Increased Platelet Aggregation in Children and Adolescents with Sleep-disordered Breathing.

Rationale: Sleep-disordered breathing (SDB) is associated with increased vascular resistance in children and adults. Persistent increased vascular resistance damages vascular endothelial cells-a marker of which is increased platelet activation.Objectives: This study compared whole-blood impedance platelet aggregation in children with clinically diagnosed SDB warranting adenotonsillectomy and healthy control subjects.Methods: Thirty children who had SDB warranting intervention clinically diagnosed by experienced pediatric otolaryngologists were recruited from adenotonsillectomy waitlists, and 20 healthy children from the community underwent overnight polysomnography to determine SDB severity (obstructive apnea-hypopnea index). Snoring frequency was collected from parents. In the morning, a fasting blood sample was taken, and whole-blood platelet aggregation was measured.Measurements and Main Results: Children with SDB exhibited increased platelet aggregation to TRAP (thrombin receptor-activating peptide) (children with SDB = 114.8 aggregation units [AU] vs. control subjects = 98.0 AU; P < 0.05) and COL antibody (96.7 vs. 82.2 AU; P < 0.05) and an increased trend in ADP antibody (82.3 vs. 69.2 AU; P < 0.07) but not aspirin dialuminate (82.1 vs. 79.5 AU; P > 0.05). No significant association was observed between either the obstructive apnea-hypopnea index and any aggregation parameter, but parental report of snoring was positively associated with TRAP aggregation (Kendall's τ-c = 0.23; P < 0.05).Conclusions: The finding of increased platelet aggregation is consistent with endothelial damage. This suggests that the profile of cardiovascular changes noted in adults with SDB may also occur in children with SDB.

Ascending aortic blood flow velocity is increased in children with primary snoring/mild sleep-disordered breathing and associated with an increase in CD8 + T cells expressing TNFα and IFNγ.

Sleep-disordered breathing (SDB) is associated with cardiovascular disease and systemic inflammation in adults but this remains to be explored in children, especially in children with the most common form of SDB, i.e. primary snoring/mild SDB. This pilot study investigated the relationship between the cardiovascular function and inflammation in children with mild SDB. Nineteen participants aged 5-14 years underwent overnight polysomnography, cardiac magnetic resonance imaging (aortic blood flow velocity and left and right ventricular systolic function) and assessment for inflammatory markers (intracellular cytokine analysis of T cells by flow cytometry). Parents also completed the Sleep Disturbances Scale for Children (SDSC). Children with mild SDB exhibited increased ascending aortic peak systolic velocity compared to controls (SDB 119.95 m/s vs. control 101.49 m/s, p < 0.05). No significant group differences were observed for left and right ventricular ejection fraction or mean aortic blood flow velocity from either the ascending aorta or pulmonary artery. Children with mild SDB had increased inflammatory markers as demonstrated by elevated T cell interferon gamma (IFNγ) (SDB 52 ± 4% vs. control 25 ± 3% positive cells, p < 0.005) and tumour necrosis factor alpha (TNFα) (SDB 39 ± 4% vs. control 20 ± 2% positive cells, p < 0.005) expression from CD8+ cells. A strong positive correlation was observed between ascending aorta peak blood flow velocity and both TNFα and IFNγ (TNFα, r = 0.54, p < 0.03; IFNγ, r = 0.63, p < 0.005, respectively). Polysomnography revealed that oxygen saturation (SaO2) nadir was significantly lower in children with mild SDB compared to controls (SDB 92.3 ± 2.7% vs. control 94.4 ± 1.6%, p < 0.05). A lower SaO2 nadir was associated with an increased ascending aorta peak systolic velocity (r = - 0.48, p < 0.05). As well, both a lower SaO2 nadir and an increased ascending aorta peak systolic velocity were associated with higher SDSC Sleep-Disordered Breathing and Disorder of Initiating and Maintaining Sleep subscale scores but not the polysomnographic-derived Obstructive Apnea-Hypopnea Index. The finding of elevated ascending aortic peak systolic blood flow velocity and its association with increased inflammatory markers suggests that the profile of cardiovascular changes noted in adult SDB may also occur in children with mild SDB.

