- Division of Cardiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
| | - Archana Shrestha
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
| | - Omar Niss
- Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
| | - Robert Fleck
- Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
| | - Charles T Quinn
- Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
| | - Michael D Taylor
- Division of Cardiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
| | - Enkhsaikhan Purevjav
- Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
| | - Bruce J Aronow
- Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
| | - Jeffrey A Towbin
- Division of Cardiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
| | - Punam Malik
- Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;
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23
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Morris CR. New strategies for the treatment of pulmonary hypertension in sickle cell disease : the rationale for arginine therapy. ACTA ACUST UNITED AC 2016; 5:31-45. [PMID: 16409014 DOI: 10.2165/00151829-200605010-00003] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Nitric oxide (NO) is inactivated in sickle cell disease (SCD), while bioavailability of arginine, the substrate for NO synthesis, is diminished. Impaired NO bioavailability represents the central feature of endothelial dysfunction, and is a key factor in the pathophysiology of SCD. Inactivation of NO correlates with the hemolytic rate and is associated with erythrocyte release of cell-free hemoglobin and arginase during hemolysis. Accelerated consumption of NO is enhanced further by the inflammatory environment of oxidative stress that exists in SCD. Based upon its critical role in mediating vasodilation and cell growth, decreased NO bioavailability has also been implicated in the pathogenesis of pulmonary arterial hypertension (PHT). Secondary PHT is a common life-threatening complication of SCD that also occurs in most hereditary and chronic hemolytic disorders. Aberrant arginine metabolism contributes to endothelial dysfunction and PHT in SCD, and is strongly associated with prospective patient mortality. The central mechanism responsible for this metabolic disorder is enhanced arginine turnover, occurring secondary to enhanced plasma arginase activity. This is consistent with a growing appreciation of the role of excessive arginase activity in human diseases, including asthma and PHT. Decompartmentalization of hemoglobin into plasma consumes endothelial NO and thus drives a metabolic requirement for arginine, whose bioavailability is further limited by arginase activity. New treatments aimed at maximizing both arginine and NO bioavailability through arginase inhibition, suppression of hemolytic rate, or oral arginine supplementation may represent novel therapeutic strategies.
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Affiliation(s)
- Claudia R Morris
- Department of Emergency Medicine, Children’s Hospital and Research Center at Oakland, Oakland, California, USA
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24
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Charlot K, Moeckesch B, Jumet S, Romana M, Waltz X, Divialle-Doumdo L, Hardy-Dessources MD, Petras M, Tressières B, Pichon A, Tarer V, Hue O, Etienne-Julan M, Antoine-Jonville S, Connes P. Physical activity level is not a determinant of autonomic nervous system activity and clinical severity in children/adolescents with sickle cell anemia: A pilot study. Pediatr Blood Cancer 2015; 62:1962-7. [PMID: 25989908 DOI: 10.1002/pbc.25604] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Accepted: 04/28/2015] [Indexed: 11/08/2022]
Abstract
BACKGROUND Autonomic nervous system (ANS) activity has been suggested to modulate the clinical severity of sickle cell anemia (SCA) by increasing the risk for vaso-occlusive events. Regular physical activity (PA) is known to improve ANS activity and health status in several cardiovascular and metabolic diseases. Whether regular PA improves the health status of SCA patients remains unknown. PROCEDURE Twenty-two patients with SCA and 15 healthy (AA) children/adolescents participated to the study. Heart rate variability was measured in supine position and after a tilt-test to quantify the ANS activity. PA energy expenditure (PAEE) was assessed with questionnaire. RESULTS 1) PAEE was lower in SCA compared to AA (190 ± 152 vs. 432 ± 277 kcal · d(-1), respectively, P < 0.01), 2) overall ANS activity was lower in SCA compared to AA, 3) parasympathetic withdrawal was observed in SCA with aging, 4) ANS reactivity was slightly impaired in SCA compared to AA (reduction in HFnu: -38 ± 27 vs. -58 ± 14%, respectively, P < 0.05), 5) ANS indices, PAEE, and rates of clinical events were not correlated. CONCLUSION Both the level of PA and ANS activity are reduced in SCA compared to AA children/adolescents, particularly in those older than 15 years. Neither PAEE, nor ANS activity seem to influence the clinical severity of children/adolescents with SCA.
