Search

Treatment with beta-blockers is characterized by inferior reduction of central versus peripheral blood pressure. We examined changes in blood pressure, cardiac function, and vascular resistance after 3 weeks of bisoprolol treatment (5 mg/day) during passive head-up tilt in 16 never-treated Caucasian males with grade I–II primary hypertension. A double-blind, randomized, placebo-controlled cross-over design was applied, and hemodynamics were recorded using continuous tonometric pulse wave analysis and whole-body impedance cardiography. Bisoprolol decreased blood pressure in the aorta (~8/10 mmHg, p ≤ 0.032) and radial artery (~10/9 mmHg, p ≤ 0.037), but upright aortic systolic blood pressure was not significantly reduced (p = 0.085). Bisoprolol reduced heart rate and left cardiac work, and increased subendocardial viability index in supine and upright positions (p ≤ 0.044 for all). Bisoprolol increased stroke volume in the supine (~11 ml, p = 0.02) but not in the upright position, while only upright (~1 l/min, p = 0.007) but not supine cardiac output was reduced. Upright elevation in systemic vascular resistance was increased 2.7-fold (p = 0.002), while upright pulse pressure amplification was decreased by ~20% (p = 0.002) after bisoprolol. Aortic augmentation index, augmentation pressure, and pulse pressure were not changed in the supine position but were increased in the upright position (from 9% to 17%, 3–6 mmHg, and 30–34 mmHg, respectively, p ≤ 0.016 for all). In conclusion, although bisoprolol treatment reduced peripheral blood pressure, central systolic blood pressure in the upright position was not decreased. Importantly, the harmful influences of bisoprolol on central pulse pressure and pressure wave reflection were manifested in the upright position.

Background Cardiac involvement accounts for the majority of morbidity and mortality in sarcoidosis. Pathological myocardial fluorodeoxyglucose (FDG)-uptake in positron emission tomography (PET) has been associated with cardiovascular events and quantitative metabolic parameters have been shown to add prognostic value. Our aim was to study whether the pattern of pathological cardiac FDG-uptake and quantitative parameters are able to predict cardiovascular events in patients with suspected cardiac sarcoidosis (CS). Methods 137 FDG-PET examinations performed in Tampere University Hospital were retrospectively analyzed visually and quantitatively. Location of pathological uptake was noted and pathological metabolic volume, average standardized uptake value (SUV), and total cardiac metabolic activity (tCMA) were calculated. Patients were followed for ventricular tachycardia, decrease in left ventricular ejection fraction, and death. Results Eleven patients had one or more cardiovascular events during the follow-up. Five patients out of 12 with uptake in both ventricles had an event during follow-up. Eight patients had high tCMA (> 900 MBq) and three of them had a cardiovascular event. Right ventricular uptake and tCMA were significantly associated with cardiovascular events during follow-up (P-value .001 and .018, respectively). Conclusions High tCMA and right ventricular uptake were significant risk markers for cardiac events among patient with suspected CS.

Increased levels of circulating cell-free DNA (cf-DNA) are associated with and predict poor health outcomes. However, its predictive ability for mortality in population-based samples remains understudied. We analysed the capability of cf-DNA to predict all-cause mortality and assessed whether it adds predictive value on top of the other risk factors in the Health 2000 survey (n = 1,257, 46–76 years of age, 15-years-follow-up, 18% deceased). When analysed in a multivariate model with the other factors that independently predicted mortality in the sample (age, gender, self-rated health, smoking and plasma levels of glucose and adiponectin), increases in cf-DNA levels were associated with increased risk of mortality (hazard ratio [HR] for 0.1 µg increase in cf-DNA: 1.017, 95% confidence interval [CI] 1.008–1.026, p = 0.0003). Inclusion of cf-DNA in the model improved the model fit and discrimination. Stratifying the analysis by cardiovascular disease (CVD) status indicated that cf-DNA predicted mortality equally well in individuals with (HR 1.018, 95% CI 1.008–1.026, p = 0.002) and without (HR 1.018, 95% CI 1.001–1.035, p = 0.033) CVD. In conclusion, our study indicates that cf-DNA level predicts mortality in middle-aged and older individuals, also among those with established CVD, and adds significant value to mortality prediction. Our results thus underscore the role of cf-DNA as a viable marker of health.

Human personality is 30–60% heritable according to twin and adoption studies. Hundreds of genetic variants are expected to influence its complex development, but few have been identified. We used a machine learning method for genome-wide association studies (GWAS) to uncover complex genotypic–phenotypic networks and environmental interactions. The Temperament and Character Inventory (TCI) measured the self-regulatory components of personality critical for health (i.e., the character traits of self-directedness, cooperativeness, and self-transcendence). In a discovery sample of 2149 healthy Finns, we identified sets of single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (i.e., SNP sets) regardless of phenotype. Second, we identified five clusters of people with distinct profiles of character traits regardless of genotype. Third, we found 42 SNP sets that identified 727 gene loci and were significantly associated with one or more of the character profiles. Each character profile was related to different SNP sets with distinct molecular processes and neuronal functions. Environmental influences measured in childhood and adulthood had small but significant effects. We confirmed the replicability of 95% of the 42 SNP sets in healthy Korean and German samples, as well as their associations with character. The identified SNPs explained nearly all the heritability expected for character in each sample (50 to 58%). We conclude that self-regulatory personality traits are strongly influenced by organized interactions among more than 700 genes despite variable cultures and environments. These gene sets modulate specific molecular processes in brain for intentional goal-setting, self-reflection, empathy, and episodic learning and memory.

Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (similar to 6 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 x 10(-49)), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.

Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P, Cardiovascular diseases (CVD) are associated with plasma lipid levels. Here, Tabassum et al. perform genome-wide association studies for lipidomic profiles with 141 (non-standard) lipid species which highlights shared genetic loci with CVD and that traditional lipids have low genetic correlation with other lipids.

Hematologic measures such as hematocrit and white blood cell (WBC) count are heritable and clinically relevant. We analyzed erythrocyte and WBC phenotypes in 52,531 individuals (37,775 of European ancestry, 11,589 African Americans, and 3,167 Hispanic Americans) from 16 population-based cohorts with Illumina HumanExome BeadChip genotypes. We then performed replication analyses of new discoveries in 18,018 European-American women and 5,261 Han Chinese. We identified and replicated four new erythrocyte trait-locus associations (CEP89, SHROOM3, FADS2, and APOE) and six new WBC loci for neutrophil count (S1PR4), monocyte count (BTBD8, NLRP12, and IL17RA), eosinophil count (IRF1), and total WBC count (MYB). The association of a rare missense variant in S1PR4 supports the role of sphingosine-1-phosphate signaling in leukocyte trafficking and circulating neutrophil counts. Loss-of-function experiments for S1pr4 in mouse and s1pr4 in zebrafish demonstrated phenotypes consistent with the association observed in humans and altered kinetics of neutrophil recruitment and resolution in response to tissue injury.

α-melanocyte-stimulating hormone (α-MSH) is processed from pro-opiomelanocortin (POMC) and mediates anti-inflammatory actions in leukocytes. α-MSH also promotes macrophage reverse cholesterol transport by inducing ATP-binding cassette transporters ABCA1 and ABCG1. Here we investigated the regulation of POMC and α-MSH expression in atherosclerosis. First, transcript levels of POMC and its processing enzymes were analyzed in human arterial plaques (n = 68) and non-atherosclerotic controls (n = 24) as well as in whole blood samples from coronary artery disease patients (n = 55) and controls (n = 45) by microarray. POMC expression was increased in femoral plaques compared to control samples as well as in unstable advanced plaques. α-MSH-producing enzyme, carboxypeptidase E, was down-regulated, whereas prolylcarboxypeptidase, an enzyme inactivating α-MSH, was up-regulated in unstable plaques compared to stable plaques, suggesting a possible reduction in intraplaque α-MSH levels. Second, immunohistochemical analyses revealed the presence of α-MSH in atherosclerotic plaques and its localization in macrophages and other cell types. Lastly, supporting the role of α-MSH in reverse cholesterol transport, POMC expression correlated with ABCA1 and ABCG1 in human plaque and whole blood samples. In conclusion, α-MSH is expressed in atherosclerotic plaques and its processing enzymes associate with plaque stability, suggesting that measures to enhance the local bioavailability of α-MSH might protect against atherosclerosis.

Fatty liver (FL) disease is the most common type of chronic liver disease. We hypothesized that liver’s response to the process where large droplets of triglyceride fat accumulate in liver cells is reflected also in gene pathway expression in blood. Peripheral blood genome wide gene expression analysis and ultrasonic imaging of liver were performed for 1,650 participants (316 individuals with FL and 1,334 controls) of the Young Finns Study. Gene set enrichment analysis (GSEA) was performed for the expression data. Fourteen gene sets were upregulated (false discovery rate, FDR

Scientific Reports 7: Article number: 45040; published online: 28 April 2017; updated: 26 May 2017 The original version of this Article contained a typographical error in the spelling of the author Martin H. de Borst, which was incorrectly given as Martin de Borst. This has now been corrected in both the PDF and HTML versions of the Article.

High L-homoarginine (hArg) levels are directly associated with several risk factors for cardiometabolic diseases whereas low levels predict increased mortality in prospective studies. The biomarker role of hArg in young adults remains unknown. To study the predictive value of hArg in the development of cardiometabolic risk factors and diseases, we utilized data on high-pressure liquid chromatography-measured hArg, cardiovascular risk factors, ultrasound markers of preclinical atherosclerosis and type 2 diabetes from the population-based Young Finns Study involving 2,106 young adults (54.6% females, aged 24–39). We used a Mendelian randomization approach involving tens to hundreds of thousands of individuals to test causal associations. In our 10-year follow-up analysis, hArg served as an independent predictor for future hyperglycaemia (OR 1.31, 95% CI 1.06–1.63) and abdominal obesity (OR 1.60, 95% 1.14–2.30) in men and type 2 diabetes in women (OR 1.55, 95% CI 1.02–2.41). The MR analysis revealed no evidence of causal associations between serum hArg and any of the studied cardiometabolic outcomes. In conclusion, lifetime exposure to higher levels of circulating hArg does not seem to alter cardiometabolic disease risk. Whether hArg could be used as a biomarker for identification of individuals at risk developing cardiometabolic abnormalities merits further investigation., published version, peerReviewed