Influence of ethnic background on left atrial markers of inflammation, endothelial function and tissue remodelling.

BACKGROUND: It has been suggested that ethnicity can make a significant difference to the likelihood of thromboembolic stroke related to atrial fibrillation. Ethnic differences have been shown to alter inflammatory and haemostatic factors; however, this may all be confounded by differences in cardiovascular risk factors between different ethnicity. The impact of different ethnicities on the thrombogenic profile is not known. The aim of this study was to investigate differences in markers of inflammation, endothelial function and tissue remodelling between Caucasian and Indian populations with supraventricular tachycardia (SVT). METHODS: Patients with structurally normal hearts undergoing catheter ablation for SVT were studied. This study included 23 Australian (Caucasian) patients from the Royal Adelaide Hospital, Adelaide, Australia and 24 Indian (Indian) patients from the Christian Medical College, Vellore, India. Blood samples were collected from the femoral vein, and right and left atria. Blood samples were analysed for the markers of endothelial function (ADMA, ET-1), inflammation (CD40L, VCAM-1, ICAM-1), and tissue remodelling (MMP-9, TIMP-1) using ELISA. RESULTS: The study populations were well matched for cardiovascular risk factors and the absence of structural heart disease. No difference in the echocardiographic measurements between the two ethnicities was found. In this context, there was no difference in markers of inflammation, endothelial function or tissue remodelling between the two SVT populations. CONCLUSION: Caucasian and Indian populations demonstrate similar inflammatory, endothelial function or tissue remodelling profiles. This study suggests a lack of an impact of different ethnicity in these populations in terms of thrombogenic risk.

The predictive capabilities of a novel cardiovascular magnetic resonance derived marker of cardiopulmonary reserve on established prognostic surrogate markers in patients with pulmonary vascular disease: results of a longitudinal pilot study.

BACKGROUND: No unified method exists to effectively predict and monitor progression of pulmonary arterial hypertension (PAH). We assessed the longitudinal relationship between a novel marker of cardiopulmonary reserve and established prognostic surrogate markers in patients with pulmonary vascular disease. METHODS AND RESULTS: Twenty participants with confirmed (n = 14) or at high risk (n = 6) for PAH underwent cardiovascular magnetic resonance (CMR) at baseline and after ~6 months of guideline-appropriate management. Ten PAH participants underwent RHC within 48 h of each CMR. RHC (mean pulmonary arterial pressure, mPAP; pulmonary vascular resistance index, PVRI; cardiac index, CI) and phase-contrast CMR (mean pulmonary arterial blood flow velocity, meanPAvel) measurements were taken at rest and during continuous adenosine infusion (70/140/210 mcg/kg/min). Initial meanPAvel's (rest and hyperemic) were correlated with validated surrogate prognostic parameters (CMR: RV ejection fraction, RVEF; RV end systolic volume indexed, RVESVI; RHC: PVRI, CI; biomarker: NT-pro brain natriuretic peptide, NTpBNP; clinical: 6-min walk distance, 6MWD), a measure of pulmonary arterial stiffness (elastic modulus) and volumetric estimation of RV ventriculoarterial (VA) coupling. Changes in meanPAvel's were correlated with changes in comparator parameters over time. At initial assessment, meanPAvel at rest correlated significantly with PVRI (inversely), CI (positively) and elastic modulus (inversely) (R 2 > 0.37,P < 0.05 for all), whereas meanPAvel at peak hyperemia correlated significantly with PVRI, RVEF, RVESVI, 6MWD, elastic modulus and VA coupling (R 2 > 0.30,P < 0.05 for all). Neither resting or hyperemia-derived meanPAvel correlated with NTpBNP levels. Initial meanPAvel at rest correlated significantly with RVEF, RVESVI, CI and VA coupling at follow up assessment (R 2 > 0.2,P < 0.05 for all) and initial meanPAvel at peak hyperemia correlated with RVEF, RVESVI, PVRI and VA coupling (R 2 > 0.37,P < 0.05 for all). Change in meanPAvel at rest over time did not show statistically significant correlation with change in prognostic parameters, while change in meanPAvel at peak hyperemia did show a significant relationship with ΔRVEF, ΔRVESVI, ΔNTpBNP and ΔCI (R 2 > 0.24,P < 0.05 for all). CONCLUSION: MeanPAvel during peak hyperemia correlated with invasive, non-invasive and clinical prognostic parameters at different time points. Further studies with predefined clinical endpoints are required to evaluated if this novel tool is a marker of disease progression in patients with pulmonary vascular disease.

