Suspected association of ventricular arrhythmia with air pollution in a motorbike rider: a case report

<p>Abstract</p> <p>Introduction</p> <p>Premature ventricular complexes are to some extent a normal finding in healthy individuals and the prevalence increases with age and is more common in men. Premature ventricular complexes can occur in association with a variety of stimuli, and a lesser known cause is the association between air pollution and ventricular arrhythmias.</p> <p>Case presentation</p> <p>A previously healthy man started to ride a lightweight motorbike in heavy traffic. A few weeks later he was admitted to hospital with premature ventricular complexes in bigeminy, which decreased after a few days when he was not exposed to exhaust fumes. A few weeks later he started using the motorbike again and the same symptoms developed once more, only to subside when he stopped riding in heavy traffic.</p> <p>Conclusion</p> <p>Studies have shown an association between air pollution and premature ventricular complexes and other kinds of arrhythmias. The mechanism may be changes in cardiac autonomic function, including heart rate and heart rate variability. Air pollution should be considered when patients present with arrhythmias and no other causes are found.</p

Integrative genomic analysis of the human immune response to influenza vaccination

Identification of the host genetic factors that contribute to variation in vaccine responsiveness may uncover important mechanisms affecting vaccine efficacy. We carried out an integrative, longitudinal study combining genetic, transcriptional, and immunologic data in humans given seasonal influenza vaccine. We identified 20 genes exhibiting a transcriptional response to vaccination, significant genotype effects on gene expression, and correlation between the transcriptional and antibody responses. The results show that variation at the level of genes involved in membrane trafficking and antigen processing significantly influences the human response to influenza vaccination. More broadly, we demonstrate that an integrative study design is an efficient alternative to existing methods for the identification of genes involved in complex traits. DOI: http://dx.doi.org/10.7554/eLife.00299.00

High-Resolution Mapping of Expression-QTLs Yields Insight into Human Gene Regulation

Recent studies of the HapMap lymphoblastoid cell lines have identified large numbers of quantitative trait loci for gene expression (eQTLs). Reanalyzing these data using a novel Bayesian hierarchical model, we were able to create a surprisingly high-resolution map of the typical locations of sites that affect mRNA levels in cis. Strikingly, we found a strong enrichment of eQTLs in the 250 bp just upstream of the transcription end site (TES), in addition to an enrichment around the transcription start site (TSS). Most eQTLs lie either within genes or close to genes; for example, we estimate that only 5% of eQTLs lie more than 20 kb upstream of the TSS. After controlling for position effects, SNPs in exons are ∼2-fold more likely than SNPs in introns to be eQTLs. Our results suggest an important role for mRNA stability in determining steady-state mRNA levels, and highlight the potential of eQTL mapping as a high-resolution tool for studying the determinants of gene regulation

Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease

Background--Plasminogen activator inhibitor type 1 (PAI-1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI-1 levels are associated with increased risk of coronary heart disease (CHD). However, it is unclear whether the association reflects a causal influence of PAI-1 on CHD risk. Methods and Results--To evaluate the association between PAI-1 and CHD, we applied a 3-step strategy. First, we investigated the observational association between PAI-1 and CHD incidence using a systematic review based on a literature search for PAI-1 and CHD studies. Second, we explored the causal association between PAI-1 and CHD using a Mendelian randomization approach using summary statistics from large genome-wide association studies. Finally, we explored the causal effect of PAI-1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta-analysis, the highest quantile of blood PAI-1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age- and sex-adjusted model. The effect size was reduced in studies using a multivariable-adjusted model (odds ratio=1.46; 95% CI: 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI-1 level on CHD risk (odds ratio=1.22 per unit increase of log-transformed PAI-1; 95% CI: 1.01, 1.47). In addition, we also detected a causal effect of PAI-1 on elevating blood glucose and high-density lipoprotein cholesterol. Conclusions--Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Mitralisringens rörelse under vänsterkammarens pumparbete