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Affiliation(s)
- Keyne Charlot
- UMR Inserm U1134, French West Indies and Guiana University, Pointe-à-Pitre, Guadeloupe, France.,Laboratory ACTES (EA 3596), Department of Physiology, French West Indies and Guiana University, Pointe-à-Pitre, Guadeloupe, France.,Laboratoire d'Excellence du Globule Rouge (LABEX GR-Ex) PRES Sorbonne, Paris, France
| | - Berenike Moeckesch
- UMR Inserm U1134, French West Indies and Guiana University, Pointe-à-Pitre, Guadeloupe, France.,Laboratory ACTES (EA 3596), Department of Physiology, French West Indies and Guiana University, Pointe-à-Pitre, Guadeloupe, France.,Laboratoire d'Excellence du Globule Rouge (LABEX GR-Ex) PRES Sorbonne, Paris, France
| | - Stéphane Jumet
- Laboratory ACTES (EA 3596), Department of Physiology, French West Indies and Guiana University, Pointe-à-Pitre, Guadeloupe, France
| | - Marc Romana
- UMR Inserm U1134, French West Indies and Guiana University, Pointe-à-Pitre, Guadeloupe, France.,Laboratoire d'Excellence du Globule Rouge (LABEX GR-Ex) PRES Sorbonne, Paris, France
| | - Xavier Waltz
- UMR Inserm U1134, French West Indies and Guiana University, Pointe-à-Pitre, Guadeloupe, France.,Laboratory ACTES (EA 3596), Department of Physiology, French West Indies and Guiana University, Pointe-à-Pitre, Guadeloupe, France.,Laboratoire d'Excellence du Globule Rouge (LABEX GR-Ex) PRES Sorbonne, Paris, France
| | - Lydia Divialle-Doumdo
- Sickle Cell Center, Academic Hospital of Pointe-à-Pitre, Pointe-à-Pitre, Guadeloupe, France
| | - Marie-Dominique Hardy-Dessources
- UMR Inserm U1134, French West Indies and Guiana University, Pointe-à-Pitre, Guadeloupe, France.,Laboratoire d'Excellence du Globule Rouge (LABEX GR-Ex) PRES Sorbonne, Paris, France
| | - Marie Petras
- Sickle Cell Center, Academic Hospital of Pointe-à-Pitre, Pointe-à-Pitre, Guadeloupe, France
| | - Benoît Tressières
- Centre Investigation Clinique Antilles Guyane 1424 Inserm, Academic Hospital of Pointe-à-Pitre, Pointe-à-Pitre, Guadeloupe, France
| | - Aurélien Pichon
- Laboratory MOVE, EA6314, University of Poitiers, Poitiers, France
| | - Vanessa Tarer
- Sickle Cell Center, Academic Hospital of Pointe-à-Pitre, Pointe-à-Pitre, Guadeloupe, France
| | - Olivier Hue
- Laboratory ACTES (EA 3596), Department of Physiology, French West Indies and Guiana University, Pointe-à-Pitre, Guadeloupe, France
| | - Maryse Etienne-Julan
- Sickle Cell Center, Academic Hospital of Pointe-à-Pitre, Pointe-à-Pitre, Guadeloupe, France
| | - Sophie Antoine-Jonville
- Laboratory ACTES (EA 3596), Department of Physiology, French West Indies and Guiana University, Pointe-à-Pitre, Guadeloupe, France
| | - Philippe Connes
- UMR Inserm U1134, French West Indies and Guiana University, Pointe-à-Pitre, Guadeloupe, France.,Laboratoire d'Excellence du Globule Rouge (LABEX GR-Ex) PRES Sorbonne, Paris, France.,Institut Universitaire de France (IUF), Paris, France.,Laboratory CRIS EA647, Section Vascular Biology and Red Blood Cell, University of Lyon, Lyon, France
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25
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Chalacheva P, Kato RM, Sangkatumvong S, Detterich J, Bush A, Wood JC, Meiselman H, Coates TD, Khoo MCK. Autonomic responses to cold face stimulation in sickle cell disease: a time-varying model analysis. Physiol Rep 2015; 3:3/7/e12463. [PMID: 26177958 PMCID: PMC4552538 DOI: 10.14814/phy2.12463] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Accepted: 06/24/2015] [Indexed: 11/24/2022] Open
Abstract
Sickle cell disease (SCD) is characterized by sudden onset of painful vaso-occlusive crises (VOC), which occur on top of the underlying chronic blood disorder. The mechanisms that trigger VOC remain elusive, but recent work suggests that autonomic dysfunction may be an important predisposing factor. Heart-rate variability has been employed in previous studies, but the derived indices have provided only limited univariate information about autonomic cardiovascular control in SCD. To circumvent this limitation, a time-varying modeling approach was applied to investigate the functional mechanisms relating blood pressure (BP) and respiration to heart rate and peripheral vascular resistance in healthy controls, untreated SCD subjects and SCD subjects undergoing chronic transfusion therapy. Measurements of respiration, heart rate, continuous noninvasive BP and peripheral vascular resistance were made before, during and after the application of cold face stimulation (CFS), which perturbs both the parasympathetic and sympathetic nervous systems. Cardiac baroreflex sensitivity estimated from the model was found to be impaired in nontransfused SCD subjects, but partially restored in SCD subjects undergoing transfusion therapy. Respiratory-cardiac coupling gain was decreased in SCD and remained unchanged by chronic transfusion. These results are consistent with autonomic dysfunction in the form of impaired parasympathetic control and sympathetic overactivity. As well, CFS led to a significant reduction in vascular resistance baroreflex sensitivity in the nontransfused SCD subjects but not in the other groups. This blunting of the baroreflex control of peripheral vascular resistance during elevated sympathetic drive could be a potential factor contributing to the triggering of VOC in SCD.