Flow-mediated dilatation, using time course data, shows maturation of the brachial artery from young children to mid-adolescents.

Flow-mediated dilatation (FMD) is a tool widely used to measure arterial responsiveness to sheer stress. However, there is scant literature to show how the peripheral arterial response changes as the vascular system matures. One reason for this is that the feasibility of measuring FMD in younger children has not been established. The aim of the present study was to assess brachial artery function at rest and during the FMD response after 4 min ischaemia of the forearm in children aged 6-15 years. Time to reach maximum FMD (FMDmax ) was found to be correlated with age (r = 0.4, P < 0.05), resting brachial artery diameter (r = 0.4, P < 0.05), height (r = 0.4, P < 0.05), body mass index (BMI; r = 0.45, P < 0.05), body surface area (r = 0.44, P < 0.05) and resting blood flow (r = 0.37, P < 0.05). However, there was no correlation between the traditional FMD response at 60 s or FMD maximal dilation and age, resting brachial artery diameter, height, weight, BMI, body surface area and resting blood flow. In conclusion, the time taken to reach the maximal dilation response is related to age, brachial artery luminal diameter and body habitus, but not the traditional measure of FMD response at 60 s or the maximal dilatation percentage.

Changes in meal composition and duration affect postprandial endothelial function in healthy humans.

Endothelial function, measured by flow-mediated dilatation (FMD), predicts cardiovascular events and is impaired postprandially. The objective of this study was to evaluate the effects of changes in composition or duration of ingestion of a meal, which slows gastric emptying and/or small intestinal nutrient exposure, on postprandial endothelial function. Twelve healthy subjects (6 male, 6 female; 33 ± 6 yr) were each studied on three occasions, in a randomized crossover design. After an overnight fast, subjects consumed a [(13)C]octanoic acid-labeled mashed potato meal ("meal 1"), or meal 1 mixed with 9 g guar ("meal 2") within 10 min, or meal 1 divided into 12 equal portions over 60 min ("meal 3"). Brachial artery FMD was measured every 30 min for 120 min. Blood glucose, serum insulin, and gastric emptying (breath test) were evaluated for 240 min. Data are means ± SE. Compared with meal 1, meal 2 was associated with slower gastric emptying (half-emptying time 285 ± 27 vs. 208 ± 15 min, P < 0.05), lower postprandial blood glucose and insulin (P < 0.001 for both), and a delayed, but more sustained, suppression of FMD (P < 0.001). After meal 3, both glycemic increment and reduction in FMD were less than after meal 2 (P < 0.05 for both). The decrement in FMD was directly related to the increment in blood glucose (r = 0.46, P = 0.02). We conclude that, in health, postprandial FMD is influenced by perturbation of gastric emptying and the duration of meal consumption, which also impact on glycemia.

Characterization of thrombogenic, endothelial and inflammatory markers in supraventricular tachycardia: a study in patients with structurally normal hearts.

Patients with atrial fibrillation (AF) are at an increased risk of thromboembolism and stroke primarily from the development of thrombi within the left atrium. Pathological changes in blood constituents and atrial endothelial damage promote left atrial thrombus formation. It is not known whether factors predisposing to left atrial thrombus formation in AF are disease specific or also evident within the normal heart. The present study examined whether there are differences in platelet reactivity, endothelial function and inflammation in blood samples obtained from intracardiac and peripheral sites in subjects within structurally normal hearts. Sixteen patients with diagnosed left-sided supraventricular tachycardia (SVT) undergoing a routine elective electrophysiological study and ablation were investigated. Blood samples were taken simultaneously from the femoral vein, right atrium and left atrium, immediately following trans-septal puncture and prior to heparin bolus administration. Between peripheral and atrial sample sites, patients with SVT showed no change in platelet reactivity or aggregation (P-selectin (CD62P) P = 0.91; platelet-derived soluble CD40 ligand P = 0.9), thrombus formation (thrombin-antithrombin complex; P = 0.55), endothelial function (von Willebrand factor P = 0.75; asymmetric dimethylarginine (ADMA) P = 0.97; nitric oxide P = 0.61), or inflammation (vascular cell adhesion molecule-1 P = 0.59; intercellular adhesion molecule-1 (ICAM-1) P = 0.69). However, SVT patients had lower ADMA and ICAM-1 levels than AF patients. The present study demonstrates, for the first time, that SVT subjects with structurally normal hearts have consistent haemostatic function between atrial and peripheral sites. These results suggest that the atria of SVT patients do not contain predisposing thrombogenic, endothelial or inflammatory factors that promote and/or initiate thrombus formation.