Cardiovascular diseases due to atherosclerosis are the leading cause of death globally. We aimed to investigate the potentially altered gene and pathway expression in advanced peripheral atherosclerotic plaques in comparison to healthy control arteries. Gene expression analysis was performed (Illumina HumanHT-12 version 3 Expression BeadChip) for 68 advanced atherosclerotic plaques (15 aortic, 29 carotid and 24 femoral plaques) and 28 controls (left internal thoracic artery (LITA)) from Tampere Vascular Study. Dysregulation of individual genes was compared to healthy controls and between plaques from different arterial beds and Ingenuity pathway analysis was conducted on genes with a fold change (FC) > ±1.5 and false discovery rate (FDR) 20). 156 pathways were differentially expressed in atherosclerotic plaques, mostly inflammation-related, especially related with leukocyte trafficking and signaling. In artery specific plaque analysis 50.4% of canonical pathways and 41.2% GO terms differentially expressed were in common for all three arterial beds. Our results confirm the inflammatory nature of advanced atherosclerosis and show novel pathway differences between different arterial beds.

The epigenetic clock, defined as the DNA methylome age (DNAmAge), is a candidate biomarker of ageing. In this study, we aimed to characterize the behaviour of this marker during the human lifespan in more detail using two follow-up cohorts (the Young Finns study, calendar age i.e. cAge range at baseline 15-24 years, 25-year-follow-up, N = 183; The Vitality 90+ study, cAge range at baseline 19-90 years, 4-year-follow-up, N = 48). We also aimed to assess the relationship between DNAmAge estimate and the blood cell distributions, as both of these measures are known to change as a function of age. The subjects' DNAmAges were determined using Horvath's calculator of epigenetic cAge. The estimate of the DNA methylome age acceleration (Δ-cAge-DNAmAge) demonstrated remarkable stability in both cohorts: the individual rank orders of the DNAmAges remained largely unchanged during the follow-ups. The blood cell distributions also demonstrated significant intra-individual correlation between the baseline and follow-up time points. Interestingly, the immunosenescence-associated features (CD8+CD28- and CD4+CD28- cell proportions and the CD4/CD8 cell ratio) were tightly associated with the estimate of the DNA methylome age. In summary, our data demonstrate that the general level of Δ-cAge-DNAmAge is fixed before adulthood and appears to be quite stationary thereafter, even in the oldest-old ages. Moreover, the blood DNAmAge estimate seems to be tightly associated with ageing-associated shifts in blood cell composition, especially with those that are the hallmarks of immunosenescence. Overall, these observations contribute to the understanding of the longitudinal aspects of the DNAmAge estimate.

Cytomegalovirus (CMV) causes an infection, which is followed by a lifelong latency. CMV has received much attention in clinical studies, but little is known about the genetic basis of this common infection. To identify genetic polymorphisms associated with the susceptibility to and strength of anti-CMV immunoglobulin G (IgG) response to CMV infection, we conducted a genome-wide association study (GWAS) using an Illumina BeadChip containing 670 000 probes and participants from the Cardiovascular Risk in Young Finns Study, including 1486 anti-CMV IgG seropositive and 648 seronegative individuals. Statistical analyses were performed using logistic (for susceptibility) and linear regression (for strength of antibody response). None of single-nucleotide polymorphisms (SNPs) was found to be associated with susceptibility to CMV infection at the level of genome-wide significance (P5 × 10(-8)). Also, none of the association signals identified reached genome-wide levels of statistical significance in the study of the strength of the antibody response to CMV although five SNPs in AGBL1 gene region displayed a suggestive association (lowest P-value=1.86 × 10(-6)). The results indicate that there is no strong evidence of major host genetic factors involved in either susceptibility to or the strength of antibody response to human CMV infection.