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Affiliation(s)
- Patjanaporn Chalacheva
- Department of Biomedical Engineering, Viterbi School of Engineering University of Southern California, Los Angeles, California, USA
| | - Roberta M Kato
- Department of Pediatrics, Children's Hospital of Los Angeles, Los Angeles, California, USA
| | - Suvimol Sangkatumvong
- Department of Biomedical Engineering, Viterbi School of Engineering University of Southern California, Los Angeles, California, USA
| | - Jon Detterich
- Department of Pediatrics, Children's Hospital of Los Angeles, Los Angeles, California, USA
| | - Adam Bush
- Department of Biomedical Engineering, Viterbi School of Engineering University of Southern California, Los Angeles, California, USA
| | - John C Wood
- Department of Pediatrics, Children's Hospital of Los Angeles, Los Angeles, California, USA
| | - Herbert Meiselman
- Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Thomas D Coates
- Department of Pediatrics, Children's Hospital of Los Angeles, Los Angeles, California, USA
| | - Michael C K Khoo
- Department of Biomedical Engineering, Viterbi School of Engineering University of Southern California, Los Angeles, California, USA
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26
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Koonrungsesomboon N, Tantiworawit A, Phrommintikul A, Saekho S, Srichairattanakool S, Chattipakorn N. Heart Rate Variability for Early Detection of Iron Overload Cardiomyopathy in β-Thalassemia Patients. Hemoglobin 2015; 39:281-6. [PMID: 26029793 DOI: 10.3109/03630269.2015.1043059] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Iron overload cardiomyopathy remains the major cause of death in β-thalassemia (β-thal). Conventional routine screening parameters such as serum ferritin and echocardiogram (ECG) do not permit early detection of this condition. Although non-transferrin-bound iron (NTBI) is a reliable indicator for iron overload, it is still not universally available. Recently, heart rate variability (HRV), representing cardiac autonomic function, was found to be depressed in thalassemia patients. We hypothesized that HRV can be used for early detection of iron overload cardiomyopathy. Fifty patients (aged 29 ± 11 years; 31 females and 19 males) with β-thal were enrolled. The 24-hour Holter monitoring for HRV, serum ferritin, NTBI, hematological values and ECG were performed for each patient. Of the 50 patients, 29 carried β-thal major (β-TM). Non-transferrin-bound iron was weakly correlated to all time-domain HRV parameters. Low- and high-frequency domain HRV parameters were also inversely weakly correlated with NTBI. Neither HRV nor NTBI was correlated with serum ferritin. With its weak but significant correlation with NTBI, HRV may be considered to be used as a potential indicator of an iron overload condition and an early marker of cardiac involvement in patients with β-thal.
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Affiliation(s)
- Nut Koonrungsesomboon
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University , Chiang Mai , Thailand
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27
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Alvarado AM, Ward KM, Muntz DS, Thompson AA, Rodeghier M, Fernhall B, Liem RI. Heart rate recovery is impaired after maximal exercise testing in children with sickle cell anemia. J Pediatr 2015; 166:389-93.e1. [PMID: 25477159 PMCID: PMC4308440 DOI: 10.1016/j.jpeds.2014.10.064] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Revised: 09/18/2014] [Accepted: 10/23/2014] [Indexed: 01/22/2023]
Abstract
OBJECTIVE To examine heart rate recovery (HRR) as an indicator of autonomic nervous system dysfunction after maximal exercise testing in children and young adults with sickle cell anemia (SCA). STUDY DESIGN Recovery phase heart rate (HR) in the first 5 minutes after maximal exercise testing in 60 subjects with SCA and 30 matched controls without SCA was assessed. The difference between peak HR and HR at both 1-minute (ΔHR1min) and 2-minutes recovery was our primary outcome. RESULTS Compared with controls, subjects with SCA demonstrated significantly smaller mean ΔHR1min (23 beats per minute [bpm], 95% CI 20-26 vs 32 bpm, 95% CI 26-37, P = .006) and the difference between maximal HR and HR at 2 minutes (39 bpm, 95% CI 36-43 vs 48 bpm, 95% CI 42-53, P = .011). Subjects with SCA also showed smaller mean changes in HR from peak HR to 1 minute, from 1 minute to 2 minutes, and from 2 through 5 minutes of recovery by repeated-measures testing. In a multivariable regression model, older age was independently associated with smaller ΔHR1min in subjects with SCA. Cardiopulmonary fitness and hydroxyurea use, however, were not independent predictors of ΔHR1min. CONCLUSIONS Children with SCA demonstrate impaired HRR after maximal exercise. Reduced postexercise HRR in SCA suggests impaired parasympathetic function, which may become progressively worse with age, in this population.
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Affiliation(s)
- Anthony M. Alvarado
- Hematology, Oncology & Stem Cell Transplant, Ann & Robert H. Lurie Children's Hospital of Chicago, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Kendra M. Ward
- Cardiology, Ann & Robert H. Lurie Children's Hospital of Chicago, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Devin S. Muntz
- Hematology, Oncology & Stem Cell Transplant, Ann & Robert H. Lurie Children's Hospital of Chicago, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Alexis A. Thompson
- Hematology, Oncology & Stem Cell Transplant, Ann & Robert H. Lurie Children's Hospital of Chicago, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL
| | | | - Bo Fernhall
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL
| | - Robert I. Liem
- Hematology, Oncology & Stem Cell Transplant, Ann & Robert H. Lurie Children's Hospital of Chicago, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL
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28
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Altunoren O, Dogan E, Sayarlioglu H, Acar G, Yavuz YC, Aydın N, Sahin M, Akkoyun M, Isik IO, Altunoren O. Effect of hemoglobin variability on mortality and some cardiovascular parameters in hemodialysis patients. Ren Fail 2014; 35:819-24. [PMID: 23751144 DOI: 10.3109/0886022x.2013.801270] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND AND OBJECTIVES Most hemodialysis patients show hemoglobin fluctuations between low-normal and high levels. This hemoglobin variability may cause left ventricle hypertrophy and may increase mortality as well. Recently, many studies were designed to evaluate the effect of hemoglobin variability on mortality but results were conflicting. We aimed to investigate the effect of hemoglobin variability on mortality and some cardiovascular parameters in hemodialysis population. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS Hundred and seventy-five prevalent hemodialysis patients classified into three hemoglobin variability groups according to their hemoglobin levels throughout 24 month observation period: Low-Normal, Low-High, Normal-High. Groups were compared in terms of laboratory, demographical data and mortality rates, initial and the end of 24 month echocardiographic data. Initial and last echocardiographic data were compared within groups in terms of left ventricle mass index increase. RESULTS Mortality rates and cardiovascular risk factors such as coronary heart disease, diabetes mellitus and hypertension that may affect mortality were same between three groups. There was no significant difference between three groups in terms of echocardiographic and laboratory parameters. Only Low-High group showed significant increase on left ventricle mass index when initial and last echocardiographic parameters were compared. CONCLUSIONS Consistent with previous studies, we found that most of the patients exhibited hemoglobin variability and our study is consistent with some of the studies that did not find any relationship between hemoglobin variability and mortality. Firstly, in this study based on objective data, it was shown that hemoglobin variability has adverse effect on left ventricle geometry independent from anemia.
