Age-related changes in left ventricular vortex and energy loss patterns: from newborns to adults.

Left ventricular vortex formation optimizes the effective transport of blood volume while minimizing energy loss (EL). Vector flow mapping (VFM)-derived EL patterns have not been described in children, especially in those less than 1 yr of age. A prospective cohort of 66 (0 days-22 yr, 14 patients ≤ 2 mo) cardiovascularly normal children was used to determine left ventricular (LV) vortex number, size (mm2), strength (m2/s), and energy loss (mW/m/m2) in systole and diastole and compared across age groups. One early diastolic (ED) vortex at the anterior mitral leaflet and one late diastolic (LD) vortex at the LV outflow tract (LVOT) were seen in all newborns ≤ 2 mo. At >2 mo, two ED vortices and one LD vortex were seen, with 95% of subjects > 2 yr demonstrating this vortex pattern. Peak and average diastolic EL acutely increased in the same 2 mo-2-yr period and then decreased within the adolescent and young adult age groups. Overall, these findings suggest that the growing heart undergoes a transition to adult vortex flow patterns over the first 2 yr of life with a corresponding acute increase in diastolic EL. These findings offer an initial insight into the dynamic changes of LV flow patterns in pediatric patients and can serve to expand our understanding of cardiac efficiency and physiology in children.NEW & NOTEWORTHY This research article demonstrates, for the first time, echocardiographic evidence of a transition in left ventricular vortex patterns from the newborn to the adult period, with an associated change in cardiac efficiency, marked by increased energy loss, during infancy.

Circulating MicroRNA Profiling in Non-ST Elevated Coronary Artery Syndrome Highlights Genomic Associations with Serial Platelet Reactivity Measurements.

Changes in platelet physiology are associated with simultaneous changes in microRNA concentrations, suggesting a role for microRNA in platelet regulation. Here we investigated potential associations between microRNA and platelet reactivity (PR), a marker of platelet function, in two cohorts following a non-ST elevation acute coronary syndrome (NSTE-ACS) event. First, non-targeted microRNA concentrations and PR were compared in a case (N = 77) control (N = 76) cohort within the larger TRILOGY-ACS trial. MicroRNA significant in this analysis plus CVD-associated microRNAs from the literature were then quantified by targeted rt-PCR in the complete TRILOGY-ACS cohort (N = 878) and compared with matched PR samples. Finally, microRNA significant in the non-targeted & targeted analyses were verified in an independent post NSTE-ACS cohort (N = 96). From the non-targeted analysis, 14 microRNAs were associated with PR (Fold Change: 0.91-1.27, p-value: 0.004-0.05). From the targeted analysis, five microRNAs were associated with PR (Beta: -0.09-0.22, p-value: 0.004-0.05). Of the 19 significant microRNAs, three, miR-15b-5p, miR-93 and miR-126, were consistently associated with PR in the TRILOGY-ACS and independent Singapore post-ACS cohorts, suggesting the measurement of circulating microRNA concentrations may report on dynamic changes in platelet biology following a cardiovascular ischemic event.

Drug Dosing and Pharmacokinetics in Children With Obesity: A Systematic Review.

IMPORTANCE: Obesity affects nearly one-sixth of US children and results in alterations to body composition and physiology that can affect drug disposition, possibly leading to therapeutic failure or toxic side effects. The depth of available literature regarding obesity's effect on drug safety, pharmacokinetics, and dosing in obese children is unknown. OBJECTIVE: To perform a systematic literature review describing the current evidence of the effect of obesity on drug disposition in children. EVIDENCE REVIEW: We searched the MEDLINE, Cochrane, and EMBASE databases (January 1, 1970-December 31, 2012) and included studies if they contained data on drug clearance, volume of distribution, or drug concentration in obese children (aged ≤18 years). We compared exposure and weight-normalized volume of distribution and clearance between obese and nonobese children. We explored the association between drug physicochemical properties and clearance and volume of distribution. FINDINGS: Twenty studies met the inclusion criteria and contained pharmacokinetic data for 21 drugs. The median number of obese children studied per drug was 10 (range, 1-112) and ages ranged from newborn to 29 years (1 study described pharmacokinetics in children and adults together). Dosing schema varied and were either a fixed dose (6 [29%]) or based on body weight (10 [48%]) and body surface area (4 [19%]). Clinically significant pharmacokinetic alterations were observed in obese children for 65% (11 of 17) of the studied drugs. Pharmacokinetic alterations resulted in substantial differences in exposure between obese and nonobese children for 38% (5 of 13) of the drugs. We found no association between drug lipophilicity or Biopharmaceutical Drug Disposition Classification System class and changes in volume of distribution or clearance due to obesity. CONCLUSIONS AND RELEVANCE: Consensus is lacking on the most appropriate weight-based dosing strategy for obese children. Prospective pharmacokinetic trials in obese children are needed to ensure therapeutic efficacy and enhance drug safety.

