Anatomical location, sex, and age modulate adipocyte progenitor populations in perivascular adipose tissues.

Perivascular adipose tissue (PVAT) regulates vascular function due to its capacity to synthesize vasoactive products and its mechanical properties. PVATs most abundant cells are adipocytes, and their populations are maintained by the maturation of adipocyte progenitor cells (APC), which may play a pivotal role in the pathogenesis of cardiovascular diseases. However, the distribution of APC within PVAT depots, their potential variation in spatial location, and the influence of sex and age on their abundance remain unknown.

Perivascular Adipose Tissue Remodels Only after Elevation of Blood Pressure in the Dahl SS Rat Fed a High-Fat Diet.

Introduction: Tunica media extracellular matrix (ECM) remodeling is well understood to occur in response to elevated blood pressure, unlike the remodeling of other tunicas. We hypothesize that perivascular adipose tissue (PVAT) is responsive to hypertension and remodels as a protective measure.

Methods: The adventitia and PVAT of the thoracic aorta were used in measuring ECM genes from 5 pairs of Dahl SS male rats on 8 or 24 weeks of feeding from weaning on a control (10% Kcal fat) or high-fat (HF; 60%) diet.

A patterned human primitive heart organoid model generated by pluripotent stem cell self-organization.

Pluripotent stem cell-derived organoids can recapitulate significant features of organ development in vitro. We hypothesized that creating human heart organoids by mimicking aspects of in utero gestation (e.g.

The "One-Step" approach for QT analysis increases the sensitivity of nonclinical QTc analysis.

Whether a compound prolongs cardiac repolarization independent of changes in beat rate is a critical question in drug research and development. Current practice is to resolve this in two steps. First, the QT interval is corrected for the influence of rate and then statistical significance is tested.

Evaluation of the Efficacy and Safety of Antiplatelet Therapeutics in Rabbits.

Hemostasis is a multifactorial process that involves vasoconstriction of blood vessels, activation of the coagulation cascade, and platelet aggregation. Inappropriate activation of hemostatic processes can result in thrombosis and tissue ischemia. In patients at risk for thrombotic events, antiplatelet therapeutic agents inhibit platelet activation, thereby reducing the incidence of pathologic clot formation.

QT Ratio: A simple solution to individual QT correction.

Preclinical risk assessment of drug-induced arrhythmias is critical for drug development and relies on heart rate corrected QT interval (QT) prolongation as a biomarker for arrhythmia risk. However, the methods used to correct QT vary in complexity and don't account for all changes in the QT-rate relationship. Thus, we developed the novel Ratio QT correction method which characterizes that relationship at each timepoint using the ratio between QT, adjusted for a species-specific constant, and rate (RR interval).

Pleiotropic effects of clopidogrel.

Clopidogrel is a widely prescribed prodrug with anti-thrombotic activity through irreversible inhibition of the P2Y receptor on platelets. It is FDA-approved for the clinical management of thrombotic diseases like unstable angina, myocardial infarction, stroke, and during percutaneous coronary interventions. Hepatic clopidogrel metabolism generates several distinct metabolites.

Increasing trust and vaccine uptake: Offering invitational rhetoric as an alternative to persuasion in pediatric visits with vaccine-hesitant parents (VHPs).

Healthcare professionals are increasingly concerned about vaccine hesitancy, an exigency the World Health Organization named one of the ten threats to global health, even before the COVID-19 pandemic. Traditional rhetorical strategies (e.g.

Improving corrected QT; Why individual correction is not enough.

The use of QT-prolongation as a biomarker for arrhythmia risk requires that researchers correct the QT-interval (QT) to control for the influence of heart rate (HR). QT correction methods can vary but most used are the universal correction methods, such as Bazett's or Van de Water's, which use a single correction formula to correct QT-intervals in all the subjects of a study. Such methods fail to account for differences in the QT/HR relationship between subjects or over time, instead relying on the assumption that this relationship is consistent.

Clopidogrel treatment inhibits P2Y-Mediated constriction in the rabbit middle cerebral artery.

Clopidogrel is an effective purinergic 2Y receptor (P2Y) antagonist used to prevent arterial thrombosis, but its use is associated with adverse bleeding. Clinical studies have demonstrated that clopidogrel users have an increased risk of cerebral microbleeds and intracerebral hemorrhage. Our previous studies suggest that non-platelet mechanisms mediate these adverse bleeding events; we hypothesize that clopidogrel or one of its metabolites interacts with blood vessels directly to cause bleeding.

Relationship of clinical adverse event reports to models of arrhythmia risk.

A vital aspect of the drug discovery and development process is the identification and filtering of drugs with high risk of dangerous adverse events. Torsade de Pointes (TdP) is one example of an adverse event that requires thorough in vitro and in vivo drug screening. This is because TdP, a tachycardic ventricular arrhythmia, can develop into fatal cardiac events if left unresolved and has been missed during drug development with profound consequences.

