Background
As the population of obese and severely obese young adults grows, it is becoming increasingly important to recognize the long‐term risks associated with adolescent obesity.
Objectives
This ...study aimed to determine the association between body mass index (BMI) in young men at enlistment for military service and later risk of venous thromboembolism (VTE).
Methods
Nationwide register‐based prospective cohort study of men enlisting 1969 to 2005, followed through the Swedish National Patient and Cause of Death registries. We identified 1 639 838 men (mean age, 18.3 years) free of prior venous thromboembolism, of whom 29 342 were obese (BMI 30 to <35 kg m−2) and 7236 severely obese (BMI ≥ 35 kg m−2). The participants were followed until a first registered diagnosis of VTE.
Results
During a median follow‐up of 28 years (interquartile interval, 20 to 36 years), 11 395 cases of deep vein thrombosis and 7270 cases of pulmonary embolism were recorded. Compared with men with a BMI of 18.5 to <20 kg m−2, men with higher BMI in young adulthood showed an incrementally increasing risk of VTE that was moderately but significantly increased already at normal BMI levels. Adolescent obese men with a BMI of 30 to 35 kg m−2 had an adjusted hazard ratio of 2.93 (95% confidence interval, 2.65 to 3.24) for VTE. Severely obese men with a BMI of ≥35 kg m−2 had a hazard ratio of 4.95 (95% confidence interval, 4.16 to 5.90).
Conclusions
Men who were obese or severely obese in young adulthood had a marked increase in risk of VTE.
Essentials
Stimulating endogenous fibrinolysis could be a novel antithrombotic strategy.
The effect of valproic acid on endothelial tissue plasminogen activator in mice was investigated.
Valproic ...acid increased tissue plasminogen activator expression in vascular endothelium.
Valproic acid reduced fibrin deposition and thrombus formation after vascular injury.
Summary
Background
The endogenous fibrinolytic system has rarely been considered as a target to prevent thrombotic disease. Tissue‐type plasminogen activator (t‐PA) production is potently increased by histone deacetylase (HDAC) inhibitors in endothelial cells in vitro, but whether this translates into increased vascular t‐PA production and an enhanced fibrinolytic capacity in vivo is unknown.
Objectives
To determine whether the HDAC inhibitor valproic acid (VPA) stimulates production of t‐PA in the vasculature of mice, and whether VPA pretreatment affects fibrin deposition and clot formation after mechanical vessel injury.
Methods
Mice were injected with VPA twice daily for up to 5 days. t‐PA mRNA, and antigen expression in the mouse aorta and the circulating levels of t‐PA were determined. Fibrin and thrombus dynamics after mechanical vessel injury were monitored with intravital confocal microscopy. Potential effects of VPA on platelets and coagulation were investigated.
Results and Conclusions
We found that VPA treatment increased vascular t‐PA production in vivo and, importantly, that VPA administration was associated with reduced fibrin accumulation and smaller thrombi in response to vascular injury, but still was not associated with an increased risk of bleeding. Furthermore, we observed that higher concentrations of VPA were required to stimulate t‐PA production in the brain than in the vasculature. Thus, this study shows that VPA can be dosed to selectively manipulate the fibrinolytic system in the vascular compartment and reduce thrombus formation in vivo.
► We examined the non-lipid lowering effects of statins in endothelial cells. ► Combinatory effects of shear stress, statins, TNF-α on hemostatic genes were studied. ► Statins have anti-inflammatory ...effects counteracting the effect of TNF-α. ► Statins have endothelial protective properties against unfavorable flow profiles. ► Time to reconsider the therapeutic window of statins?
Atherosclerotic plaque formation and progression are dependent on local shear stress patterns and inflammatory cytokines. Statins effectively reduce the progression of atherosclerosis and the incidence of cardiovascular events. However, the benefit of statins cannot be explained by cholesterol reduction alone. This study, investigated the non-lipid lowering effects of simvastatin and rosuvastatin on endothelial anti- and prothrombotic genes under different biomechanical and inflammatory stress conditions. Endothelial cells responded in a similar way to simvastatin and rosuvastatin. However, they were more sensitive to simvastatin. The statins had anti-inflammatory properties counteracting the TNF-α effect on the hemostatic genes studied. There was no observed synergistic effect between shear stress and simvastatin. Simvastatin had a counteracting effect on t-PA and PAI-1 compared to TNF-α and shear stress. Simvastatin blocked the TNF-α suppressive effect on thrombomodulin and eNOS, irrespective of shear stress. The strong inductive effect of TNF-α on VCAM-1 was counteracted by simvastatin and shear stress in an additive dose–response dependent way.