Clopidogrel improves microvascular endothelial function in subjects with stable coronary artery disease.

BACKGROUND: Clopidogrel therapy has recently been shown to reduce cardiovascular events in patients with stable vascular disease. This benefit may be due to effects not exclusively related to platelet aggregation. The aim of this study was to evaluate the effect of clopidogrel therapy on microvascular endothelial function in subjects with stable coronary artery disease (CAD). METHODS AND RESULTS: Forty subjects with stable CAD were randomised to clopidogrel therapy (75mg/day) or control. Blood and endothelial function testing occurred at baseline, one week and three months following randomisation. Microvascular endothelial function was assessed via reactive hyperaemic index (RHI). Platelet function was assessed by adenosine diphosphate (ADP)-induced whole blood aggregation and the VerifyNow™ system. Plasma markers of endothelial function (asymmetric dimethylarginine, ADMA) and oxidative stress (myeloperoxidase, MPO) were also tested. The primary endpoint was endothelial function assessment (RHI) at three months. At one week RHI increased by 20±10% in the clopidogrel group; this effect was maintained at three months (21±9% increase from baseline; P<0.01). A significant decrease in ADP-induced platelet aggregation and P2Y12 reaction units was observed in the clopidogrel therapy group (P<0.01). There was no correlation between endothelial function and platelet function testing in the clopidogrel therapy group. CONCLUSION: Clopidogrel therapy is associated with improved microvascular endothelial function in patients with stable CAD. This effect is independent of its effects on ADP-induced platelet reactivity.

Endothelial function, oxidative stress and inflammatory studies in chronic coronary slow flow phenomenon patients.

The coronary slow flow phenomenon (CSFP) is associated with coronary microvascular dysfunction although the responsible mechanisms are unknown. This study compared endothelial function assessed by changes in augmentation index (AIx) following endothelium-independent (glyceryl trinitrate, GTN) and endothelium-dependent vasodilators (salbutamol), in 40 stable CSFP patients and 23 age-matched healthy controls. Plasma concentrations of inflammatory proteins (myeloperoxidase and high-sensitivity C-reactive protein), oxidative stress biomarkers (malondialdehyde and homocysteine), and asymmetric dimethylarginine levels were also determined. There were no differences between CSFP and controls in response to salbutamol (AIx: -2.28 ± 0.88% vs. -3.22 ± 0.70%, p = 0.4) or GTN (AIx: -11.30 ± 0.75% vs. -13.30 ± 1.00%, p = 0.12). Similarly, there were no differences in the measured biomarkers. Thus, alternate mechanisms to the assessed endothelial function, inflammatory and oxidative stress processes should be explored to explain the microvascular dysfunction in CSFP patients.

Assessment of endothelial function in atrial fibrillation: utility of peripheral arterial tonometry.