Contemporary use of and outcomes associated with ultra-low contrast volume in patients undergoing percutaneous coronary interventions.

Background: The risk of contrast-induced acute kidney injury (CI-AKI) increases in a nonlinear fashion with increasing volume of contrast media. Prior studies recommend limiting contrast volume to less than three times the estimated creatinine clearance (CC). Recently, a number of operators have reported successful percutaneous coronary intervention (PCI) using even lower volumes of contrast.

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.

Sildenafil citrate for prophylaxis of nephropathy in an animal model of contrast-induced acute kidney injury.

Contrast-induced acute kidney injury (CIAKI) is one of the commonest complications associated with contrast media (CM). Although the exact etiology of CIAKI remains unclear, one hypothesis involves vasoconstriction of afferent arterioles resulting in renal ischemia. Increased renal blood flow, therefore, might represent an attractive target for the treatment of CIAKI.

Formation, reactivity, and antiplatelet activity of mixed disulfide conjugates of clopidogrel.

In this work, we investigated the formation, reactivity, and antiplatelet activity of various mixed disulfide conjugates of clopidogrel. Our results showed that the production of the active metabolite (AM) from 2-oxoclopidogrel by human liver microsomes (HLMs) is greatly affected by the thiol reductants used. Among the 10 thiol compounds tested, glutathione (GSH) is most efficient in producing the AM at a rate of 167 pmoles AM/min/mg HLM.

Oral pretreatment with liposomal glutathione attenuates reperfusion injury in rabbit isolated hearts.

Reactive oxygen species are a key mediator of myocardial reperfusion injury. Endogenous cellular defenses against reactive oxygen species often become overwhelmed after ischemia and reperfusion. Therefore, exogenous supplementation of various antioxidant compounds has been hypothesized to protect against reperfusion.

Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1.

Pain associated with inflammation involves prostaglandins synthesized from arachidonic acid (AA) through cyclooxygenase-2 (COX-2) pathways while thromboxane A(2) formed by platelets from AA via cyclooxygenase-1 (COX-1) mediates thrombosis. COX-1 and COX-2 are both targets of nonselective nonsteroidal antiinflammatory drugs (nsNSAIDs) including aspirin whereas COX-2 activity is preferentially blocked by COX-2 inhibitors called coxibs. COXs are homodimers composed of identical subunits, but we have shown that only one subunit is active at a time during catalysis; moreover, many nsNSAIDS bind to a single subunit of a COX dimer to inhibit the COX activity of the entire dimer.

Disodium disuccinate astaxanthin prevents carotid artery rethrombosis and ex vivo platelet activation.

Background/aims: The disodium disuccinate derivative of astaxanthin (DDA) is a carotenoid antioxidant under development for the treatment of ischemic cardiovascular events. Recent evidence suggests that reactive oxygen species (ROS) play an important role in platelet activation. This study seeks to investigate the effects of a reactive oxygen species quencher, DDA, in a canine model of carotid artery thrombosis.

Sulodexide: a renewed interest in this glycosaminoglycan.

Glycosaminoglycans (GAGs) are the most abundant group of heteropolysaccharides found in the body. These long unbranched molecules contain a repeating disaccharide unit. GAGs are located primarily in the extracellular matrix or on the surface of cells.

Disodium Disuccinate Astaxanthin (Cardax) attenuates complement activation and reduces myocardial injury following ischemia/reperfusion.

Carotenoids are a naturally occurring group of compounds that possess antioxidant properties. Most natural carotenoids display poor aqueous solubility and tend to form aggregates in solution. Disodium disuccinate astaxanthin (DDA; Cardax) is a water-dispersible synthetic carotenoid that rapidly and preferentially associates with serum albumin, thereby preventing the formation of supramolecular complexes and facilitating its efficacy after parenteral administration.

Sulodexide attenuates myocardial ischemia/reperfusion injury and the deposition of C-reactive protein in areas of infarction without affecting hemostasis.

Several glycosaminoglycans (GAGs) have been demonstrated to protect the ischemic heart against reperfusion injury, in part, by modulating activation of the complement cascade. The present study assessed the cardioprotective effects of sulodexide (KRX-101), a mixture of GAGs composed of 80% low-molecular mass heparin and 20% dermatan sulfate. KRX-101 differs from other GAGs (e.

Comparative analysis of various platelet glycoprotein IIb/IIIa antagonists on shear-induced platelet activation and adhesion.

Platelet accretion into arterial thrombus in stenotic arterial vessels involves shear-induced platelet activation and adhesion. The Cone and Plate(let) Analyzer (CPA) is designed to simulate such conditions in vitro under a rotating high shear rate in whole blood. In the present study, we evaluated various experimental conditions (including aspirin, temperature, and calcium concentration) and investigated the effects of small molecules along with peptide glycoprotein IIb/IIIa antagonists on platelet adhesion using the CPA system.