ABSTRACT
Although sickle cell disease (SCD) patients carry both significant left atrial (LA) remodeling and increased risk of stroke, the prevalence of atrial arrhythmia (AA) has never been prospectively evaluated. This study aims to investigate the prevalence and predictors of atrial arrhythmia in homozygous SCD (SCA). From 2019 to 2022, 130 patients with SCA were referred to the physiology department to specifically analyze cardiac function and prospectively included in the DREPACOEUR registry. They underwent a 24-hour electrocardiogram monitoring (24h-Holter), transthoracic echocardiography, and laboratory tests on the same day. The primary endpoint was the occurrence of AA, defined by the presence of excessive supraventricular ectopic activity (ESVEA) on ECG-Holter (i.e., >720 premature atrial contractions [PACs] or any run ≥ 20 PACs), recent history of paroxysmal atrial fibrillation (AF), or persistent AF. The mean patient age was 45±12 years and 48% of male. Overall, AA was found in 34 (26%) patients. Age (52±9 vs. 42±12 years, P=0.002), LA dilation (LAVi, 71±24 vs. 52±14 ml/m², P<0.001) and history of stroke without underlying cerebral vasculopathy or other defined cause (26% vs. 5%, P=0.009, OR=6.6 [1.4; 30.3]) were independently associated with AA. Age and LAVi correlated with PAC load per 24 hours on ECG-Holter (R=0.56 and 0.33, P<0.001 respectively) and an age over 47 years or a LAVi >55mL/m² could predict AA with a PPV of 33% and a NPV of 92%. AAs are frequent in SCA patients and increase with age and LA remodeling, leading to a major additional risk factor for ischemic stroke. This study provides arguments and means to early screen for AA potentially preventing cerebral complications.
ABSTRACT
Voxelotor (GBT440, OXBRYTA®) appeared recently as one of the possible treatments for sickle cell disease. This molecule, by binding the alpha globin of hemoglobin, causes hyperaffinity of the latter for oxygen and reduces its polymerization properties. Several therapeutic trials have been able to show its effectiveness on certain aspects of sickle cell disease; thus, the french HAS (High Authority of Health) college issued an early access authorization and, since 2021, this treatment can be offered to patients under a temporary authorization for use. Consequently, the laboratories that carry out the biological monitoring of sickle cell patients will be confronted with new profiles characteristic of the presence of hemoglobin combined with GBT440. This work presents a collection of images obtained by different techniques: HPLC, capillary electrophoresis, isoelectrofocusing, alkaline gel and acid agar gel electrophoresis in transfused or non-transfused sickle cell disease patients. The ability to observe the presence of GBT440 by these analyzes could be useful in order to characterize the therapeutic follow-up of patients.
Subject(s)
Anemia, Sickle Cell , Hemoglobin, Sickle , Humans , Hemoglobin, Sickle/chemistry , Hemoglobin, Sickle/metabolism , Hemoglobin, Sickle/therapeutic use , Hemoglobins/metabolism , Anemia, Sickle Cell/diagnosis , Anemia, Sickle Cell/therapy , Benzaldehydes/adverse effectsABSTRACT
BACKGROUND: Cerebral vasculopathy can induce chronic cerebral hypoperfusion leading to stroke in patients with sickle cell disease (SCD) and is treated by blood exchange transfusion (BET). However, no prospective clinical study has demonstrated the benefit of BET in adults with SCD and cerebral vasculopathy. Near Infrared Spectroscopy (NIRS) is a recent non-invasive method complementary to Magnetic Resonance Imaging (MRI). We evaluated cerebral perfusion using NIRS during erythracytapheresis in patients with SCD with and without steno-occlusive arterial disease. METHODS: We conducted a monocentric, prospective study in 16 adults with SCD undergoing erythracytapheresis in 2014. Among them, 10 had cerebral steno-occlusive arterial disease. NIRS measured the relative amounts of oxyhemoglobin (OxyHb), deoxyhemoglobin (DeoxyHb) and total hemoglobin (Total Hb) in brain tissue and in muscle. RESULTS: In cerebral hemispheres associated with steno-occlusive arterial disease, we observed a significant increase of OxyHb and Total Hb during BET, without modification of DeoxyHb. CONCLUSION: Using NIRS during BET showed that BET improves cerebral perfusion in adult patients with SCD with cerebral vasculopathy.