Endothelial function is an independent predictor of adverse cardiovascular outcomes. The evaluation of endothelial function via changes in vessel diameter or blood flow may be inaccurate during atrial fibrillation (AF) because of non-uniform stroke volumes. Using peripheral arterial tonometry, 50 patients with AF (25 in AF, 25 in sinus rhythm) had digital pulse amplitudes assessed at baseline and during reactive hyperaemia. Hyperaemic responses were compared over varying measurement durations (5, 10 and 15beats; 30s; and 1-10min) to determine optimal measurement duration. Endothelial responses were significantly decreased (indicating endothelial dysfunction) in patients in AF compared with patients in sinus rhythm (1.48±0.60 vs 2.05±1.13, respectively; P=0.03). Beat-to-beat pulse amplitude was highly variable during AF; although coefficients of variation (CV) for short measurement durations were large, these decreased with longer measurement durations. Bland-Altman plots revealed that limits of agreement for short measurement durations were poor. Limits of agreement became consistently narrower when measurement durations of at least 1min were used. In contrast, limits of agreement and CV for short measurement durations during sinus rhythm were significantly narrower and smaller, respectively, than during AF over similar measurement durations. Pulse amplitudes are highly variable owing to the non-uniform stroke volumes in AF. Our results suggest that methods of determining endothelial function via vessel diameters or blood flow during reactive hyperaemia should use measurement durations of at least 1min to ensure accurate and reproducible results.

Significant cognitive impairment likely associated with COVID-19 infection with relatively nonsevere symptoms.

COVID-19 infection may involve the nervous system and has been associated with a number of neuropsychiatric complications, including impairment of cognition and dementia. Such complications are more likely to occur in (but are not limited to) patients with severe COVID-19 infections and those with concomitant risk factors. In this case report, the authors describe a normally functioning 51-year-old woman who developed cognitive impairment of a degree that rendered her unable to care for herself most likely related to a relatively nonsevere infection with COVID-19 about 2 months earlier. A detailed report of her deficits of different areas of cognitive functioning is provided. This report aims to make clinicians more aware of the potential for cognitive impairment in patients who have suffered from COVID-19, including those with infections that were not severe.

The effect of electrogram duration on quantification of complex fractionated atrial electrograms and dominant frequency.

INTRODUCTION: Sites of complex fractionated atrial electrograms (CFAEs) and highest dominant frequency (DF) have been proposed as critical regions maintaining atrial fibrillation (AF). This study aimed to determine the minimum electrogram recording duration that accurately characterizes CFAE or DF sites for ablation without unduly lengthening the procedure. METHODS AND RESULTS: Fourteen patients with AF undergoing catheter ablation had high-density (498 +/- 174 points) biatrial mapping performed during AF before ablation. At each point, 8-second electrograms were recorded. CFAE characterization using the NavX software provided a representation of electrogram complexity (CFE-mean). CFE-mean for each point from 7-, 6-, 5-, 4-, 3-, 2-, and 1-second subsamples were compared with the index 8-second CFE-mean. Offline spectral analysis defined DF as the frequency with greatest power, and DF of subsamples were compared with index DF. Index 8-second electrogram CFE-mean was 114 +/- 20 ms for right atria and 102 +/- 17 ms for left atria (P = 0.01); DF was 5.7 +/- 0.8 Hz for right atria and 6.0 +/- 0.8 Hz for left atria (P = 0.02). Means from shorter electrograms were nonsignificantly decreased for CFE-mean and overestimated for DF (P < 0.001). Mean absolute differences between subsampled and index values ranged from 3.3 to 20.1 ms for CFE-mean and 0.11 to 1.18 Hz for DF. Subsampled electrograms deviating >10% from index values ranged from 2.5 to 56% for CFE-mean and 3.5 to 41% for DF. Intraclass correlation coefficients ranged from 0.992 to 0.788 for CFE-mean and 0.897 to 0.233 for DF. Unacceptable differences from index values were found with CFE-mean and DF from electrograms <5 seconds. CONCLUSION: Electrograms of >or=5-second duration are required to accurately characterize CFAE and DF sites for ablation.

Effects of perhexiline and nitroglycerin on vascular, neutrophil and platelet function in patients with stable angina pectoris.

