Plasminogen activator inhitor-1 associates with cardiovascular risk factors in healthy young adults in the Cardiovascular Risk in Young Finns Study

AimsHypofibrinolysis displayed by elevated serum plasminogen activator inhibitor 1 (PAI-1) level has been associated with cardiovascular disease (CVD) and its risk factors such as obesity and insulin resistance. However, no studies have examined associations between PAI-1 and CVD risk factors in healthy subjects. We examined associations between serum PAI-1, ultrasound markers of atherosclerosis and CVD risk factors and whether PAI-1 improves prediction of atherosclerosis over known risk factors in a cohort of asymptomatic adults.MethodsWe analyzed PAI-1 and CVD risk factors and assessed carotid intima-media thickness (cIMT), distensibility (CDist) and the presence of a carotid atherosclerotic plaque and flow-mediated dilation (FMD) ultrasonographically for 2202 adults (993 men and 1,209 women, aged 30–45 years) participating in the ongoing longitudinal cohort study, The Cardiovascular Risk in Young Finns Study. High cIMT was defined as >90th percentile and/or carotid plaque and low CDist and low FMD as <20th percentile.ResultsIn bivariate analyses, PAI-1 correlated directly with cIMT and the risk factors: blood pressure, BMI, waist and hip circumference, alcohol use, total and LDL-cholesterol, triglycerides, glomerular filtration rate, high-sensitivity CRP and glucose (all P < 0.005). PAI-1 was higher in men and increased with age. Inverse correlation was observed with CDist, HDL-cholesterol and adiponectin in both sexes, with testosterone and sex hormone binding globulin in men and with creatinine and oral contraceptive use in women (P < 0.005). Independent direct associations were observed between PAI-1 and waist circumference, serum triglycerides, insulin, alcohol use and age and inverse with serum creatinine, HDL-cholesterol and adiponectin. PAI-1 did not improve estimation of high cIMT, low CDist and low FMD over conventional risk factors (P for difference in area under curve ≥ 0.37).ConclusionPAI-1 was independently associated with several known CVD risk factors, especially obesity markers, in both men and women. However, addition of PAI-1 to known risk factors did not improve cross-sectional prediction of high cIMT, low CDist and low FMD suggesting that PAI-1 is not a clinically important biomarker in early atherosclerosis.     

Acute central nervous system toxicity during treatment of pediatric acute lymphoblastic leukemia: phenotypes,risk factors and genotypes

Central nervous system (CNS) toxicity is common at diagnosis and during treatment of pediatric acute lymphoblastic leukemia (ALL). We studied CNS toxicity in 1,464 children aged 1.0–17.9 years, diagnosed with ALL and treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol. Genome-wide association studies, and a candidate single-nucleotide polymorphism (SNP; n=19) study were performed in 1,166 patients. Findings were validated in an independent Australian cohort of children with ALL (n=797) in whom two phenotypes were evaluated: diverse CNS toxicities (n=103) and methotrexate-related CNS toxicity (n=48). In total, 135/1,464 (9.2%) patients experienced CNS toxicity for a cumulative incidence of 8.7% (95% confidence interval: 7.31–10.20) at 12 months from diagnosis. Patients aged ≥10 years had a higher risk of CNS toxicity than had younger patients (16.3% vs. 7.4%; P<0.001). The most common CNS toxicities were posterior reversible encephalopathy syndrome (n=52, 43 with seizures), sinus venous thrombosis (n=28, 9 with seizures), and isolated seizures (n=16). The most significant SNP identified by the genome-wide association studies did not reach genomic significance (lowest P-value: 1.11x10^-6), but several were annotated in genes regulating neuronal functions. In candidate SNP analysis, ATXN1 rs68082256, related to epilepsy, was associated with seizures in patients <10 years (P=0.01). ATXN1 rs68082256 was validated in the Australian cohort with diverse CNS toxicities (P=0.04). The role of ATXN1 as well as the novel SNP in neurotoxicity in pediatric ALL should be further explored.     