Subject(s)
Lymphohistiocytosis, Hemophagocytic , Lymphoma, Extranodal NK-T-Cell , Lymphoma, T-Cell , Nose Neoplasms , Humans , Janus Kinase 3 , Killer Cells, Natural/pathology , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/etiology , Lymphohistiocytosis, Hemophagocytic/pathology , Lymphoma, T-Cell/complications , Lymphoma, T-Cell/genetics , Lymphoma, T-Cell/pathology , Nose Neoplasms/pathologyABSTRACT
Sickle cell disease (SCD) is characterised by chronic haemolysis and oxidative stress. Herein, we investigated 30 SCD patients and found 40% with elevated mitochondria levels (SS-mito+ ) in their mature red blood cells, while 60% exhibit similar mitochondria levels compared to the AA group (SS-mito- ). The SS-mito+ patients are characterised by higher reticulocytosis and total bilirubin levels, lower foetal haemoglobin, and non-functional mitochondria. Interestingly, we demonstrated decreased levels of mitophagy inducers, PINK1 and NIX, and higher levels of HSP90 chaperone in their red cells. Our results highlighted for the first time an abnormal retention of mitochondria in SCD linked with mitophagy-related proteins.
Subject(s)
Anemia, Sickle Cell/blood , Erythrocytes/metabolism , Mitochondria/metabolism , Mitophagy , Adult , Anemia, Sickle Cell/pathology , Bilirubin/blood , Erythrocytes/pathology , Female , HSP90 Heat-Shock Proteins/metabolism , Humans , Male , Membrane Proteins/metabolism , Mitochondria/pathology , Protein Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Reticulocytosis , Tumor Suppressor Proteins/metabolismABSTRACT
Translocator protein (TSPO) and voltage dependent anion channels (VDAC) are two proteins forming a macromolecular complex in the outer mitochondrial membrane that is involved in pleiotropic functions. Specifically, these proteins were described to regulate the clearance of damaged mitochondria by selective mitophagy in non-erythroid immortalized cell lines. Although it is well established that erythroblast maturation in mammals depends on organelle clearance, less is known about mechanisms regulating this clearance throughout terminal erythropoiesis. Here, we studied the effect of TSPO1 downregulation and the action of Ro5-4864, a drug ligand known to bind to the TSPO/VDAC complex interface, in ex vivo human terminal erythropoiesis. We found that both treatments delay mitochondrial clearance, a process associated with reduced levels of the PINK1 protein, which is a key protein triggering canonical mitophagy. We also observed that TSPO1 downregulation blocks erythroblast maturation at the orthochromatic stage, decreases the enucleation rate, and increases cell death. Interestingly, TSPO1 downregulation does not modify reactive oxygen species (ROS) production nor intracellular adenosine triphosphate (ATP) levels. Ro5-4864 treatment recapitulates these phenotypes, strongly suggesting an active role of the TSPO/VDAC complex in selective mitophagy throughout human erythropoiesis. The present study links the function of the TSPO/VDAC complex to the PINK1/Parkin-dependent mitophagy induction during terminal erythropoiesis, leading to the proper completion of erythroid maturation.
Subject(s)
Cell Nucleus/metabolism , Down-Regulation , Erythropoiesis , Mitochondria/metabolism , Mitophagy , Receptors, GABA/metabolism , Benzodiazepinones/pharmacology , Cell Differentiation/drug effects , Cell Nucleus/drug effects , Down-Regulation/drug effects , Erythropoiesis/drug effects , Humans , Kinetics , Mitochondria/drug effects , Mitophagy/drug effects , Phenotype , RNA, Small Interfering/metabolismABSTRACT
Gaucher disease (GD) is a genetic disease with mutations in the GBA gene that encodes glucocerebrosidase causing complications such as anaemia and bone disease. GD is characterized by accumulation of the sphingolipids (SL) glucosylceramide (GL1), glucosylsphingosine (Lyso-GL1), sphingosine (Sph) and sphingosine-1-phosphate (S1P). These SL are increased in the plasma of GD patients and the associated complications have been attributed to the accumulation of lipids in macrophages. Our recent findings indicated that red blood cells (RBCs) and erythroid progenitors may play an important role in GD pathophysiology. RBCs abnormalities and dyserythropoiesis have been observed in GD patients. Moreover, we showed higher SL levels in the plasma and in RBCs from untreated GD patients compared with controls. In this study, we quantified SL in 16 untreated GD patients and 15 patients treated with enzyme replacement therapy. Our results showed that the treatment significantly decreases SL levels in the plasma and RBCs. The increased SL content in RBCs correlates with abnormal RBC properties and with markers of disease activity. Because RBCs lack glucocerebrosidase activity, we investigated how lipid overload could occur in these cells. Our results suggested that SL overload in RBCs occurs both during erythropoiesis and during its circulation in the plasma.