Perhexiline, a "metabolic" anti-anginal agent currently under investigation in management of congestive heart failure and acute coronary syndromes improves platelet nitric oxide responsiveness in patients with impaired responsiveness. The current study investigated possible interactions between perhexiline and the nitric oxide donor nitroglycerin on arterial stiffness, neutrophil superoxide release and on platelet nitric oxide responsiveness. Patients (n=39) with stable angina pectoris, awaiting cardiac catheterization were randomized to additional perhexiline or unchanged drug therapy; all patients received nitroglycerin infusion for 2 h. Vasomotor responses to perhexiline and combined perhexiline/nitroglycerin were examined using changes in augmentation index, measured via applanation tonometry. Neutrophil superoxide release was measured ex vivo utilizing lucigenin mediated chemiluminescence and effect of perhexiline on inhibition of platelet aggregation by sodium nitroprusside was also measured. Perhexiline alone did not affect augmentation index, neutrophil superoxide release, or ex vivo platelet sodium nitroprusside response. Nitroglycerin decreased augmentation index (P<0.01) and superoxide release (P<0.05). Magnitude of inhibition of superoxide release was significantly enhanced by perhexiline pre-treatment (P<0.05); however perhexiline had no effect on magnitude of vasomotor response to nitroglycerin. In conclusion, perhexiline exerts no effects on arterial stiffness and does not potentiate nitroglycerin induced dilatation. In patients with normal platelet function perhexiline does not affect platelet nitric oxide responsiveness. In vivo low dose nitroglycerin inhibits neutrophil superoxide release; this effect is potentiated by pre-treatment with perhexiline. These "anti-inflammatory" effects of nitroglycerin may contribute to utility in acute coronary syndromes and congestive heart failure.

Relationship between Vascular Resistance and Sympathetic Nerve Fiber Density in Arterial Vessels in Children With Sleep Disordered Breathing.

BACKGROUND: Sleep disordered breathing in children is associated with increased blood flow velocity and sympathetic overactivity. Sympathetic overactivity results in peripheral vasoconstriction and reduced systemic vascular compliance, which increases blood flow velocity during systole. Augmented blood flow velocity is recognized to promote vascular remodeling. Importantly, increased vascular sympathetic nerve fiber density and innervation in early life plays a key role in the development of early-onset hypertension in animal models. Examination of sympathetic nerve fiber density of the tonsillar arteries in children undergoing adenotonsillectomy for Sleep disordered breathing will address this question in humans. METHODS AND RESULTS: Thirteen children scheduled for adenotonsillectomy to treat sleep disordered breathing underwent pupillometry, polysomnography, flow-mediated dilation, resting brachial artery blood flow velocity (velocity time integral), and platelet aggregation. The dorsal lingual artery (tonsil) was stained and immunofluorescence techniques used to determine sympathetic nerve fiber density. Sympathetic nerve fiber density was correlated with increased resting velocity time integral (r=0.63; P<0.05) and a lower Neuronal Pupillary Index (r=-0.71, P<0.01), as well as a slower mean pupillary constriction velocity (mean, r=-0.64; P<0.05). A faster resting velocity time integral was associated with a slower peak pupillary constriction velocity (r=-0.77; P<0.01) and higher platelet aggregation to collagen antigen (r=0.64; P<0.05). Slower mean and peak pupillary constriction velocity were associated with higher platelet aggregation scores (P<0.05; P<0.01, respectively). CONCLUSIONS: These results indicate that sympathetic activity is associated with change in both the function and structure of systemic vasculature in children with sleep disordered breathing.

Platelet nitric oxide responsiveness: a novel prognostic marker in acute coronary syndromes.

OBJECTIVE: Nitric oxide (NO) is critically important in the regulation of vascular tone and the inhibition of platelet aggregation. We have shown previously that patients with acute coronary syndromes (ACS) or stable angina pectoris have impaired platelet responses to NO donors when compared with normal subjects. We tested the hypotheses that platelet hyporesponsiveness to NO is a predictor of (1) cardiovascular readmission and/or death and (2) all-cause mortality in patients with ACS (unstable angina pectoris or non-Q-wave myocardial infarction). METHODS AND RESULTS: Patients (n=51) with ACS had evaluation of platelet aggregation within 24 hours of coronary care unit admission using impedance aggregometry. Patients were categorized as having "normal" (> or =32% inhibition of ADP-induced aggregation with the NO donor sodium nitroprusside; 10 micromol/L; n=18) or "impaired" (<32% inhibition of ADP-induced aggregation; n=33) NO responses. We then compared the incidence of cardiovascular readmission and death during a median of 7 years of follow-up in these 2 groups. Using a Cox proportional hazards model adjusting for age, sex, index event, postdischarge medical treatment, revascularization status, left ventricular systolic dysfunction, concurrent disease states, and cardiac risk factors, impaired NO responsiveness was associated with an increased risk of the combination of cardiovascular readmission and/or death (relative risk, 2.7; 95% CI, 1.03 to 7.10; P=0.041) and all-cause mortality (relative risk, 6.3; 95% CI, 1.09 to 36.7; P=0.033). CONCLUSIONS: Impaired platelet NO responsiveness is a novel, independent predictor of increased mortality and cardiovascular morbidity in patients with high-risk ACS.