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Affiliation(s)
- Orcun Altunoren
- Department of Nephrolory, Faculty of Medicine, Kahramanmaraş Sütçü İmam University, Kahramanmaraş, Turkey.
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29
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Koonrungsesomboon N, Chattipakorn SC, Fucharoen S, Chattipakorn N. Early detection of cardiac involvement in thalassemia: From bench to bedside perspective. World J Cardiol 2013; 5:270-279. [PMID: 24009816 PMCID: PMC3761180 DOI: 10.4330/wjc.v5.i8.270] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Revised: 07/31/2013] [Accepted: 08/06/2013] [Indexed: 02/06/2023] Open
Abstract
Myocardial siderosis is known as the major cause of death in thalassemia major (TM) patients since it can lead to iron overload cardiomyopathy. Although this condition can be prevented if timely effective intensive chelation is given to patients, the mortality rate of iron overload cardiomyopathy still remains high due to late detection of this condition. Various direct and indirect methods of iron assessment, including serum ferritin level, echocardiogram, non-transferrin-bound iron, cardiac magnetic resonance T2*, heart rate variability, and liver biopsy and myocardial biopsy, have been proposed for early detection of cardiac iron overload in TM patients. However, controversial evidence and limitations of their use in clinical practice exist. In this review article, all of these iron assessment methods that have been proposed or used to directly or indirectly determine the cardiac iron status in TM reported from both basic and clinical studies are comprehensively summarized and presented. Since there has been growing evidence in the past decades that cardiac magnetic resonance imaging as well as cardiac autonomic status known as the heart rate variability can provide early detection of cardiac involvement in TM patients, these two methods are also presented and discussed. The existing controversy regarding the assessment of cardiac involvement in thalassemia is also discussed.
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30
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Upadhya B, Ntim W, Brandon Stacey R, Henderson R, Leedy D, O'Brien FX, Knovich MA. Prolongation of QTc intervals and risk of death among patients with sickle cell disease. Eur J Haematol 2013; 91:170-8. [DOI: 10.1111/ejh.12127] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/23/2013] [Indexed: 02/02/2023]
Affiliation(s)
- Bharathi Upadhya
- Cardiology section; Wake Forest University School of Medicine; Winston-Salem; NC
| | | | | | - Rick Henderson
- Cardiology section; Wake Forest University School of Medicine; Winston-Salem; NC
| | - David Leedy
- Hematology and Oncology; Wake Forest University School of Medicine; Winston-Salem; NC
| | - Francis X. O'Brien
- Internal Medicine; Wake Forest University School of Medicine; Winston-Salem; NC; USA
| | - Mary Ann Knovich
- Hematology and Oncology; Wake Forest University School of Medicine; Winston-Salem; NC
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32
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L'Esperance VS, Cox SE, Simpson D, Gill C, Makani J, Soka D, Mgaya J, Kirkham FJ, Clough GF. Peripheral vascular response to inspiratory breath hold in paediatric homozygous sickle cell disease. Exp Physiol 2012; 98:49-56. [PMID: 22660812 PMCID: PMC4463767 DOI: 10.1113/expphysiol.2011.064055] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
New Findings • What is the central question of this study? Autonomic nervous dysfunction is implicated in complications of sickle cell anaemia (SCA). In healthy adults, a deep inspiratory breath hold (IBH) elicits rapid transient SNS- mediated vasoconstriction detectable using Laser Doppler Flux (LDF) assessment of the finger-tip cutaneous micovasculature. • What is the main finding and its importance? We demonstrate significantly increased resting peripheral blood flow and sympathetic activity in African children with SCA compared to sibling controls and increased sympathetic stimulation in response to vasoprovocation with DIG. This study is the first to observe an inverse association between resting peripheral blood flow and haemoglobin oxygen saturation (SpO2). These phenomena may be an adaptive response to the hypoxic exposure in SCA. There is increasing evidence that autonomic dysfunction in adults with homozygous sickle cell (haemoglobin SS) disease is associated with enhanced autonomic nervous system-mediated control of microvascular perfusion. However, it is unclear whether such differences are detectable in children with SS disease. We studied 65 children with SS disease [38 boys; median age 7.2 (interquartile range 5.1–10.6) years] and 20 control children without symptoms of SS disease [8 boys; 8.7 (5.5–10.8) years] and recorded mean arterial blood pressure (ABP) and daytime haemoglobin oxygen saturation (). Cutaneous blood flux at rest (RBF) and during the sympathetically activated vasoconstrictor response to inspiratory breath hold (IBH) were measured in the finger pulp of the non-dominant hand using laser Doppler fluximetry. Local factors mediating flow motion were assessed by power spectral density analysis of the oscillatory components of the laser Doppler signal. The RBF measured across the two study groups was negatively associated with age (r=−0.25, P < 0.0001), ABP (r=−0.27, P= 0.02) and daytime (r=−0.30, P= 0.005). Children with SS disease had a higher RBF (P= 0.005) and enhanced vasoconstrictor response to IBH (P= 0.002) compared with control children. In children with SS disease, higher RBF was associated with an increase in the sympathetic interval (r=−0.28, P= 0.022). The SS disease status, daytime and age explained 22% of the variance in vasoconstrictor response to IBH (P < 0.0001). Our findings suggest that blood flow and blood flow responses in the skin of young African children with SS disease differ from those of healthy control children, with increased resting peripheral blood flow and increased sympathetic stimulation from a young age in SS disease. They further suggest that the laser Doppler flowmetry technique with inspiratory breath hold manoeuvre appears to be robust for use in young children with SS disease, to explore interactions between , ABP and autonomic function with clinical complications, e.g. skin ulceration.
