The first in-human study to evaluate the antiplatelet properties of the clopidogrel conjugate DT-678 in acute coronary syndrome patients and healthy volunteers.

Background And Purpose: DT-678 is a novel antiplatelet prodrug, capable of releasing the antiplatelet active metabolite of clopidogrel (AM) upon exposure to glutathione. In this study, we investigated factors responsible for clopidogrel high on-treatment platelet reactivity (HTPR) in acute coronary syndrome (ACS) patients and evaluated the capacity of DT-678 to overcome HTPR.

Experimental Approach: A total of 300 consecutive ACS patients naive to P2Y receptor inhibitors were recruited and genotyped for CYP2C19 alleles.

Inhibition of sodium-glucose cotransporter-2 improves anaemia in mice and humans with sickle cell disease, and reduces infarct size in a murine stroke model.

Sodium-glucose cotransporter-2 (SGLT-2) is expressed in the kidney and may contribute to anaemia and cardiovascular diseases. The effect of SGLT-2 inhibition on anaemia and vascular endpoints in sickle cell disease (SCD) is unknown. A murine model of SCD was studied to determine the effects of the SGLT-2 inhibitor, empagliflozin, on anaemia and stroke size.

Resolution of Sickle Cell Crisis Following Administration of Amiodarone.

Unlabelled: Sickle cell disease is a prevalent hematologic condition, but some of the factors that lead to erythrocyte sickling are not fully known. A 58-year-old male patient with a history of sickle cell disease (SCD) and paroxysmal atrial fibrillation was transferred from an outside hospital for further management of refractory sickle cell crisis with acute chest syndrome. Before transfer, the patient received antibiotics and multiple packed red blood cell (pRBC) transfusions, with minimal effect on symptoms or anemia.

Beta1-receptor blockade attenuates atherosclerosis progression following traumatic brain injury in apolipoprotein E deficient mice.

Traumatic brain injury (TBI) is associated with cardiovascular mortality in humans. Enhanced sympathetic activity following TBI may contribute to accelerated atherosclerosis. The effect of beta1-adrenergic receptor blockade on atherosclerosis progression induced by TBI was studied in apolipoprotein E deficient mice.

Amiodarone improves anemia in a murine model of sickle cell disease and is associated with increased erythrocyte bis(monoacylglycerol) phosphate.

Sickle cell disease (SCD) is associated with altered plasma and erythrocyte lipid profiles. In a previous study, SCD mice with deficiency of proprotein convertase subtilisin/kexin type 9 (PCSK9) were observed to have more severe anemia and increased sickling compared to control SCD mice. Although PCSK9 affects circulating low density lipoprotein (LDL) by regulation of the LDL receptor, the effect of PCSK9 on anemia was independent of LDL receptor expression.

Interleukin-1 receptor antagonism leads to improved anaemia in a murine model of sickle cell disease and is associated with reduced ex vivo platelet-mediated erythrocyte sickling.

Sickle cell disease (SCD) is associated with haemolytic anaemia and secondary activation of leucocytes and platelets, which in turn may further exacerbate haemolysis. As cytokine signalling pathways may participate in this cycle, the present study investigated whether pharmacological blockade of the interleukin-1 receptor (IL-1R) would mitigate anaemia in a murine model of SCD. Within 2 weeks of treatment, reduced markers of haemolysis were observed in anakinra-treated mice compared to vehicle-treated mice.

KLF11 Protects against Venous Thrombosis via Suppressing Tissue Factor Expression.

Krüppel-like factors (KLFs) play essential roles in multiple biological functions, including maintaining vascular homeostasis. KLF11, a causative gene for maturity-onset diabetes of the young type 7, inhibits endothelial activation and protects against stroke. However, the role of KLF11 in venous thrombosis remains to be explored.

Non-hematopoietic deficiency of proprotein convertase subtilisin/kexin type 9 deficiency leads to more severe anemia in a murine model of sickle cell disease.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) deficiency leads to lower cholesterol and is associated with reduced vascular complications in the general population. Cholesterol lowering may also have beneficial effects in sickle cell disease (SCD). The objective of this study was to determine effects of PCSK9 deficiency in a mouse model of SCD.

Diversity, Equity, and Inclusiveness in Medicine and Cardiology: Next Steps for .

We, the Editors of the , sincerely regret the publication of the article "Diversity, Inclusion, and Equity: Evolution of Race and Ethnicity Considerations for the Cardiology Workforce in the United States of America From 1969 to 2019". We are aware that the publication of this flawed and biased article has caused a great deal of unnecessary pain and anguish to a number of parties, and reflects extremely poorly on us. We fully support the retraction of this article.

Interleukin-1 receptor inhibition reduces stroke size in a murine model of sickle cell disease.

Sickle cell disease (SCD) is associated with chronic hemolytic anemia and a heightened inflammatory state. The causal role of inflammatory pathways in stroke associated with SCD is unclear. Therefore, the hypothesis that deletion of the non-hematopoietic interleukin-1 receptor (IL-1R) pool may be beneficial in SCD was pursued.

Clopidogrel Resistance in a Murine Model of Diet-Induced Obesity Is Mediated by the Interleukin-1 Receptor and Overcome With DT-678.