Biomechanical stress modulates vascular tone, vascular remodelling and the spatial localisation of atherosclerotic plaques. Inflammatory cytokines, such as TNF-α, regulate expression of genes that ...impair the function of endothelial cells. This study investigates the combinatory effect of different biomechanical stresses and TNF-α on the expression of endothelial anti- and prothrombotic genes. Human umbilical vein endothelial cells were exposed to TNF-α and different levels of static/pulsatile tensile stress or shear stress. The response in endothelial cells to TNF-α was not modulated by tensile stress. However, shear stress was a more potent stimulus. Shear stress counteracted the cytokine-induced expression of VCAM-1, and the cytokine-suppressed expression of thrombomodulin and eNOS. Shear stress and TNF-α additively induced PAI-1, whereas shear stress blocked the cytokine effect on t-PA and u-PA. A flow profile characterized by high laminar shear stress seems to render the endothelial cell more resistant to inflammatory stress.
Free, biologically active tissue‐type plasminogen activator (tPA) is the main initiator of intravascular fibrinolysis, but little is known about the regulation of active tPA on the organ level. The ...aim was to investigate if the local availability of active tPA on the organ level depends on the local release rate of tPA or the arterial input of tPA and plasminogen activator inhibitor type 1 (PAI‐1). Also, we wanted to evaluate if plasma levels predict capacity for endothelial release of fibrinolytic proteins. Invasive perfused‐forearm studies were performed in 96 healthy subjects. Local release rates of fibrinolytic proteins were assessed at baseline and during endothelial stimulation. Stimulation by methacholine and desmopressin induced a 6‐ and 12‐fold increase in total tPA release rates, respectively. With increasing local release rates of tPA a gradually closer correlation emerged between the total tPA secretion and the forearm output of active tPA (from r = 0.102, ns to r = 0.85, P < 0.0001). Forearm availability of active tPA was not related to arterial input of either tPA or PAI‐1. Release rates and plasma levels of tPA were not correlated. Baseline release rates of active tPA increased to noon. The major determinant for the local availability of active tPA is the capacity of the endothelium to release tPA rather than the arterial input of PAI‐1 or tPA. Despite a molar excess of PAI‐1, the majority of tPA released during stimulation does not undergo local inactivation. The capacity to release tPA locally cannot be predicted from its plasma concentration.
Aims: Myocardial ischemia remains a significant perioperative complication in coronary artery disease (CAD) patients. We hypothesized that noxious stimuli during major surgery are associated with an ...acute release of tissue‐type plasminogen activator (t‐PA) into the coronary circulation, and that this response is reduced by CAD.
Methods and results: Two patient groups, with (n=14) and without (n=8) CAD, were studied during the initial phase of heart surgery. After retrograde great cardiac vein catheterizations during closed‐chest conditions, coronary arterial–venous concentration gradients of t‐PA and plasminogen activator inhibitor type‐1 (PAI‐1) were measured together with coronary blood flow measurements, allowing derivation of coronary net release rates. Pre‐surgery atrial pacing, performed to evaluate the influence of increases in heart rate (+40 beats/min) and coronary blood flow (+80 ml/min), did not significantly alter coronary net release of t‐PA or PAI‐1 in either patient group. Sternotomy induced a prominent increase in coronary net release of both total and active t‐PA in the non‐CAD group. This response was considerably reduced in the CAD group.
Conclusions: This study provides the first analysis of coronary t‐PA release during major surgery and demonstrates a deficient local endothelial t‐PA release in patients with CAD. This suggests a reduced local fibrinolytic capacity in CAD patients, which may explain the increased risk for coronary thrombosis in this patient group.
. Ridderstråle W, Saluveer O, Johansson MC, Bergbrant A, Jern S, Hrafnkelsdóttir TJ (Sahlgrenska University Hospital Östra, Gothenburg; AstraZeneca, Mölndal, Sweden, Landspítali University Hospital, ...Reykjavík, Iceland). Consistency of blood pressure and impact on cardiovascular structure over 20 years in young men. J Intern Med 2010; 267: 295–304.
Objective. To identify, in a prospective study, how blood pressure levels at the age of twenty predict hypertension and cardiovascular remodelling 20 years later.
Methods. Twenty‐year‐old men with blood pressure (BP) elevation systolic blood pressure (SBP) 140–160 and/or diastolic blood pressure (DBP) 85–95 mmHg; blood pressure elevation (BPE) group or normal BP SBP 110–130 and DBP 60–80 mmHg; normal controls (NC) group entered the study in 1987. In 2007, follow‐up was conducted including ambulatory BP, echocardiography, anthropometric and intima media thickness (IMT) measurements.