We evaluated the adult bone structural traits in relation to childhood overweight in 832 men and women. Childhood overweight was associated with larger cross-sections at long bones in both sexes. Excess weight in childhood may also lead to higher trabecular density in females and somewhat lower cortical density in men. Excess body weight in childhood may impose more loading on growing skeleton and thus lead to more robust structure in adulthood. This prospective cohort study evaluated the adult bone structural traits in relation to childhood overweight in a subgroup of 456 women and 376 men from the population-based cohort of Cardiovascular Risks in Young Finns Study. Between-group differences were evaluated with analysis of covariance. According to established body mass index (BMI) criterion at the age of 12 years, 31 women and 34 men were classified overweight in childhood. At the mean age (SD) of 36.1 (2.7) years, total cross-sectional (ToA) and cortical area (CoA) at the distal and shaft sites and cortical (shaft CoD) and trabecular (distal TrD) bone density of the nonweight-bearing radius and weight-bearing tibia were evaluated with pQCT. Despite being taller in adolescence, the adult body height of overweight children was similar. In both sexes, childhood overweight was consistently associated with 5–10% larger ToA at all bone sites measured in adulthood. CoA did not show such a consistent pattern. Women, who were overweight in childhood, had ~5% denser TrD with no difference in CoD. In contrast, TrD in men who were overweight in childhood was not different but their CoD was ~1% lower. Childhood overweight was consistently associated with larger long bone cross-sections in both sexes. Excess weight in childhood may also lead to higher trabecular density in women and somewhat lower cortical density in men. Specific mechanisms underlying these associations are not known.

Recent healthcare policies have influenced the manner in which patient data is handled in research projects, and the regulations concerning protected health information have become significantly tighter. Thus, new procedures are needed to facilitate research while protecting the confidentiality of patient data and ensuring the integrity of clinical work in the expanding environment of electronic files and databases. We have addressed this problem in a university hospital setting by developing the Tampere Research Archival System (TARAS), an extensive data warehouse for research purposes. This dynamic system includes numerous integrated and pseudonymized imaging studies and clinical data. In a pilot study on asthma patients, we tested and improved the functionality of the data archival system. TARAS is feasible to use in retrieving, analyzing, and processing both image and non-image data. In this paper, we present a detailed workflow of the implementation process of the data warehouse, paying special attention to administrative, ethical, practical, and data security concerns. The establishment of TARAS will enhance and accelerate research practice at Tampere University Hospital, while also improving the safety of patient information as well as the prospects for national and international research collaboration. We hope that much can be learned from our experience of planning, designing, and implementing a research data warehouse combining imaging studies and medical records in a university hospital.

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits1, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait2,3. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways ( P=0.016) and that underlie skeletal growth defects ( P

Summary Peripheral bone strength and fracture risk were studied in young adult Finns. Peripheral bone measures were associated with risk factors of osteoporosis in young adults and discriminated between those with and without low-energy fractures. In men, trabecular bone loss at peripheral bone sites starts before the age of 40 years.

Use of lipid-lowering agents, mainly statins, is a proven strategy to prevent cardiovascular disease events. Because most of the beneficial effect of statins is accounted for by the improved lipid profile, more than 40 genes have been studied to ascertain whether variation therein modulates lipid response or prevention of cardiovascular disease during statin therapy. In addition, recent studies have also shown that genetic variation may stratify pleiotropic statin effects. Although this review briefly covers the pharmacogenetic implications on biochemical markers such as low-density lipoprotein cholesterol, it mainly focuses on recent findings (after 2005) on cardiovascular disease outcomes during statin therapy. Pharmacogenomic analysis of large trials of statin treatment is becoming a predominant trend. Another future direction is genome-wide analysis, which will reveal additional candidate genes to be further tested in prospective trials. The results so far are preliminary, and successful replication of the findings is needed in large unrelated populations before the evidence for any polymorphism is solid enough for clinical applications.

We tested the hypothesis that the change from the peak to recovery values of systolic arterial pressure (SAP recovery) and rate-pressure product (RPP recovery) can be used to predict all-cause and cardiovascular mortality, as well as sudden cardiac death (SCD) in patients referred to a clinical exercise stress test. As a part of the Finnish Cardiovascular Study (FINCAVAS), consecutive patients (n=2029; mean age+/-SD=57+/-13 years; 1290 men and 739 women) with a clinically indicated exercise test using a bicycle ergometer were included in the present study. Capacities of attenuated SAP recovery, RPP recovery and heart rate recovery (HRR) to stratify the risk of death were estimated. During a follow-up (mean+/-s.d.) of 47+/-13 months, 122 patients died; 58 of the deaths were cardiovascular and 33 were SCD. In Cox regression analysis after adjustment for the peak level of the variable under assessment, age, sex, use of beta-blockers, previous myocardial infarction and other common coronary risk factors, the hazard ratio of the continuous variable RPP recovery (in units 1000 mm Hg x b.p.m.) was 0.85 (95% CI: 0.73-0.98) for SCD, 0.87 (0.78-0.97) for cardiovascular mortality, and 0.87 (0.81 to 0.94) for all-cause mortality. SAP recovery was not a predictor of mortality. The relative risks of having HRR below 18 b.p.m., a widely used cutoff point, were as follows: for SCD 1.28 (0.59-2.81, ns), for cardiovascular mortality 2.39 (1.34-4.26) and for all-cause mortality 2.40 (1.61-3.58). In conclusion, as a readily available parameter, RPP recovery is a promising candidate for a prognostic marker.