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Affiliation(s)
- Veline S L'Esperance
- Vascular Research Group, Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK
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33
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Voskaridou E, Christoulas D, Terpos E. Sickle-cell disease and the heart: review of the current literature. Br J Haematol 2012; 157:664-73. [DOI: 10.1111/j.1365-2141.2012.09143.x] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Ersi Voskaridou
- Thalassaemia Centre; Laikon General Hospital; Athens; Greece
| | | | - Evangelos Terpos
- Department of Clinical Therapeutics; University of Athens School of Medicine; Athens; Greece
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34
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Selective enhancement of contractions to α1-adrenergic receptor activation in the aorta of mice with sickle cell disease. J Cardiovasc Pharmacol 2012; 57:263-6. [PMID: 21107280 DOI: 10.1097/fjc.0b013e318204bb34] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Sickle cell disease (SCD), the most common inherited hematologic disorder in the United States and the most common single gene disorder in the world, causes substantial morbidity and mortality. The major pathobiologic processes that underlie SCD include vaso-occlusion, inflammation, procoagulant processes, hemolysis, and altered vascular reactivity. The present study examined the vasoactive response to a-adrenergic activation in a murine model of SCD. Isolated aortas from sickle mice as compared with wild-type mice exhibit heightened contractions to norepinephrine and phenylephrine; such responses were completely blocked by an a1-receptor antagonist, prazosin. Aortas from either group exhibited comparable contractile responses to potassium chloride and the thromboxane agonist U46619 and no contractile response to an a2-adrenergic receptor agonist, UK14304. We conclude that there is an exaggerated vasoconstrictive response to a1-receptor agonists in SCD. Because sickle crisis is induced by diverse forms of stress, the latter attended by increased adrenergic activity, our findings may be relevant to the occurrence of sickle crisis. We also suggest that such heightened reactivity may contribute to vaso-occlusive processes that underlie ischemic injury in SCD. Finally, our findings urge caution in the use of phenylephrine in patients with SCD.
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35
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Oguanobi NI, Ejim EC, Anisiuba BC, Onwubere BJC, Ike SO, Ibegbulam OG. Electrocardiographic findings in sickle cell cardiovascular autonomic neuropathy. Clin Auton Res 2012; 22:137-45. [PMID: 22261695 DOI: 10.1007/s10286-011-0156-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2011] [Accepted: 12/13/2011] [Indexed: 01/07/2023]
Abstract
BACKGROUND There is a lack of data on the relationship between cardiovascular autonomic neuropathy (CAN) and electrocardiographic parameters in sickle cell anaemia. AIMS AND OBJECTIVES The purpose of the study was to compare the electrocardiographic findings in adult sickle cell anaemia patients with CAN with those of patients without this complication. METHODS A cross sectional study was done using 62 consecutively recruited sickle cell anaemia patients who met the inclusion criteria for the study. Cardiovascular autonomic dysfunction was determined based on abnormal values in at least two of five non-invasive tests: Valsalva manoeuver, heart rate variation during deep breathing, heart rate response to standing, blood pressure response to sustained hand grip, and blood pressure response to standing. The subjects were subsequently evaluated with electrocardiography. RESULTS Sickle cell anaemia patients with CAN had statistically significantly increased P-wave duration (p < 0.001), PR-interval (p < 0.05) and QTc dispersion (p < 0.05) compared with patients without CAN. Significantly increased frequencies of Q waves and first degree atrio-ventricular block were found in patients with CAN than in those without CAN (p = 0.026, p = 0.014, respectively). Significant correlations were noted between the severity of CAN [number of abnormal autonomic function tests (AFT)] and (1) P-wave duration (p = 0.008), (2) PR- interval (p = 0.013). Significant association was found between the number of abnormal AFT and (1) presence of Q-waves, and (2) degree of anaemia (haematocrit class). CONCLUSION Electrocardiographic features consistent with atrio-ventricular and ventricular repolarization abnormalities are associated with CAN in sickle cell anaemia. Further studies are required to evaluate the prognostic implications of these findings in sickle cell patients with cardiovascular autonomic dysfunction.
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Affiliation(s)
- N I Oguanobi
- Department of Medicine, University of Nigeria Teaching Hospital, Enugu, Nigeria.