Necrotizing enterocolitis in infants with ductal-dependent congenital heart disease.

OBJECTIVE: Infants with congenital heart disease (CHD) receiving prostaglandins (PGEs) may be at an increased risk for necrotizing enterocolitis (NEC). Enteral feeding may further increase the risk of NEC in these patients. We evaluated the incidence of NEC and its association with enteral feeding in infants with ductal-dependent CHD. STUDY DESIGN: We examined a cohort of infants with CHD receiving PGE in neonatal intensive care units managed by the Pediatrix Medical Group (Sunrise, FL) between 1997 and 2010. We used logistic regression to evaluate the association between NEC and enteral feeding, as well as other risk factors, including antacid medications, inotropic and ventilator support, and anatomic characteristics, controlling for gestational age. RESULTS: We identified 6,710 infants with ductal-dependent CHD receiving PGE for 17,158 infant days. NEC occurred in 21 of the 6,710 (0.3%) infants, of whom 12/21 (57%) were < 37 weeks gestational age. The incidence of NEC was 1.2/1,000 infant days while on enteral feeds versus 0.4/1,000 infant days while not on enteral feeds (p = 0.27). Enteral feeding was not associated with a statistically significant increased odds of NEC on the day of diagnosis (odds ratio [OR] 2.08; 95% confidence interval [CI] 0.38, 11.7). Risk factors associated with a significant increased odds of NEC included a diagnosis of single-ventricle heart defect (OR 2.82; 95% CI 1.23, 6.49), although the overall risk in this population remained low (8/1,631, 0.5%). CONCLUSION: The incidence of NEC in our cohort of infants with ductal-dependent CHD on PGE therapy was low and did not increase with enteral feeding.

Use of the complete blood cell count in early-onset neonatal sepsis.

BACKGROUND: Early-onset sepsis (EOS) is an important cause of morbidity and mortality in neonates, and its diagnosis remains challenging. The complete blood cell count and differential have been previously evaluated as diagnostic tools for EOS in small, single-center reports. We evaluated the diagnostic accuracy of the complete blood cell count and differential in EOS in a large, multicenter population of neonates admitted to the neonatal intensive care unit. METHODS: Using a cohort of 166,092 neonates with suspected EOS with cultures admitted to 293 neonatal intensive care units, we calculated odds ratios and receiver operating characteristic curves for complete blood cell count indices and prediction of a positive culture. We determined sensitivity, specificity and likelihood ratios for various commonly used cutoff values from the complete blood cell count. RESULTS: Low white blood cell counts, low absolute neutrophil counts and high immature-to-total neutrophil ratios were associated with increasing odds of infection (highest odds ratios: 5.38, 6.84 and 7.97, respectively). Specificity and negative predictive values were high (73.7%-99.9% and >99.8%). However, sensitivities were low (0.3%-54.5%) for all complete blood cell count indices analyzed. CONCLUSION: Low white blood cell count, absolute neutrophil count and high immature-to-total neutrophil ratio were associated with increasing odds of infection, but no complete blood cell count-derived index possesses the sensitivity to rule out reliably EOS in neonates.

Use of the complete blood cell count in late-onset neonatal sepsis.