Subject(s)
Erythrocytes/metabolism , Gaucher Disease/blood , Glucosylceramidase/genetics , Sphingolipids/blood , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers/blood , Child , Child, Preschool , Erythropoiesis/genetics , Female , Gaucher Disease/genetics , Gaucher Disease/pathology , Humans , Lysophospholipids/blood , Macrophages/metabolism , Male , Middle Aged , Psychosine/analogs & derivatives , Psychosine/blood , Sphingosine/analogs & derivatives , Sphingosine/blood , Young AdultABSTRACT
A man experienced pain in the right hemithorax 6 months after a first-line therapy for multiple myeloma (MM). FDG PET/CT showed a large extramedullary extent in the right hemithorax, which was biopsy proven. During the second-line treatment, FDG PET/CT showed no response as well as a suspected myocardium spread, a rare extramedullary location in MM. F-Fluorocholine PET/CT and then MRI confirmed myocardium lesions. This case confirms that F-fluorocholine PET/CT is able to detect MM recurrence and may be used to complete FDG PET/CT in difficult cases such as suspicion of cardiac MM.
Subject(s)
Choline/analogs & derivatives , Fluorodeoxyglucose F18 , Heart/diagnostic imaging , Multiple Myeloma/diagnostic imaging , Positron Emission Tomography Computed Tomography , Biopsy , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Multiple Myeloma/pathologyABSTRACT
Black people are at increased risk of thrombotic thrombocytopenic purpura (TTP). Whether clinical presentation of TTP in Black patients has specific features is unknown. We assessed here differences in TTP presentation and outcome between Black and White patients. Clinical presentation was comparable between both ethnic groups. However, prognosis differed with a lower death rate in Black patients than in White patients (2.7% versus 11.6%, respectively, P = .04). Ethnicity, increasing age and neurologic involvement were retained as risk factors for death in a multivariable model (P < .05 all). Sixty-day overall survival estimated by the Kaplan-Meier curves and compared with the Log-Rank test confirmed that Black patients had a better survival than White patients (P = .03). Salvage therapies were similarly performed between both groups, suggesting that disease severity was comparable. The comparison of HLA-DRB1*11, -DRB1*04 and -DQB1*03 allele frequencies between Black patients and healthy Black individuals revealed no significant difference. However, the protective allele against TTP, HLA-DRB1*04, was dramatically decreased in Black individuals in comparison with White individuals. Black people with TTP may have a better survival than White patients despite a comparable disease severity. A low natural frequency of HLA-DRB1*04 in Black ethnicity may account for the greater risk of TTP in this population.
Subject(s)
Black People/genetics , Black or African American/genetics , Purpura, Thrombotic Thrombocytopenic/ethnology , Purpura, Thrombotic Thrombocytopenic/genetics , Adult , Alleles , Female , Gene Frequency , HLA-DQ beta-Chains/genetics , HLA-DRB1 Chains/genetics , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Purpura, Thrombotic Thrombocytopenic/mortality , Registries , Risk Factors , Treatment Outcome , White People/geneticsABSTRACT
Second-generation tyrosine kinase inhibitors (TKI2) often induce molecular remission, and prolonged survival with a better tolerance in imatinib-resistant chronic myelogenous leukaemia (CML) patients. We report the case of a CML in first chronic phase who was diagnosed in August 2003 in a young 24 year-old Caucasian woman. Our patient received first imatinib and then dasatinib and nilotinib. Imatinib was well tolerated and she developed TTP/HUS on dasatinib without documented evolution of CML and finally obtained MR5.0 with nilotinib and without any side effect. This case also illustrates the absence of cross-resistance and side-effects between the different TKIs and the feasibility of kidney transplantation associated with a nilotinib treatment of CML allowing a continuing MR5.0 and no further side effects.