This thesis focus on the role of the mitral annulus motion (MAM) versus outer contour changes in the short axis, in left ventricular (LV) pumping. The influence of atrial contraction on LV dimensions and volumes and the relation between MAM and ejection fraction (EF) in sinus rhythm and in atrial fibrillation was also studied. Echocardiography was used in all studies and in the study about circumflex artery motion angiography was also used. In a study including 20 healthy adults the role of MAM, i.e. the systolic shortening of the left ventricle in the long axis, as the main mechanism of LV pumping was confirmed. There was also, however, a significant contribution to the stroke volume from an outer contour decrease in the short axis during systole. At the chordae tendineae level a cross sectional area decrease of 24% was measured. From calculations based on measures of the long axis shortening of the LV, the outer short axis diameter of the LV and calculated stroke volume, a mean systolic cross sectional area decrease of about 6% was found along the whole length of the ventricle. The higher cross-sectional area decrease at the chordae level is thougth to be caused by regional differences. In previous studies the relation between EF and MAM has been assumed to be linear, but in a meta-analysis of 434 patients it was shown that the relation is non-linear and that a linear regression model overestimates EF in the low range of MAM. It was shown that the relation between EF and MAM in adults is influenced by age but only in the normal range of EF or MAM and not in patients with decreased EF (EF &lt;0.5 or MAM &lt; 10mm). The relation was also shown to be influenced by the LV wall thickness. In 20 patients with atrial fibrillation the ratio EF/MAM was shown to be higher than in 20 age- and gender matched patients with sinus rhythm, due to a decrease in MAM, caused by the loss of atrial contraction. The relation between EF and MAM is thus complex and it therefore seems logical not to "translate" MAM to EF. MAM should be used as such related to reference values in the assessment of LV systolic function. In 13 patients who had atrial fibrillation the stroke volume was shown to increase after successful direct-current cardioversion due to an increase in long axis diastolic elongation of the LV and thereby increased diastolic volume, when atrial contraction was regained. In 28 patients the angiographic measure of circumflex artery motion amplitude tended to be higher than MAM in the higher range of amplitudes while the opposite was found in the lower range of amplitudes. In 13 patients with normal EF it was shown that the motion amplitude of a site epicardially at the most basal lateral part of the LV wall was significantly (P &lt; 0.001) higher than endocardially, but in 13 patients with decreased EF (&lt; 0.5) there was no significant difference between the two sites. The motion amplitude epicardially corresponds to the motion amplitude of the circumflex artery. In the 13 patients with normal EF the motion amplitude of the closed mitral valves was significantly lower than the motion amplitude epi- and endocardially during systole, with a rather conic shape of the atrioventricular plane at the onset of systole. In end-systole the different parts of the left atrioventricular plane, the epicardial part, the endocardial part (mitral annulus) and the valves were almost on the same level.Den här avhandlingen fokuserar på den roll som mitralringsrörelsen (MRR), d v s vänster kammares (VK) förkortning i längsaxelriktning, och yttre konturforändringen i kortaxelriktning spelar under kammarens kontraktion. Förmakskontraktionernas inverkan på VK dimensioner och volymer samt relationen mellan MRR och ejektionsfraktion (EF) hos patienter med sinusrytm och förmaksflimmer studeras också. Ekokardiografi (ultraljud av hjärtat) användes i alla studier och i studien om arteria cirkumflexas rörelse användes också angiografi (kranskärlsröntgen). I ett delarbete med 20 friska vuxna bekräftas rollen av MRR, d v s den systoliska forkortningen av VK i längsaxeliktning, som den huvudsakliga mekanismen for VK:s pumparbete. I tillägg till detta finns dock ett signifikant bidrag till slagvolymen genom en forändring av den yttre konturen i kortaxelriktning under systole. På chordae tendineae nivå minskar tvärsnittsytan med ungefar 24% under systole. Genom beräkningar, som bygger på forkortningen av VK i längaxelriktning under systole, VK:s yttre kortaxel diameter och berälmad slagvolym, erhålls en systolisk minskning av tvärsnittsytan i medeltal på cirka 6% längs hela VK:s längd. Den större minskningen av tvärsnittsytan i höjd med chordae tendineae antas bero på regionala skillnader i ytterkonturen av VK under systole. I tidigare studier harrelationen mellan EF och MRR antagits vara linjär, men i en metastudie med 434 patienter visas att relationen är icke-linjär och att en linjär regressionsmodell överskattar EF i det lägre intervallet av MRR. Det visas att relationen mellan EF och MRR hos vuxna påverkas av åldern i det normala intervallet av EF eller IviRR, men inte hos patienter med nedsatt EF (EF &lt; 0.5 eller MRR &lt; 10 mm). Det visas också att relationen mellan EF och MRR påverkas av VK:s väggtjocklek. Hos 20 patientermed formaksflimmer visas att kvoten EF/MRR är högre än hos 20 ålders- och könsmatchade patienter med sinusrytm, beroende på en minskning av MRR genom förlusten av förmakskontraktionerna hos patienterna med förmaksflimmer. Relationen mellan EF och MRR är sålunda komplex och det förefaller därför logiskt att inte "översätta" MRR till EF utan istället använda MRR som sådan i relation till referensvärden vid bedömning av V K: s systoliska funktion. Hos 13 patientermed förmaksflimmervisas att slagvolymen ökar efter framgångsrik elkonvertering beroende på en ökad diastolisk förlängning av VIC och därigenom ökad diastolisk volym när förmakskontraktionerna återkommer. Hos 28 patienter visas att de angiografiska måtten på cirkumflexans rörelseamplitud tenderar att vara högre än MRR i det högre intervallet av amplituder medan motsatsen gäller i det lägre intervallet av amplituder. Hos 13 patienter med normal EF visas att rörelseamplituden for en punkt epikardiellt vid den mest basala laterala delen av VK-väggen är signifikant högre än endokardiet, men hos 13 patienter med nedsatt EF (&lt; 0.5) är det ingen signifikant skillnad mellan de två mätställena. Den epikardiella rörelseamplituden motsvarar cirkumflexans rörelseamplitud. Hos 13 patienter mednormal EF visas att rörelseamplituden för de stängda mitralldaffama under systele är signifikant lägre än rörelseamplituderna epi- och endokardiellt. Atrioventrikulärplanet intar en ganska konisk fmm i början av systole. Mot slutet av systele befinner sig de olika delarna av atrioventrikulärplanet, den epikardiella delen, den endokardiella delen (milralringen) och mitraiklaffama på nästan samma nivå