Smoking induced differences in autonomic responses in military pilot candidates

The effects of smoking on autonomic function, the renin—angiotensin—aldosterone system, plasma catecholamine and 11-dehydro-thromboxane B₂ values were studied in 37 young male military pilot candidates, 19 smokers and 18 nonsmokers. There was a higher diastolic blood pressure at rest and higher systolic blood pressure after 5 min during the orthostatic test in smokers. Smokers also had higher diastolic blood pressure levels after exercise in the hand-grip test. Smokers had a lower Valsalva ratio and higher tachycardia ratio in the modified Valsalva manoeuvre, suggesting a degree of autonomic dysfunction. Plasma renin levels at rest and plasma noradrenaline levels after hand-grip test were significantly higher in smokers, implying increased sympathetic activity and enhanced activation of the renin—angiotensin system. Our findings indicate that smoking in fit young men increases sympathetic activity and changes physiological responses to autonomic tests.     

Effects of Low and High Plasma Concentrations of Dexmedetomidine on Myocardial Perfusion and Cardiac Function in Healthy Male Subjects

Background: Dexmedetomidine, a selective [alpha]2-adrenoceptor agonist, has counteracting effects on the cardiovascular system. It mediates sympatholysis by activating [alpha]2 adrenoceptors in the central and peripheral nervous system, and vasoconstriction and vasorelaxation by activating postsynaptic [alpha]2 adrenoceptors in blood vessels. The goal of this study was to determine the effects of therapeutic and high concentrations of dexmedetomidine on myocardial perfusion and cardiac function in healthy subjects.

Methods: The authors studied 12 healthy young men. Myocardial blood flow (assessed with positron emission tomography), myocardial function (by echocardiography), and hemodynamic data were collected before and during low (measured mean plasma concentration, 0.5 ng/ml) and high (5 ng/ml) plasma concentrations of dexmedetomidine.

Results: The low concentration of dexmedetomidine reduced myocardial perfusion (mean difference, -27% from baseline [95% confidence interval, -31 to -23%], P < 0.001) in parallel with a reduction in myocardial oxygen demand (estimated by the rate-pressure product (-23% [-28 to -18%], P < 0.001). The high dexmedetomidine plasma concentration did not further attenuate myocardial perfusion (-3% [-12 to +6%] from low dexmedetomidine, P > 0.05; -29% [-39 to -18%] from baseline, P < 0.001) or statistically significantly affect the rate-pressure product (+5% [0 to +10%], P > 0.05). Systolic myocardial function was attenuated by sympatholysis during the low infusion rate and was further attenuated by a combination of the sustained sympatholysis and increased afterload during the high infusion rate.     

Effects of low and high plasma concentrations of dexmedetomidine on myocardial perfusion and cardiac function in healthy male subjects

BACKGROUND: Dexmedetomidine, a selective alpha2-adrenoceptor agonist, has counteracting effects on the cardiovascular system. It mediates sympatholysis by activating alpha2 adrenoceptors in the central and peripheral nervous system, and vasoconstriction and vasorelaxation by activating postsynaptic alpha2 adrenoceptors in blood vessels. The goal of this study was to determine the effects of therapeutic and high concentrations of dexmedetomidine on myocardial perfusion and cardiac function in healthy subjects. METHODS: The authors studied 12 healthy young men. Myocardial blood flow (assessed with positron emission tomography), myocardial function (by echocardiography), and hemodynamic data were collected before and during low (measured mean plasma concentration, 0.5 ng/ml) and high (5 ng/ml) plasma concentrations of dexmedetomidine. RESULTS: The low concentration of dexmedetomidine reduced myocardial perfusion (mean difference, -27% from baseline [95% confidence interval, -31 to -23%], P < 0.001) in parallel with a reduction in myocardial oxygen demand (estimated by the rate-pressure product (-23% [-28 to -18%], P < 0.001). The high dexmedetomidine plasma concentration did not further attenuate myocardial perfusion (-3% [-12 to +6%] from low dexmedetomidine, P > 0.05; -29% [-39 to -18%] from baseline, P < 0.001) or statistically significantly affect the rate-pressure product (+5% [0 to +10%], P > 0.05). Systolic myocardial function was attenuated by sympatholysis during the low infusion rate and was further attenuated by a combination of the sustained sympatholysis and increased afterload during the high infusion rate. CONCLUSIONS: In healthy subjects, plasma concentrations of dexmedetomidine that significantly exceed the recommended therapeutic level do not seriously attenuate myocardial perfusion below the level that is observed with usual therapeutic concentrations and do not induce evident myocardial ischemia.