Objective: Clopidogrel is a commonly used P2Y inhibitor to treat and prevent arterial thrombotic events. Clopidogrel is a prodrug that requires bioactivation by CYP (cytochrome P450) enzymes to exert antiplatelet activity. Diabetes mellitus is associated with an increased risk of ischemic events, and impaired ability to generate the active metabolite (AM) from clopidogrel.

Increased mitochondrial NADPH oxidase 4 (NOX4) expression in aging is a causative factor in aortic stiffening.

Aging is characterized by increased aortic stiffness, an early, independent predictor and cause of cardiovascular disease. Oxidative stress from excess reactive oxygen species (ROS) production increases with age. Mitochondria and NADPH oxidases (NOXs) are two major sources of ROS in cardiovascular system.

KLF11 (Krüppel-Like Factor 11) Inhibits Arterial Thrombosis via Suppression of Tissue Factor in the Vascular Wall.

Objective- Mutations in Krüppel like factor-11 ( KLF11), a gene also known as maturity-onset diabetes mellitus of the young type 7, contribute to the development of diabetes mellitus. KLF11 has anti-inflammatory effects in endothelial cells and beneficial effects on stroke. However, the function of KLF11 in the cardiovascular system is not fully unraveled.

Traumatic Brain Injury Leads to Accelerated Atherosclerosis in Apolipoprotein E Deficient Mice.

Traumatic brain injury (TBI) has been associated with atherosclerosis and cardiovascular mortality in humans. However the causal relationship between TBI and vascular disease is unclear. This study investigated the direct role of TBI on vascular disease using a murine model of atherosclerosis.

Obesity-induced Endothelial Dysfunction is Prevented by Neutrophil Extracellular Trap Inhibition.

Endothelial dysfunction precedes atherosclerosis and may constitute a critical link between obesity-related inflammation and cardiovascular disease. Neutrophil extracellular traps (NETs) have been shown to promote vascular damage in murine models of autoimmune disease and atherosclerosis. The impact of NETs towards endothelial dysfunction associated with obesity is unknown.

Angiotensin II-induced Hypertension is Reduced by Deficiency of P-selectin Glycoprotein Ligand-1.

Identification of inflammatory mediators that regulate the vascular response to vasopressor molecules may aid in the development of novel therapeutic agents to treat or prevent hypertensive vascular diseases. Leukocytes have recently been shown to be capable of modifying blood pressure responses to vasopressor molecules. The purpose of this study was to test the hypothesis that deficiency of the leukocyte ligand, Psgl-1, would reduce the pressor response to angiotensin II (Ang II).

Proprotein convertase subtilisin/kexin type 9 (PCSK9) Deficiency is Protective Against Venous Thrombosis in Mice.

The effect of lipid lowering on the incidence of deep venous thrombosis (DVT) is controversial. The purpose of this study was to determine the effect of proprotein convertase subtilisin/kexin type 9 (PCSK9) deficiency on development of DVT in mice. Pcsk9 deficient (pcsk9 ) and wild-type (WT) littermates underwent partial inferior vena cava (IVC) ligation to induce venous thrombosis.

Membrane-Tethered Metalloproteinase Expressed by Vascular Smooth Muscle Cells Limits the Progression of Proliferative Atherosclerotic Lesions.

Background: The MMP (matrix metalloproteinase) family plays diverse and critical roles in directing vascular wall remodeling in atherosclerosis. Unlike secreted-type MMPs, a member of the membrane-type MMP family, MT1-MMP (membrane-type 1 MMP; MMP14), mediates pericellular extracellular matrix degradation that is indispensable for maintaining physiological extracellular matrix homeostasis. However, given the premature mortality exhibited by MT1-MMP-null mice, the potential role of the proteinase in atherogenesis remains elusive.

Hematopoietic Deficiency of miR-223 Attenuates Thrombosis in Response to Photochemical Injury in Mice.

Some studies have shown that levels of MicroRNA (miR)-223 derived from platelets in the plasma are reduced following inhibition of platelet function, while others have shown a correlation between low plasma miR-223 and high on-treatment platelet reactivity. The present study seeks to investigate the role of miR-223 in arterial thrombosis. A model of photochemical-induced carotid thrombosis was applied to miR-223 deficient mice and littermate (WT) controls.

T-Cells Specific for a Self-Peptide of ApoB-100 Exacerbate Aortic Atheroma in Murine Atherosclerosis.

On the basis of mouse I-A-binding motifs, two sequences of the murine apolipoprotein B-100 (mApoB-100), mApoB-100 (designated P3) and mApoB-100 (designated P6), were found to be immunogenic. In this report, we show that P6 is also atherogenic. Immunization of mice fed a high-fat diet (HFD) with P6 resulted in enhanced development of aortic atheroma as compared to control mice immunized with an irrelevant peptide MOG or with complete Freund's adjuvant alone.

Significant Improvement of Antithrombotic Responses to Clopidogrel by Use of a Novel Conjugate as Revealed in an Arterial Model of Thrombosis.

Clopidogrel is a prodrug that requires bioactivation by cytochrome P450 (P450) enzymes to a pharmacologically active metabolite for antiplatelet action. The clinical limitations of clopidogrel are in large part due to its poor pharmacokinetics resulting from inefficient bioactivation by P450s. In this study, we determined the pharmacokinetics and pharmacodynamics of a novel conjugate of clopidogrel, referred to as ClopNPT, in animal models and we evaluated its potential to overcome the limitations of clopidogrel.