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Martins WDA, Lopes HF, Consolim-Colombo FM, Gualandro SDFM, Arteaga-Fernández E, Mady C. Cardiovascular autonomic dysfunction in sickle cell anemia. Auton Neurosci 2012; 166:54-9. [DOI: 10.1016/j.autneu.2011.07.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2011] [Revised: 06/25/2011] [Accepted: 07/28/2011] [Indexed: 10/17/2022]
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Sangkatumvong S, Khoo MCK, Kato R, Detterich JA, Bush A, Keens TG, Meiselman HJ, Wood JC, Coates TD. Peripheral vasoconstriction and abnormal parasympathetic response to sighs and transient hypoxia in sickle cell disease. Am J Respir Crit Care Med 2011; 184:474-81. [PMID: 21616995 DOI: 10.1164/rccm.201103-0537oc] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
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.
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Affiliation(s)
- Suvimol Sangkatumvong
- Biomedical Engineering Department, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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Connes P. Altered Autonomic Nervous System Function in Sickle Cell Disease. Am J Respir Crit Care Med 2011; 184:398-400. [DOI: 10.1164/rccm.201105-0941ed] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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Abstract
BACKGROUND Previous studies of healthy children have indicated a link between autonomic nervous system (ANS) reactivity and health outcomes, but there is limited research on whether ANS reactivity is similar for children with chronic conditions. OBJECTIVE The aim of this study was to determine if ANS reactivity differs for children with sickle cell disease (SCD) compared with a community sample of children without SCD. METHOD In two cross-sectional, descriptive studies, 32 public school children without chronic health problems were compared with 33 children with SCD. The children were 5-8 years old and they completed standardized protocols measuring ANS responses (respiratory sinus arrhythmia and preejection period) during rest and challenge conditions in social, cognitive, sensory, and emotion domains. Reactivity was calculated as the difference between challenge response minus rest for each domain and overall. RESULTS There were differences in the distributions of the samples in parent education and child age, so these variables were adjusted for in subsequent analyses. The community sample showed parasympathetic withdrawal (low respiratory sinus arrhythmia scores) and greater parasympathetic reactivity (low respiratory sinus arrhythmia difference scores and percentage of negative scores) compared with the children with SCD in the social (p < .05) and sensory (p < .05) domains. The children with SCD showed greater sympathetic reactivity (low preejection period difference scores) compared with the community children in the cognitive domain (p < .05), and a greater percentage of children with SCD versus the community children showed negative preejection period difference scores (sympathetic reactivity) in the social domain (p < .05). The community sample, but not the children with SCD, showed changes in respiratory sinus arrhythmia across domains (p < .05). DISCUSSION Children with SCD may display a different pattern of ANS responses to laboratory challenges compared with children without SCD from the same community.
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Nebor D, Bowers A, Hardy-Dessources MD, Knight-Madden J, Romana M, Reid H, Barthélémy JC, Cumming V, Hue O, Elion J, Reid M, Connes P. Frequency of pain crises in sickle cell anemia and its relationship with the sympatho-vagal balance, blood viscosity and inflammation. Haematologica 2011; 96:1589-94. [PMID: 21750084 DOI: 10.3324/haematol.2011.047365] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Recent evidence suggests that autonomic nervous system activity could be involved in the pathophysiology of sickle cell disease, but it is unclear whether differences in autonomic nervous system activity are detectable during steady state in patients with mild and severe disease. The aim of the present study was to compare the autonomic nervous system activity, blood rheology, and inflammation in patients with sickle cell anemia according to the frequency of acute pain crisis. DESIGN AND METHODS Twenty-four healthy volunteers, 20 patients with sickle cell anemia with milder disease, and 15 patients with sickle cell anemia with more severe disease were recruited. Milder disease was defined as having no pain crisis within the previous year. More severe disease was defined as having had within the previous year three or more pain crises which were documented by a physician and required treatment with narcotics. The autonomic nervous system activity was determined by spectral analysis of nocturnal heart rate variability. Blood viscosity determination and measurements of several inflammatory markers (interleukin-6, soluble vascular cell adhesion molecule-1, soluble CD40 ligand and sL-selectin) were made on blood samples collected in steady-state conditions. RESULTS Results showed that: 1) patients who had suffered more frequent pain crises had lower parasympathetic activity and greater sympatho-vagal imbalance than both controls and patients with milder disease. However, when adjusted for age, no significant difference was detected between the two sickle cell anemia patient groups; 2) patients who had suffered more frequent pain crises had higher blood viscosity than patients with milder disease, and this was not dependent on age. CONCLUSIONS Results from the present study indicate that both the autonomic nervous system activity and blood viscosity are impaired in patients with sickle cell anemia exhibiting high frequency of pain crisis in comparison with those who did not experience a crisis within the previous year.