Generalized arteriolar narrowing is one of the retinal changes influenced by systemic hypertension. The ratio of retinal arteriolar to venular diameters is often used as a marker of generalized arteriolar narrowing. There are several ways to determine the retinal arteriovenous ratio (A/V ratio). However, no comparison of retinal vascular measurements and A/V ratios determined by different formulae has been presented. Eighty-seven men participating in the Tampere Ambulatory Hypertension Study returned for a 10-year follow-up examination in which fundus photographs were taken of both eyes. The diameters of retinal arterioles and venules were measured 1 and 2 disc diameters from the optic disc edge. The A/V ratio was determined using mean arteriole and venule width, the sum of widths of arterioles and venules, the sum of squares of widths of arterioles and venules, the central retinal artery equivalent (CRAE) and the central retinal venous equivalent (CRVE). The repeatability of measurements and A/V ratios was determined. Comparison was made between A/V ratios determined by different calculation formulas. In general, determination of A/V ratios yielded lower deviation than that of diameters of arterioles and venules separately. Calculation of A/V ratios using different formulas gave different ratio levels. According to linear regression analysis, the A/V ratio calculated using the sum of squares of widths of arterioles and venules correlated best with CRAE/CRVE (R 2 0.92) and A/V ratios calculated using the mean arteriole and venule widths or the sum of widths of arterioles and venules resulted in clearly lower associations (R 2 0.38–0.40 and R2 0.41–0.48, respectively). Of all A/V ratios, CRAE/CRVE had the best repeatability. No statistically significant differences were found between measurements from right and left eyes. The high repeatability of CRAE/CRVE and sum of squares of widths of arterioles/sum of squares of widths of venules, as well as the good association of the two formulae, favor the use of these in evaluation of retinal vascular changes in systemic diseases. Our results also showed that if only one eye can be examined, it seems to suffice if fundus vascular alterations associated with systemic hypertension are evaluated.

The purpose of the study was to compare the systemic safety and risk-benefit ratio of 0.1% timolol hydrogel and 0.5% aqueous timolol eye drops in the treatment of glaucoma.An 8-week randomised, double-blind, cross-over, multicentre study. A total of 25 patients with primary open-angle glaucoma, exfoliation glaucoma, or ocular hypertension was enrolled. After completing a wash-out period, patients were randomly chosen to receive either 0.1% timolol hydrogel once daily or 0.5% aqueous timolol eye drops twice daily. Intraocular pressure and heart rate during rest and exercise, head-up tilt test results, spirometry readings, and plasma concentrations of timolol were recorded. The risk-benefit ratio was determined by calculating the ratio between several heart rate endpoints and the change in intraocular pressure (IOP).The mean drug-induced change in the peak heart rate during exercise was -13.5 beats/min (SD 7.6) in the 0.5% aqueous timolol group and -5.1 beats/min (SD 6.7) in the 0.1% timolol hydrogel group (P0.001; 95% CI 4.06-12.18). There was no significant difference in the IOP-reducing efficacy between these compounds. The risk-benefit ratio was significantly improved when 0.1% timolol hydrogel was used, compared with 0.5% aqueous timolol in the exercise test. In the head-up tilt test the risk-benefit ratio was significantly improved at rest (P0.05), at 1 min (P0.05) and at 5 min (P0.001) after patients had received 0.1% timolol hydrogel. There were, however, no differences in spirometry readings. After patients had been treated with 0.1% timolol hydrogel, plasma concentrations of timolol were 1/6 (at peak) and 1/50 (at trough) of those of 0.5% aqueous timolol.Drug-induced changes in the peak heart rate, and head-up tilt test results as well as plasma concentrations of timolol, were significantly more pronounced after treatment with 0.5% aqueous timolol than with 0.1% timolol hydrogel. Because of the statistically similar IOP-reducing efficacy of these formulations the risk-benefit ratio was significantly improved when patients used 0.1% timolol hydrogel instead of 0.5% aqueous timolol.

To test the hypotheses that (1) CYP2D6 genotype is associated with pharmacokinetics of ophthalmic timolol and (2) variation in genotypes of ADRB1 (beta(1)-adrenoceptor) and GNAS1 (alpha-subunit of G-protein) modulate heart rate (HR), and systolic (SAP) and diastolic (DAP) arterial pressure responses to timolol.Nineteen glaucoma patients and eighteen healthy volunteers were treated with 0.5% aqueous and 0.1% hydrogel formulations of ophthalmic timolol using a randomised cross-over design. The participants conducted head-up tilt and maximum exercise test at four visits. Plasma concentration of timolol was measured twice for glaucoma patients and ten times for healthy volunteers on each visit. Also, the genotypes for CYP2D6, ADRB1 and GNAS1 were determined.Among healthy volunteers using aqueous timolol, poor metabolisers (PMs, n=2) of CYP2D6 had higher maximum plasma concentrations (C(max), values 2.63 and 2.94 ng/ml), longer elimination half-lives ( T(1/2), 5.49 and 6.75 h), and higher area-under-curve (AUC, 19.54 and 23.25 ng.h/ml) than intermediate [IMs, n=6, mean+/-SD 1.73+/-0.59 ng/ml (not significant), 3.30+/-0.48 h, 11.32+/-3.72 ng.h/ml], extensive (EMs, n=8, 1.60+/-0.72 ng/ml, 3.24+/-1.24 h, 8.52+/-6.12 ng.h/ml) and ultra-rapid (UMs, n=2, values 1.23 and 1.67 ng/ml, 2.22 and 2.52 h, 6.16 and 6.94 ng.h/ml) metabolisers. The IMs, EMs and UMs did not differ from each other for any of the kinetic variables. Also, the elevation of HR from rest to maximum level tended to differ between PMs and IMs, and between PMs and UMs. The pharmacokinetics and pharmacodynamics between the CYP2D6 groups did not differ with statistical significance when hydrogel timolol was used. Upon head-up tilt, the Ser49 homozygotes (n=26) had higher SAP (P=0.03) and DAP (P0.01) than the Gly carriers (n=11). The change in DAP from rest to maximum during exercise was lower (P0.01) in subjects with CC alleles of GNAS1 (n=13) than those with at least one T allele (n=24).The CYP2D6 poor metabolisers may be more prone to systemic adverse events with aqueous timolol than extensive metabolisers. Since CYP2D6 genotyping is not routine clinical practice, using 0.1% timolol hydrogel instead of 0.5% aqueous preparation will increase patient safety.