Results. Assessed with 24‐h ambulatory BP, the prevalence of hypertension was 35/47 (74.5%) and 1/17 (5.9%) in the BPE and NC group at follow‐up respectively. Twenty‐four hour mean arterial pressure (MAP) increased from 86.6 (0.8) to 97.2 (1.2) (P < 0.0001), and from 83.1 (1.5) to 88.1 (1.2) mmHg (P < 0.01) from baseline to follow‐up in the BPE and NC group respectively. At follow‐up, left ventricular mass index (LVMI) was 122 (4) and 106 (4) g m−1 in the BPE and NC group (unpaired t‐test; P < 0.01) respectively, whilst IMT was 0.61 (0.01) and 0.57 (0.01) mm in the BPE and NC group (P < 0.05) respectively. In a logistic regression model, prevalence of hypertension was best explained by office MAP and 24‐h DBP at baseline (R2 0.333; P < 0.05). A combined model of office MAP, body mass index and insulin levels at baseline explained 56% of LVMI at follow‐up.
Conclusions. BP elevation in young age predicts hypertension and adverse cardiovascular remodelling at the age of 40 years. Baseline office MAP is the best predictor of hypertension, 24‐h MAP and LVMI.
African Americans have greater precordial QRS voltages than whites, with concomitant higher prevalences of electrocardiographic (ECG) left ventricular hypertrophy (LVH) and lower specificity of ECG ...LVH criteria for the identification of anatomic hypertrophy. However, the high mortality associated with LVH in African American patients makes more accurate ECG detection of LVH in these patients a clinical priority.
Electrocardiograms and echocardiograms were obtained at study baseline in 120 African American and 751 white hypertensive patients enrolled in the Losartan Intervention For Endpoint (LIFE) echocardiographic substudy. The ECG LVH was determined using Sokolow-Lyon, 12-lead sum, and Cornell voltage criteria. Echocardiographic LVH was defined by LV mass indexed to height
2.7 >46.7 g/m
2.7 in women and >49.1 g/m
2.7 in men.
After adjusting for ethnic differences in LV mass, body mass index, sex, and prevalence of diabetes, mean Sokolow-Lyon and 12-lead sum of voltage were significantly higher, but Cornell voltage was lower, in African Americans than in whites. As a consequence of these differences, when identical partition values were used in both ethnic groups, Sokolow-Lyon and 12-lead voltage criteria had lower specificity in African Americans than whites (44%
v 69%,
P = .007 and 44%
v 59%,
P = .10) but had greater sensitivity in African Americans (51%
v 27%,
P < .001 and 62%
v 45%,
P = .003). In contrast, Cornell voltage specificity was higher (78%
v 62%,
P = .09) but sensitivity was slightly lower (49%
v 57%,
P = 0.16) in African Americans. However, when overall test performance was compared using receiver operating curve analyses that were independent of partition value selection, ethnic differences in test performance disappeared, with no differences in accuracy of any of the ECG voltage criteria for the identification of LVH between African American and white hypertensive individuals.
When standard, non–ethnicity-specific thresholds for the identification of LVH are used, Sokolow-Lyon and 12-lead voltage overestimate and Cornell voltage underestimates the presence and severity of LVH in African American relative to white individuals. However, these apparent ethnic differences in test performance disappear when ethnic differences in the distribution of ECG LVH criteria are taken into account. These findings demonstrate that ethnicity-specific ECG criteria can equalize detection of anatomic LVH in African American and white patients.
The mechanism of ADP‐mediated platelet activation has been difficult to unravel due to the large number of receptors for extracellular nucleotides (P2 receptors). mRNA levels in circulating platelets ...are very low, but have been shown to be translationally active. By optimizing mRNA extraction and using real time (RT)‐PCR we were able to establish a protocol for highly sensitive platelet mRNA quantification in human regular blood samples. In platelets from healthy volunteers, only P2X1, P2Y1 and P2Y12 were found in significant levels, with the following order of expression: P2Y12 >> P2X1 > P2Y1. Other P2 receptors (P2Y2, P2Y4, P2Y6, P2Y11, P2Y13, P2X4, P2X7) had very low expression. As a control measurement to exclude contamination, P2 receptors in buffy coat were quantified but had a completely different profile. Incubation in vitro revealed a more rapid degradation rate for P2X1 receptor mRNA than for P2Y1 and P2Y12, indicating that the level of P2X1 may be relatively higher in newly released platelets and in megacaryocytes. In conclusion, we have developed the first protocol for quantifying mRNA expression in human platelets limiting the P2 receptor drug development targets to P2Y12, P2Y1 and P2X1. Furthermore, the method could be used to study platelet expression for any gene in human materials.
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