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Rutjanaprom W, Kanlop N, Charoenkwan P, Sittiwangkul R, Srichairatanakool S, Tantiworawit A, Phrommintikul A, Chattipakorn S, Fucharoen S, Chattipakorn N. Heart rate variability in beta-thalassemia patients. Eur J Haematol 2009; 83:483-9. [DOI: 10.1111/j.1600-0609.2009.01314.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Liem RI, Young LT, Thompson AA. Prolonged QTc interval in children and young adults with sickle cell disease at steady state. Pediatr Blood Cancer 2009; 52:842-6. [PMID: 19229972 DOI: 10.1002/pbc.21973] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
BACKGROUND Prolongation of the QTc interval may be more common than previously believed among individuals with sickle cell disease (SCD). The clinical associations and natural history of QTc prolongation remain unclear in this population. Our objectives were to determine the prevalence of prolonged QTc and evaluate its relationship to clinical factors in children and young adults with SCD. PROCEDURES We analyzed data from subjects 10 to 25 years old with SCD enrolled in our pulmonary hypertension screening protocol. Screening included echocardiography (ECHO), 12-lead electrocardiogram (ECG) and laboratory testing at steady state. QTc interval >440 msec was considered prolonged. RESULTS ECG data from 76 subjects (57% male, mean age 14.2 +/- 3 years old, range 10-24) were analyzed. We observed prolonged QTc in 29/76 (38%) subjects. Despite evidence of left ventricular hypertrophy (LVH) in 50/76 (66%) subjects, the frequency of LVH was not significantly different in subjects with and without QTc prolongation. When compared to subjects with normal QTc, subjects with prolonged QTc had higher mean tricuspid regurgitant jet velocity (2.51 +/- 0.27 m/sec vs. 2.33 +/- 0.26 m/sec, P = 0.010) as well as higher mean lactate dehydrogenase (433 +/- 142 IU/L vs. 343 +/- 142 IU/L, P = 0.000) and aspartate aminotransferase (48 +/- 20 IU/L vs. 39 +/- 15 IU/L, P = 0.026). A larger proportion of subjects with prolonged QTc also had a history of recurrent acute chest syndrome (66% vs. 38%, P = 0.038). CONCLUSIONS We conclude that QTc prolongation is a frequent finding in SCD not associated with LVH. Elevated pulmonary pressures, hemolysis and acute chest syndrome may represent risk factors for prolonged QTc in this population.
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Affiliation(s)
- Robert I Liem
- Division of Hematology, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
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Sangkatumvong S, Khoo MCK, Coates TD. Abnormal cardiac autonomic control in sickle cell disease following transient hypoxia. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2009; 2008:1996-9. [PMID: 19163084 DOI: 10.1109/iembs.2008.4649581] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Abnormalities in autonomic control in sickle cell anemia (SCA) patients have been reported by multiple researchers. However their potential causal association with sickle cell crisis remains unknown. We employed hypoxia, a known trigger to sickle cell crisis, to perturb the autonomic systems of the subjects. Cardiac autonomic control was non-invasively assessed by tracking the changes in heart rate variability (HRV) that occur following brief exposure to a hypoxia stimulus. Time varying spectral analysis of HRV was applied to estimate the cardiac autonomic response to the transient episode of hypoxia. The results demonstrate that cardiovascular autonomic response to hypoxia is substantially more sensitive in SCA than in normal controls. We also developed a model to compensate for the confounding effects of respiration on the HRV spectral indices by using the corresponding respiration signal to compensate for the respiratory correlated part of the HRV. This technique improved the resolution with which the effect of hypoxia on changes in HRV could be measured.
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Affiliation(s)
- Suvimol Sangkatumvong
- Biomedical Engineering Department, University of Southern California, Los Angeles, CA 90089, USA.
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Inamo J, Connes P, Barthélémy JC, Dan V, Coates T, Loko G. Pulmonary hypertension does not affect the autonomic nervous system dysfunction of sickle cell disease. Am J Hematol 2009; 84:311-2. [PMID: 19260125 DOI: 10.1002/ajh.21377] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Abstract
Asthma is a common comorbidity in sickle cell disease (SCD) with a reported prevalence of 30-70%. The high frequency of asthma in this population cannot be attributed to genetic predisposition alone, and likely reflects in part, the contribution of overlapping mechanisms shared between these otherwise distinct disorders. There is accumulating evidence that dysregulated arginine metabolism and in particular, elevated arginase activity contributes to pulmonary complications in SCD. Derangements of arginine metabolism are also emerging as newly appreciated mechanism in both asthma and pulmonary hypertension independent of SCD. Patients with SCD may potentially be at risk for an asthma-like condition triggered or worsened by hemolysis-driven release of erythrocyte arginase and low nitric oxide bioavailability, in addition to classic familial asthma. Mechanisms that contributed to asthma are complex and multifactorial, influenced by genetic polymorphisms as well as environmental and infectious triggers. Given the association of asthma with inflammation, oxidative stress and hypoxemia, factors known to contribute to a vasculopathy in SCD, and the consequences of these factors on sickle erythrocytes, comorbid asthma would likely contribute to a vicious cycle of sickling and subsequent complications of SCD. Indeed a growing body of evidence documents what should come as no surprise: Asthma in SCD is associated with acute chest syndrome, stroke, pulmonary hypertension, and early mortality, and should therefore be aggressively managed based on established National Institutes of Health Guidelines for asthma management. Barriers to appropriate asthma management in SCD are discussed as well as strategies to overcome these obstacles in order to provide optimal care.
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Affiliation(s)
- Claudia R Morris
- Department of Emergency Medicine, Children's Hospital and Research Center Oakland, Oakland, California 94609, USA.