The aims of the study were to assess the correlation between the plasma concentration of ophthalmic timolol and cardiovascular parameters, and the influence of timolol on advanced haemodynamic variables, such as stroke (SI), cardiac (CI) and systemic vascular resistance (SVRI) indices and arterial pulse wave velocity (PWV). Twenty-five glaucoma or ocular hypertensive patients were treated with 0.5% aqueous and 0.1% hydrogel formulations of timolol using a randomised, double-masked, crossover, multicentre design. All the patients were subjected to passive head-up tilt, electrocardiography, exercise test and measurement of plasma concentration of timolol. In the analysis, the data on the two treatments were combined, and the Spearman correlation coefficients between the plasma level of timolol and physiological effects were calculated. During the head-up tilt test before rising the bed up, the resting heart rate (HR; R=−0.52, P=0.001) and PWV (R=−0.34, P=0.04) were inversely correlated with timolol level. In the upright position, ophthalmic timolol effectively suppressed the rise in HR (R=−0.36, P=0.03). The SI did not change with timolol concentration, while CI diminished as timolol concentration rose (R=−0.39, P=0.02). The SVRI correlated with timolol concentration (R=0.38, P=0.02). In the exercise test, correlation between HR and plasma level of timolol steadily grew stronger as the load increased, reaching R=−0.60 (P

Objectives: Liquorice consumption elevates blood pressure [1–3], but the liquorice-induced haemodynamic changes in the upright position are unknown. We investigated haemodynamics after liquorice exposure in healthy volunteers during orthostatic challenge. Methods: Haemodynamics were recorded from 22 normotensive subjects during passive 10- minute head-up tilt before and after two weeks of liquorice consumption (glycyrrhizin dose 290–370 mg/day) using radial pulse wave analysis, whole-body impedance cardiography, and spectral analysis of heart rate variability. Thirty age-matched healthy subjects maintaining their habitual diet served as controls. Results: Liquorice ingestion elevated radial systolic (p < 0.001) and diastolic (p = 0.018) blood pressure and systemic vascular resistance (p = 0.037). During orthostatic challenge, heart rate increased less after the liquorice versus control diet (p = 0.003) and low frequency power of heart rate variability decreased within the liquorice group (p = 0.034). Liquorice intake increased central pulse pressure (p < 0.001) and augmentation index (p = 0.002) supine and upright, but in the upright position the elevation of augmentation index was accentuated (p = 0.007). Liquorice diet also increased extracellular fluid volume (p = 0.024) and aortic to popliteal pulse wave velocity (p = 0.027), and aortic characteristic impedance in the upright position (p = 0.002). Conclusions: In addition to increased extracellular fluid volume and large arterial stiffness, two weeks of liquorice ingestion elevated systemic vascular resistance and augmentation index. Measurements performed at rest may underestimate the haemodynamic effects of liquorice ingestion, as enhanced central wave reflection and reduced chronotropic response were especially observed in the upright position.

BACKGROUND: The aims were to evaluate the effect of pregnancy on carotid artery elasticity and determine the associations between maternal lipids, endothelial function and arterial elasticity during pregnancy. METHODS: We examined 99 pregnant and 99 matched non-pregnant control women as part of a population-based prospective cohort study. Carotid artery elasticity indexes; carotid artery distensibility (CAD), Young's elastic modulus (YEM) and stiffness index (SI) as well as brachial artery flow-mediated dilation (FMD) were assessed using ultrasound; serum lipid levels were also determined. RESULTS: SI was 57% and YEM 75% higher and CAD 36% lower in the third trimester group than the corresponding values in the first trimester group. Serum cholesterol and triglyceride levels were significantly higher in women at the end of the pregnancy than at the beginning of pregnancy (P