BACKGROUND: Late-onset sepsis is an important cause of morbidity and mortality in infants. Diagnosis of late-onset sepsis can be challenging. The complete blood cell count and differential have been previously evaluated as diagnostic tools for late-onset sepsis in small, single-center reports. OBJECTIVE: We evaluated the diagnostic accuracy of the complete blood cell count and differential in late-onset sepsis in a large multicenter population. STUDY DESIGN: Using a cohort of all infants with cultures and complete blood cell count data from a large administrative database, we calculated odds ratios for infection, as well as sensitivity, specificity, positive and negative predictive values and likelihood ratios for various commonly used cut-off values. RESULTS: High and low white blood cell counts, high absolute neutrophil counts, high immature-to-total neutrophil ratios and low platelet counts were associated with late-onset sepsis. Associations were weaker with increasing postnatal age at the time of the culture. Specificity was highest for white blood cell counts <1000/mm and >50,000/mm (>99%). Positive likelihood ratios were highest for white blood cell counts <1000/mm (4.1) and platelet counts <50,000/mm (3.5). CONCLUSION: No complete blood cell count index possessed adequate sensitivity to reliably rule out late-onset sepsis in this population.

Factor IXa as a target for pharmacologic inhibition in acute coronary syndrome.

Anticoagulant therapy, combined with platelet-directed inhibitors, represents a standard-of-care in the management of patients with acute coronary syndrome, particularly those who require percutaneous coronary interventions. While a vast clinical experience, coupled with large clinical trials have collectively provided guidance, an optimal anticoagulant drug and applied strategy, defined as one that reduces thrombotic and hemorrhagic events consistently, with minimal off-target effects and active control of systemic anticoagulation according to patient and clinical-setting specific need, remains at large. An advancing knowledge of coagulation, hemostasis, and thrombosis suggests that factor IXa, a protease that governs thrombin generation in common thrombotic disorders may represent a prime target for pharmacologic inhibition.

Reciprocal regulation of 11ß-hydroxysteroid dehydrogenase 1 and glucocorticoid receptor expression by dexamethasone inhibits human coronary artery smooth muscle cell proliferation in vitro.

The actions of glucocorticoids are mediated, in part, by 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1), which amplifies their effects at the pre-receptor level by converting cortisone to cortisol. Glucocorticoids, such as dexamethasone, inhibit vascular smooth muscle cell proliferation; however, the role of 11ß-HSD1 in this response remains unknown. Accordingly, we treated human coronary artery smooth muscle cells (HCSMC) with dexamethasone (10(-9)-10(-6) mol/l) and found that after 72 h dexamethasone increased 11ß-HSD1 expression (14.16 ± 1.6-fold, P < 0.001) and activity (6.21 ± 1.2-fold, P < 0.001) in a dose- and time-dependent manner, which was dependent upon glucocorticoid receptor (GR) activation and C/EBPß and C/EBPδ signaling. As glucocorticoids are known to negatively regulate GR expression, we examined the effect of decreasing 11ß-HSD1 expression on GR expression. In HCSMC transfected with 11ß-HSD1 siRNA, GR expression was increased; this effect was associated with protein kinase A activation and CREB phosphorylation. To examine the role of 11ß-HSD1 in HCSMC proliferation, we decreased 11ß-HSD1 expression and stimulated cells with platelet-derived growth factor (PDGF) (10 ng/ml). Decreased 11ß-HSD1 expression was associated with increased cell proliferation in the absence of PDGF compared to scrambled control-transfected cells (236.10 ± 13.11%, n = 4, P < 0.001) and this effect was augmented by PDGF. Furthermore, the inhibitory effect of dexamethasone on cellular proliferation was abrogated in 11ß-HSD1 siRNA-transfected HCSMC. Downregulation of 11ß-HSD1 was associated with decreased p27(kip1) expression and increased phosphorylated retinoblastoma protein, consistent with a proliferative response. These findings suggest that 11ß-HSD1 plays a role in the effects of glucocorticoids on vascular smooth muscle cell phenotype.

Antidote-controlled antithrombotic therapy targeting factor IXa and von Willebrand factor.