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Kim YS, Nur E, van Beers EJ, Truijen J, Davis SCAT, Biemond BJ, van Lieshout JJ. Dynamic cerebral autoregulation in homozygous Sickle cell disease. Stroke 2009; 40:808-14. [PMID: 19150866 DOI: 10.1161/strokeaha.108.531996] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND AND PURPOSE Sickle cell disease (SCD) is associated with cerebral hyperperfusion and an increased risk of stroke. Also, both recurrent microvascular obstruction and chronic hemolysis affect endothelial function, potentially interfering with systemic and cerebral blood flow control. We addressed the question whether cerebrovascular control in patients with SCD is affected and related to hemolysis. METHODS Systemic and cerebrovascular control were studied in 18 patients with SCD and 10 healthy subjects. Dynamic cerebral autoregulation was evaluated by transfer function analysis assessing the relationship between mean cerebral blood flow velocity and mean arterial pressure. RESULTS Normal baroreflex sensitivity and postural cardiovascular reflex responses indicated integrity of systemic cardiovascular control. In the low- (0.07 to 0.15 Hz) frequency region, mean arterial pressure variability was comparable for both groups, but a larger mean cerebral blood flow velocity variability in SCD (6.1 [4.6 to 7.0] versus 4.2 [2.6 to 5.2] [cm x s(-1)](2) x Hz(-1); P<0.05) indicated a reduced capacity to buffer the transfer of blood pressure surges to the cerebral tissue. Impairment of dynamic cerebrovascular control was confirmed by a reduced mean arterial pressure-to-mean cerebral blood flow velocity transfer function phase lead in SCD versus healthy subjects (32+/-17 degrees versus 50+/-19 degrees , P<0.05) that was unrelated to the severity of hemolysis. CONCLUSIONS In patients with SCD, dynamic cerebral autoregulation is impaired but appears unrelated to hemolysis.
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Affiliation(s)
- Yu-Sok Kim
- Department of Internal Medicine, AMC Center for Heart Failure Research, Academic Medical Center, Amsterdam, The Netherlands
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Jaja S, Kehinde M, Ogungbemi S. Cardiac and autonomic responses to change in posture or vitamin C supplementation in sickle cell anemia subjects. PATHOPHYSIOLOGY 2008; 15:25-30. [DOI: 10.1016/j.pathophys.2007.12.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2007] [Revised: 12/07/2007] [Accepted: 12/08/2007] [Indexed: 10/22/2022] Open
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Sangkatumvong S, Coates TD, Khoo MCK. Abnormal autonomic cardiac response to transient hypoxia in sickle cell anemia. Physiol Meas 2008; 29:655-68. [PMID: 18460753 DOI: 10.1088/0967-3334/29/5/010] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The objective of this study was to non-invasively assess cardiac autonomic control in subjects with sickle cell anemia (SCA) by tracking the changes in heart rate variability (HRV) that occur following brief exposure to a hypoxic stimulus. Five African-American SCA patients and seven healthy control subjects were recruited to participate in this study. Each subject was exposed to a controlled hypoxic stimulus consisting of five breaths of nitrogen. Time-varying spectral analysis of HRV was applied to estimate the cardiac autonomic response to the transient episode of hypoxia. The confounding effects of changes in respiration on the HRV spectral indices were reduced by using a computational model. A significant decrease in the parameters related to parasympathetic control was detected in the post-hypoxic responses of the SCA subjects relative to normal controls. The spectral index related to sympathetic activity, on the other hand, showed a tendency to increase the following hypoxic stimulation, but the change was not significant. This study suggests that there is some degree of cardiovascular autonomic dysfunction in SCA that is revealed by the response to transient hypoxia.
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Affiliation(s)
- S Sangkatumvong
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA
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Brunelli SM, Joffe MM, Israni RK, Yang W, Fishbane S, Berns JS, Feldman HI. History-adjusted marginal structural analysis of the association between hemoglobin variability and mortality among chronic hemodialysis patients. Clin J Am Soc Nephrol 2008; 3:777-82. [PMID: 18337553 PMCID: PMC2386696 DOI: 10.2215/cjn.04281007] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2007] [Accepted: 02/01/2008] [Indexed: 11/23/2022]
Abstract
BACKGROUND AND OBJECTIVES Hemoglobin variability is common among dialysis patients, and has been associated with increased mortality. The causal nature of this association has been difficult to ascertain because of potential time-dependent confounding, for which traditional statistical methods do not control. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS A retrospective cohort of 34,963 Fresenius Medical care dialysis patients from 1996 was assembled. Hemoglobin variability, absolute hemoglobin level, and temporal hemoglobin trend were measured over rolling 6-mo exposure windows. Their association with mortality was estimated using history-adjusted marginal structural analysis that adjusts for time-dependent confounding by applying weights to observations inversely related to the predictability of observed levels of hemoglobin. RESULTS In the primary analysis, each g/dl increase in hemoglobin variability was associated with an adjusted hazard ratio (HR) [95% confidence interval (CI)] for all-cause mortality of 1.93 (1.20 to 3.10). Neither higher absolute hemoglobin level nor increasing hemoglobin trend were significantly associated with mortality; adjusted HR (95% CI) 0.85 (0.64 to 1.11) and 0.60 (0.25 to 1.45), respectively. CONCLUSIONS Marginal structural analysis demonstrates that hemoglobin variability is associated with increased mortality among chronic hemodialysis patients, and that this effect is more pronounced than appreciated using standard statistical techniques that do not take time-dependent confounding into account.
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Affiliation(s)
- Steven M Brunelli
- Renal, Electrolyte and Hypertension Division of the Department of Medicine, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
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Fontaine JM, Ofili EO, Adenaike MB, VanDecker W, Julian Haywood L. Clinical Assessment of the Risk for Sudden Cardiac Death in Patients with Sickle Cell Anemia. J Natl Med Assoc 2008; 100:360-8. [DOI: 10.1016/s0027-9684(15)31268-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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