The majority of the findings concerning arterial physiology and pathophysiology originate from studies with experimental animals, while only limited information exists about the functional characteristics of human arteries. Therefore, the aim of the present work was to compare the control of vascular tone in vitro in mesenteric arterial rings of corresponding size (outer diameter 0.75–1 mm) from humans and Wistar-Kyoto rats. The relaxations to acetylcholine (ACh) were clearly less marked in the mesenteric arteries of humans when compared with rats. How-ever, when calcium ionophore A23187 was used as the vasodilator, the endothelium-mediated relaxations did not significantly differ between these species. The NO synthase inhibitor N G-nitro-l-arginine methyl ester (l-NAME) attenuated the relaxations to ACh and A23187 in both groups. The endothelium-independent relaxations to the β-adrenoceptor agonist isoprenaline and the nitric oxide (NO)-donor nitroprusside were somewhat lower in human arteries, while vasodilation induced by the K+ channel opener cromakalim was similar between humans and rats. Arterial contractile sensitivity to noradrenaline and serotonin was slightly lower in human vessels, whereas contractile sensitivity to KCl was similar between these species. The contractions induced by cumulative addition of Ca2+ with noradrenaline as the agonist were effectively inhibited in both groups by the calcium channel blocker nifedipine, the effect of which was clearly more pronounced in human arteries. In conclusion, the control of vascular tone of isolated arteries of corresponding size from humans and rats appeared to be rather similar. The most marked differences between these species were the impaired endothelium-mediated dilation to ACh and the more pronounced effect of nifedipine on the Ca2+-induced contractions in human arteries.

We evaluated the relationship between the variability in the left ventricular mass index (LVMI) and different hemodynamic factors. LVMI was associated with blood pressure and, in one subgroup, strongly to arterial pulse wave velocity (PWV). High physical activity was connected to increased LVMI, and a combination of low stroke index (SI) and high heart rate (HR) to decreased LVMI.

Responses to cumulative addition of Ca2+ (0.2–2.5 mM) after precontraction with potassium chloride (KCl) and noradrenaline in Ca2+-free medium were studied in isolated mesenteric arterial rings from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). The Ca2+ contractions in 125 mM KCl-stimulated endothelium-denuded rings in the presence of atenolol (10 μM) and phentolamine (10 μM) were less marked in SHR than WKY, although the contractions to high concentrations of KCl in normal organ bath Ca2+ (1.6 mM) were similar in these strains. The difference in Ca2+ contractions between SHR and WKY during KCl stimulation was also present after 10-min pretreatment with 1 mM ethylene glycol bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA) in Ca2+-free medium. However, when noradrenaline (1 μM) was used as the agonist the Ca2+ contractions of endothelium-denuded rings in the two strains were comparable, while exposure to EGTA reduced these responses more effectively in SHR than WKY. Nifedipine (0.5 nM and 10 nM in KCl- and noradrenaline-stimulated rings, respectively) more efficiently inhibited the Ca2+ contractions in hypertensive than in normotensive rats. The presence of intact vascular endothelium attenuated the contractions to Ca2+ addition comparably (during KCl stimulation) or even more (during noradrenaline) in SHR when compared with WKY NG-nitro-L-arginine methyl ester (L-NAME, 0.1 mM) counteracted this attenuation correspondingly in WKY and SHR, and L-arginine (1 mM) restored it in both strains, whereas indomethacin (10 mM) was without effect on the response. However, mesenteric arterial relaxations induced by the endothelium-dependent agonists acetylcholine and ADP in noradrenaline-precontracted (1 μM) rings were clearly impaired in SHR, and also L-NAME (0.1 mM) reduced the responses to acetylcholine more efficiently in SHR. In contrast, the relaxations to acetylcholine and ADP in KCl-precontracted (60 mM) rings in the absence and presence of L-NAME were comparable between the two strains. In conclusion, attenuated contractile response to cumulative Ca2+ addition during stimulation with KCl clearly differentiated arterial smooth muscle of hypertensive and normotensive rats, suggesting altered function of cell membrane in SHR. The more pronounced effect of nifedipine on the response indicates abnormal function of voltage-dependent Ca2+ channels, and higher diminishing effect of EGTA on the contraction during noradrenaline suggests exaggerated action of the chelator on membrane-bound Ca2+ in SHR. Interestingly, the depressant effect of intact endothelium on the Ca2+ contraction response, mediated largely via nitric oxide, was not attenuated in SHR. Furthermore, impaired endothelium-dependent agonist-induced relaxations can be attributed to reduced release of endothelium-derived hyperpolarizing factor in this type of genetic hypertension.