Thrombotic disorders and their common clinical phenotypes of acute myocardial infarction, ischemic stroke, and venous thromboembolism are the proximate cause of substantial morbidity, mortality, and health care expenditures worldwide. Accordingly, therapies designed to attenuate thrombus initiation and propagation, reflecting integrated platelet-mediated and coagulation protease-mediated events, respectively, represent a standard of care. Unfortunately, there are numerous inherent limitations of existing therapies that include target nonselectivity, variable onset and offset of pharmacodynamic effects, a narrow efficacy-safety profile, and the absence of a safe and reliable platform for either accurate titration, based on existing patient-specific, disease-specific, and clinical conditions, or active reversibility. Herein, we summarize our experience with oligonucleotide antithrombotic agents and their complementary antidotes, targeting the platelet adhesive protein von Willebrand factor and the pivotal coagulation protease factor IXa.

Factor IXa inhibitors as novel anticoagulants.

Currently available anticoagulants are limited by modest therapeutic benefits, narrow clinical applications, increased bleeding risk, and drug-induced thrombophilia. Because factor IX plays a pivotal role in tissue factor (TF)-mediated thrombin generation, it may represent a promising target for drug development. Several methods of attenuating factor IX activity, including monoclonal antibodies, synthetic active site-blocked competitive inhibitors, oral inhibitors, and RNA aptamers, have undergone investigation. This review summarizes present knowledge of factor IX inhibitors with emphasis on biology, pharmacology, preclinical data, and early-phase clinical experience in humans.

Nucleic acid aptamers as adjuncts to vaccine development.

Nucleic acid 'aptamers', a term derived from the Latin word aptus, 'to fit', are RNA or DNA oligonucleotides that conform to the three-dimensional structure of a selected protein, peptide or small molecules' functional moiety. The 'lock and key' relationship between aptamers and their binding partner permits distinction between closely related but non-identical members of a protein family, or between different functional or conformational states of the same protein. This, along with other properties, separates aptamers from antibodies--the most popular class of molecular recognition tool for the past three decades. Despite the chemical, biological and manufacturing advantages offered by nucleic acid aptamers in a wide variety of conditions, and their generation against a range of clinically relevant targets, including growth factors, transcription factors and coagulation proteins, by two dozen or more companies devoted to the technology platform, only one aptamer, developed for the treatment of wet age-related macular degeneration, is currently available for use in humans. Nevertheless, phase I and II clinical trials for several indications are proceeding with considerable enthusiasm. The potential application of nucleic acid aptamers in novel arenas, including molecular imaging, vaccine development, immunomodulation, decoys for natural RNA-binding events, antiviral therapeutics and both cancer prophylaxis and treatment, is emerging with a pioneering mentality destined to change the paradigm of patient care.

The effect of temperature variation in vitro on platelet-leukocyte interactions and individual prothrombotic potential.

BACKGROUND: Temperature variation within human atheromatous plaques, a finding which supports inflammatory cell-mediated thermogenesis, predicts clinical events among patients with coronary artery disease. PURPOSE: Our study was designed to investigate the effect of ambient temperature in vitro on platelet-leukocyte interactions, monocyte tissue factor expression and platelet-dependent thrombin generation. METHODS/RESULTS: Whole blood samples obtained from healthy volunteers were incubated at 37 degrees, 38 degrees and 39 degrees C for three hours. Platelet-leukocyte aggregates, determined by flow cytometry before and after stimulation with lipopolysaccharide (10 ng/ml), increased from 15.0 +/- 2.3% at 37 degrees C to 19.4% at 38 degrees C (22.6% increase; p < 0.01), decreasing to 12.2 +/- 0.9% at 39 degrees C. The responses for individual subpopulations of platelet-lymphocyte, platelet-neutrophil and platelet-monocyte heterotypic aggregates were similar. Monocyte tissue factor expression, quantitated by flow cytometry with CD14 and FITC-labeled anti-human tissue factor antibody stains, increased from 45.2 +/- 3.8% (37 degrees C) to 62.0 +/- 4.3 (38 degrees C), representing a 27.1% rise (p < 0.005). Changes in temperature did not influence the initiation or propagation phases of platelet-dependent thrombin generation. CONCLUSION: A modest increase in ambient temperature increases platelet-leukocyte and monocyte tissue factor expression, providing an additional mechanistic link between atherosclerosis, inflammation and thrombosis. Whether therapies designed to lower vessel wall temperature will provide an antithrombotic effect requires further evaluation.