Delayed brachial artery dilation response and increased resting blood flow velocity in young children with mild sleep-disordered breathing.

AIM: This study aimed to evaluate whether the vascular dysfunction perceived in adults with sleep-disordered breathing (SDB) was also evident in children with snoring referred for evaluation of clinically suspected SDB. OBJECTIVES: This study compared flow-mediated dilatation (FMD), measured at the brachial artery, at rest and during hyperaemic stress between children who snore [n = 23; mean standard deviation (SD) age = 7.51 (1.3) years] and healthy, non-snoring children [n = 11; age = 8.0 (1.3) years]. METHODS: Children with suspected obstructive sleep apnoea (OSA) and healthy non-snoring controls underwent overnight polysomnography (PSG). Using standard techniques, non-invasive FMD and brachial arterial blood flow velocity during rest and hyperaemia were subsequently measured by ultrasound imaging MEASUREMENTS: Resting and hyperaemic velocity time integral (area under the curve of mean systolic velocity × ejection time), maximal dilation response (highest percentage difference from baseline diameter) and the time taken to reach maximal dilation were calculated. RESULTS: Children awaiting adenotonsillectomy compared to healthy non-snoring control children had higher velocity time integrals at rest (14 ± 3 m vs. 20 ± 8 m, p < 0.01) and during hyperaemic stress (56 ± 6m vs. 63 ± 13m, p < 0.01) despite having only mild SDB on polysomnographic assessment. Lower nadir oxygen saturation values during non-rapid eye movement sleep were negatively associated with higher resting (r = -0.58, p <0.001) and hyperaemic (r = -0.36, p < 0.05) velocity time integrals. Maximal FMD dilatation response was not significantly different between snoring and non-snoring groups, but the estimated time to reach maximal dilation was significantly delayed in children who snored (60.7 ± 28.4 vs. 39.2 ± 13.2 s, p < 0.05). CONCLUSIONS: Children with mild SDB showed increased blood flow velocity at rest and during hyperaemic stress suggesting altered cardiovascular and haemodynamic function. The delay in time to maximal vessel dilatation in children who snored also suggests possible reduced vascular compliance in response to hyperaemic sheer stress. Mild SDB appears to alter the peripheral vascular response in young children. The long-term vascular implications of these changes in the growing child are unknown and warrant further investigation.

Attenuated platelet aggregation in patients with septic shock is independent from the activity state of myosin light chain phosphorylation or a reduction in Rho kinase-dependent inhibition of myosin light chain phosphatase.