Background The purpose of the Finnish Cardiovascular Study (FINCAVAS) is to construct a risk profile – using genetic, haemodynamic and electrocardiographic (ECG) markers – of individuals at high risk of cardiovascular diseases, events and deaths. Methods and design All patients scheduled for an exercise stress test at Tampere University Hospital and willing to participate have been and will be recruited between October 2001 and December 2007. The final number of participants is estimated to reach 5,000. Technically successful data on exercise tests using a bicycle ergometer have been collected of 2,212 patients (1,400 men and 812 women) by the end of 2004. In addition to repeated measurement of heart rate and blood pressure, digital high-resolution ECG at 500 Hz is recorded continuously during the entire exercise test, including the resting and recovery phases. About 20% of the patients are examined with coronary angiography. Genetic variations known or suspected to alter cardiovascular function or pathophysiology are analysed to elucidate the effects and interactions of these candidate genes, exercise and commonly used cardiovascular medications. Discussion FINCAVAS compiles an extensive set of data on patient history, genetic variation, cardiovascular parameters, ECG markers as well as follow-up data on clinical events, hospitalisations and deaths. The data enables the development of new diagnostic and prognostic tools as well as assessments of the importance of existing markers.

Hostility is a multidimensional personality trait with changing expression over the life course. We performed a genome-wide association study (GWAS) of the components of hostility in a population-based sample of Finnish men and women for whom a total of 2.5 million single-nucleotide polymorphisms (SNPs) were available through direct or in silico genotyping. Hostility dimensions (anger, cynicism and paranoia) were assessed at four time points over a 15-year interval (age range 15-30 years at phase 1 and 30-45 years at phase 4) in 982-1780 participants depending on the hostility measure. Few promising areas from chromosome 14 at 99 cM (top SNPs rs3783337, rs7158754, rs3783332, rs2181102, rs7159195, rs11160570, rs941898, P values3.9 × 10(-8) with nearest gene Enah/Vasp-like (EVL)) were found suggestively to be related to paranoia and from chromosome 7 at 86 cM (top SNPs rs802047, rs802028, rs802030, rs802026, rs802036, rs802025, rs802024, rs802032, rs802049, rs802051, P values6.9 × 10(-7) with nearest gene CROT (carnitine O-octanoyltransferase)) to cynicism, respectively. Some shared suggestive genetic influence for both paranoia and cynicism was also found from chromosome 17 at 2.8 cM (SNPs rs12936442, rs894664, rs6502671, rs7216028) and chromosome 22 at 43 cM (SNPs rs7510759, rs7510924, rs7290560), with nearest genes RAP1 GTPase activating protein 2 (RAP1GAP2) and KIAA1644, respectively. These suggestive associations did not replicate across all measurement times, which warrants further study on these SNPs in other populations.

This study investigates bradykinin and nitric oxide as potential mediators of AT2-receptor-stimulated duodenal mucosal alkaline secretion. Duodenal mucosal alkaline secretion was measured in methohexital- and α-chloralose-anaesthetised rats by means of in situ pH-stat titration. Immunohistochemistry and Western blot were used to identify the BK2 receptors. The AT2 receptor agonist CGP42112A (0.1 μg kg-1 min-1) administered intravenously increased the duodenal mucosal alkaline secretion by ~50 %. This increase was sensitive to the selective BK2 receptor blocker HOE140 (100 ng/kg iv), but not to luminal administration of the NOS blocker L-NAME (0.3 mM). Mean arterial pressure did not differ between groups during the procedures. Immunohistochemistry showed a distinct staining of the crypt epithelium and a moderate staining of basal cytoplasm in villus enterocytes. The results suggest that the AT2-receptor-stimulated alkaline secretion is mediated via BK2 receptors located in the duodenal cryptal mucosal epithelium.

The aim of this study was to explore the principal frequency components of the heart rate and blood pressure variability in the low frequency (LF) and very low frequency (VLF) band. The spectral composition of the R–R interval (RRI) and systolic arterial blood pressure (SAP) in the frequency range below 0.15 Hz were carefully analyzed using three different spectral methods: Fast Fourier transform (FFT), Wigner-Ville distribution (WVD), and autoregression (AR). All spectral methods were used to create time–frequency plots to uncover the principal spectral components that are least dependent on time. The accurate frequencies of these components were calculated from the pole decomposition of the AR spectral density after determining the optimal model order – the most crucial factor when using this method – with the help of FFT and WVD methods. Spectral analysis of the RRI and SAP of 12 healthy subjects revealed that there are always at least three spectral components below 0.15 Hz. The three principal frequency components are 0.026 ± 0.003 (mean ± SD) Hz, 0.076 ± 0.012 Hz, and 0.117 ± 0.016 Hz. These principal components vary only slightly over time. FFT-based coherence and phase-function analysis suggests that the second and third components are related to the baroreflex control of blood pressure, since the phase difference between SAP and RRI was negative and almost constant, whereas the origin of the first component is different since no clear SAP–RRI phase relationship was found. The above data indicate that spontaneous fluctuations in heart rate and blood pressure within the standard low-frequency range of 0.04–0.15 Hz typically occur at two frequency components rather than only at one as widely believed, and these components are not harmonically related. This new observation in humans can help explain divergent results in the literature concerning spontaneous low-frequency oscillations. It also raises methodological and computational questions regarding the usability and validity of the low-frequency spectral band when estimating sympathetic activity and baroreflex gain.