One size does not fit all: Sex bias in pharmacologic venous thromboembolism prophylaxis.

BACKGROUND: The optimal enoxaparin dosing strategy to achieve venous thromboembolism (VTE) prophylaxis in trauma patients remains unclear. Current dosing guidelines often include weight, age, and renal function but still fail to achieve appropriate prophylactic anti-Xa levels in many patients. We hypothesized that additional patient factors influence anti-Xa response to enoxaparin in trauma patients. METHODS: This is a retrospective review of patients admitted to a Level 1 trauma center for ≥4 days from July 2015 to September 2020, who received enoxaparin VTE prophylaxis per protocol (50-59 kg, 30 mg/dose; 60-99 kg, 40 mg/dose; ≥100 kg, 50 mg/dose; all doses every 12 hours) and had an appropriately timed peak anti-Xa level. Multivariate regression was performed to identify independent predictors of prophylactic anti-Xa levels (0.2-0.4 IU/mL) upon first measurement. RESULTS: The cohort (N = 1,435) was 76.4% male, with a mean ± SD age of 49.9 ± 20.0 years and a mean ± SD weight of 82.5 ± 20.2 kg (males, 85.2 kg; females, 73.7 kg; p <0.001). Overall, 68.6% of patients (n = 984) had a prophylactic anti-Xa level on first assessment (69.6% of males, 65.1% of females). Males were more likely to have a subprophylactic level than females (22.1% vs. 8.0%, p <0.001), whereas females were more likely to have supraprophylactic levels than males (26.9% vs. 8.3%, p < 0.001). When controlling for creatinine clearance, anti-Xa level was independently associated with dose-to-weight ratio (odds ratio, 0.191 for 0.5 mg/kg; p < 0.001; confidence interval, 0.151-0.230) and female sex (odds ratio, 0.060; p < 0.001; confidence interval, 0.047-0.072). Weight and age were not significant when controlling for the other factors. CONCLUSION: Male patients have a decreased anti-Xa response to enoxaparin when compared with female patients, leading to a greater incidence of subprophylactic anti-Xa levels in male patients at all dose-to-weight ratios. To improve the accuracy of VTE chemoprophylaxis, sex should be considered as a variable in enoxaparin dosing models. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Protein Kinase D1 Regulates Cardiac Hypertrophy, Potassium Channel Remodeling, and Arrhythmias in Heart Failure.

Background Structural and electrophysiological remodeling characterize heart failure (HF) enhancing arrhythmias. PKD1 (protein kinase D1) is upregulated in HF and mediates pathological hypertrophic signaling, but its role in K+ channel remodeling and arrhythmogenesis in HF is unknown. Methods and Results We performed echocardiography, electrophysiology, and expression analysis in wild-type and PKD1 cardiomyocyte-specific knockout (cKO) mice following transverse aortic constriction (TAC). PKD1-cKO mice exhibited significantly less cardiac hypertrophy post-TAC and were protected from early decline in cardiac contractile function (3 weeks post-TAC) but not the progression to HF at 7 weeks post-TAC. Wild-type mice exhibited ventricular action potential duration prolongation at 8 weeks post-TAC, which was attenuated in PKD1-cKO, consistent with larger K+ currents via the transient outward current, sustained current, inward rectifier K+ current, and rapid delayed rectifier K+ current and increased expression of corresponding K+ channels. Conversely, reduction of slowly inactivating K+ current was independent of PKD1 in HF. Acute PKD inhibition slightly increased transient outward current in TAC and sham wild-type myocytes but did not alter other K+ currents. Sham PKD1-cKO versus wild-type also exhibited larger transient outward current and faster early action potential repolarization. Tachypacing-induced action potential duration alternans in TAC animals was increased and independent of PKD1, but diastolic arrhythmogenic activities were reduced in PKD1-cKO. Conclusions Our data indicate an important role for PKD1 in the HF-related hypertrophic response and K+ channel downregulation. Therefore, PKD1 inhibition may represent a therapeutic strategy to reduce hypertrophy and arrhythmias; however, PKD1 inhibition may not prevent disease progression and reduced contractility in HF.

Hyperglycemia regulates cardiac K+ channels via O-GlcNAc-CaMKII and NOX2-ROS-PKC pathways.

Chronic hyperglycemia and diabetes lead to impaired cardiac repolarization, K+ channel remodeling and increased arrhythmia risk. However, the exact signaling mechanism by which diabetic hyperglycemia regulates cardiac K+ channels remains elusive. Here, we show that acute hyperglycemia increases inward rectifier K+ current (IK1), but reduces the amplitude and inactivation recovery time of the transient outward K+ current (Ito) in mouse, rat, and rabbit myocytes. These changes were all critically dependent on intracellular O-GlcNAcylation. Additionally, IK1 amplitude and Ito recovery effects (but not Ito amplitude) were prevented by the Ca2+/calmodulin-dependent kinase II (CaMKII) inhibitor autocamtide-2-related inhibitory peptide, CaMKIIδ-knockout, and O-GlcNAc-resistant CaMKIIδ-S280A knock-in. Ito reduction was prevented by inhibition of protein kinase C (PKC) and NADPH oxidase 2 (NOX2)-derived reactive oxygen species (ROS). In mouse models of chronic diabetes (streptozotocin, db/db, and high-fat diet), heart failure, and CaMKIIδ overexpression, both Ito and IK1 were reduced in line with the downregulated K+ channel expression. However, IK1 downregulation in diabetes was markedly attenuated in CaMKIIδ-S280A. We conclude that acute hyperglycemia enhances IK1 and Ito recovery via CaMKIIδ-S280 O-GlcNAcylation, but reduces Ito amplitude via a NOX2-ROS-PKC pathway. Moreover, chronic hyperglycemia during diabetes and CaMKII activation downregulate K+ channel expression and function, which may further increase arrhythmia susceptibility.