BACKGROUND: Impaired coagulation contributes to the morbidity and mortality associated with septic shock. Whether abnormal platelet contraction adds to the bleeding tendency is unknown. Platelets contract when Ca(2+)-dependent myosin light chain kinase (MLCK) phosphorylates Ser19 of myosin light chain (MLC20), promoting actin-myosin cross-bridge cycling. Contraction is opposed when myosin light chain phosphatase (MLCP) dephosphorylates MLC20. It is thought that Rho kinase (ROK) inhibits MLCP by phosphorylating Thr855 of the regulatory subunit MYPT, favouring platelet contraction. This study tested the hypotheses that in septic shock, (i) platelet function is inversely correlated with illness severity and (ii) ROK-dependent MLCP inhibition and myosin light chain phosphorylation are reduced. METHODS: Blood was sampled from non-septic shock patients and patients in the first 24 h of septic shock. Platelet function was assessed using whole blood impedance aggregation induced by 1) ADP (1.6 and 6.5 µM), 2) thrombin receptor-activating protein (TRAP; 32 µM), 3) arachidonic acid (500 µM) and 4) collagen (3.2 µg/ml). Arachidonic acid-induced aggregation was measured in the presence of the ROK inhibitor Y27632. Illness severity was evaluated using sequential organ failure assessment (SOFA) and acute physiology and chronic health evaluation (APACHE) II scores. Western blot analysis of [Ser19]MLC20 and [Thr855]MYPT phosphorylation quantified activation and inhibition of platelet MLC20 and MLCP, respectively. Data were analysed using Spearman's rank correlation coefficient, Student's t-test and Mann-Whitney test; p < 0.05 was considered significant. RESULTS: Agonist-induced aggregation was attenuated in septic shock patients (n = 22 to 34; p < 0.05). Aggregation correlated inversely with SOFA and APACHE II scores (n = 34; p < 0.05). Thr855 phosphorylation of MYPT from unstimulated platelets was not decreased in patients with septic shock (n = 22 to 24). Both septic shock and ROK inhibition attenuated arachidonic acid-induced platelet aggregation independent of changes in [Ser19]MLC20 and [Thr855]MYPT phosphorylation (n = 14). CONCLUSIONS: Impairment of whole blood aggregation in patients within the first 24 h of septic shock was correlated with SOFA and APACHE II scores. Attenuated aggregation was independent of molecular evidence of diminished platelet contraction or reduced ROK inhibition of MLCP. Efforts to restore platelet function in septic shock should therefore focus on platelet adhesion and degranulation.

Thrombogenic Risk in Patients With Atrial Fibrillation: Importance of Comorbid Conditions and Intracardiac Changes.

OBJECTIVES: This study sought to determine the differences between the prothrombotic properties and chamber characteristics in patients with lone atrial fibrillation (AF) and those with AF and comorbidities. BACKGROUND: Thromboembolic risk is increased in patients with AF; however, whether this is due to AF per se or its comorbidities remains unclear. METHODS: A total of 87 patients undergoing ablation were prospectively recruited for the study, including 30 patients with lone AF, 30 patients with AF and comorbidities in sinus rhythm, and 27 patients with left-sided accessory pathways as controls. Blood samples were obtained from the left atrium (LA), right atrium (RA), and femoral vein (FV) after transseptal puncture. Platelet activation (P-selectin) was measured by flow cytometry. Thrombin generation (thrombin-antithrombin [TAT] complex), endothelial dysfunction (asymmetric-dimethylarginine [ADMA]), and platelet-derived inflammation (soluble CD40 ligand [sCD40L]) were measured using enzyme-linked immunosorbent assay. RESULTS: Platelet activation in the LA was significantly elevated compared to that in the FV in patients with lone AF and those with AF and comorbidities compared with that in the FV (p < 0.05 respectively). Thrombin generation was significantly elevated in the LA compared with RA in AF patients (p < 0.05). There were no significant differences in P-selectin, TAT, and sCD40L among the 3 groups. However, there was a significant stepwise increase in endothelial dysfunction measured by ADMA from controls to lone AF and then to patients with AF and comorbidities (p < 0.001 between the 2 groups). CONCLUSIONS: Patients with lone AF and those with AF and comorbidities had a greater propensity for atrial thrombogenesis than controls. Prothrombotic risk is greatest in those with comorbid conditions, in whom enhanced thrombogenesis occurs predominantly through increase in endothelial dysfunction.

The effect of laboratory-induced depressed mood state on responses to pain.

Some researchers have suggested that a depressed mood state is associated with alterations in responses to pain. The authors examined cognitive, behavioral, and affective responses of 75 randomly assigned participants to depressed, neutral, or elated mood state induction conditions and subjected them to the cold-pressor task. Because they were unsuccessful in inducing elated moods, the authors used only the data for the depressed and neutral states as they measured pain threshold, tolerance, and unpleasantness during the test. After the task, the authors measured sensory, affective, and evaluative responses to the cold-pressor pain, as well as the participants' catastrophizing ideation about the painful procedure. The depressed mood state group, compared with the neutral group, had significantly lower cold-pressor tolerance times and higher pain catastrophizing scores. These results support previous findings that a depressed mood state may be associated with alterations in some pain responses.