Hemostatic factors and risk of coronary heart disease in general populations: new prospective study and updated meta-analyses

<p>Background: Activation of blood coagulation and fibrinolysis may be associated with increased risk of coronary heart disease. We aimed to assess associations of circulating tissue plasminogen activator (t-PA) antigen, D-dimer and von Willebrand factor (VWF) with coronary heart disease risk.</p> <p>Design: Prospective case-control study, systematic review and meta-analyses.</p> <p>Methods: Measurements were made in 1925 people who had a first-ever nonfatal myocardial infarction or died of coronary heart disease during follow-up (median 19.4 years) and in 3616 controls nested within the prospective population-based Reykjavik Study.</p> <p>Results: Age and sex-adjusted odds ratios for coronary heart disease per 1 standard deviation higher baseline level were 1.25 (1.18, 1.33) for t-PA antigen, 1.01 (0.95, 1.07) for D-dimer and 1.11 (1.05, 1.18) for VWF. After additional adjustment for conventional cardiovascular risk factors, corresponding odds ratios were 1.07 (0.99, 1.14) for t-PA antigen, 1.06 (1.00, 1.13) for D-dimer and 1.08 (1.02, 1.15) for VWF. When combined with the results from previous prospective studies in a random-effects meta-analysis, overall adjusted odds ratios were 1.13 (1.06, 1.21) for t-PA antigen (13 studies, 5494 cases), 1.23 (1.16, 1.32) with D-dimer (18 studies, 6799 cases) and 1.16 (1.10, 1.22) with VWF (15 studies, 6556 cases).</p> <p>Conclusions: Concentrations of t-PA antigen, D-dimer and VWF may be more modestly associated with first-ever CHD events than previously reported. More detailed analysis is required to clarify whether these markers are causal risk factors or simply correlates of coronary heart disease.</p&gt

Patent Foramen Ovale, Ischemic Stroke and Migraine: Systematic Review and Stratified Meta-Analysis of Association Studies

BACKGROUND: Observational data have reported associations between patent foramen ovale (PFO), cryptogenic stroke and migraine. However, randomized trials of PFO closure do not demonstrate a clear benefit either because the underlying association is weaker than previously suggested or because the trials were underpowered. In order to resolve the apparent discrepancy between observational data and randomized trials, we investigated associations between (1) migraine and ischemic stroke, (2) PFO and ischemic stroke, and (3) PFO and migraine. METHODS: Eligibility criteria were consistent; including all studies with specifically defined exposures and outcomes unrestricted by language. We focused on studies at lowest risk of bias by stratifying analyses based on methodological design and quantified associations using fixed-effects meta-analysis models. RESULTS: We included 37 studies of 7,686 identified. Compared to reports in the literature as a whole, studies with population-based comparators showed weaker associations between migraine with aura and cryptogenic ischemic stroke in younger women (OR 1.4; 95% CI 0.9–2.0; 1 study), PFO and ischemic stroke (HR 1.6; 95 CI 1.0–2.5; 2 studies; OR 1.3; 95% CI 0.9–1.9; 3 studies), or PFO and migraine (OR 1.0; 95% CI 0.6–1.6; 1 study). It was not possible to look for interactions or effect modifiers. These results are limited by sources of bias within individual studies. CONCLUSIONS: The overall pairwise associations between PFO, cryptogenic ischemic stroke and migraine do not strongly suggest a causal role for PFO. Ongoing randomized trials of PFO closure may need larger numbers of participants to detect an overall beneficial effect

The role of CO2 decline for the onset of Northern Hemisphere glaciation

The Pliocene–Pleistocene Transition (PPT), from around 3.2 to 2.5 million years ago (Ma), represented a major shift in the climate system and was characterized by a gradual cooling trend and the appearance of large continental ice sheets over northern Eurasia and North America. Paleo evidence indicates that the PPT was accompanied and possibly caused by a decrease in atmospheric CO2, but the temporal resolution of CO2 reconstructions is low for this period of time and uncertainties remain large. Therefore, instead of applying existent CO2 reconstructions we solved an ‘inverse’ problem by finding a schematic CO2 concentration scenario that allows us to simulate the temporal evolution of key climate characteristics in agreement with paleoclimate records. To this end, we performed an ensemble of transient simulations with an Earth system model of intermediate complexity from which we derived a best guess transient CO2 scenario for the interval from 3.2 to 2.4 Ma that gives the best fit between the simulated and reconstructed benthic δ18O and global sea surface temperature evolution. Our data-constrained CO2 scenarios are consistent with recent CO2 reconstructions and suggest a gradual CO2 decline from 375–425 to 275–300 ppm, between 3.2 and 2.4 Ma. In addition to a gradual decline, the best fit to paleoclimate data requires the existence of pronounced CO2 variability coherent with the 41-kyr (1 kyr = 1000 years) obliquity cycle. In our simulations the long-term CO2 decline is accompanied by a relatively abrupt intensification of Northern Hemisphere glaciation at around 2.7 Ma. This is the result of a threshold behaviour of the ice sheets response to gradual CO2 decrease and orbital forcing. The simulated Northern Hemisphere ice sheets during the early Pleistocene glacial cycles reach a maximum volume equivalent to a sea level drop of about 40 m. Both ice volume and benthic δ18O are dominated by 41-kyr cyclicity. Our simulations suggest that before 2.7 Ma Greenland was ice free during summer insolation maxima and only partly ice covered during periods of minimum summer insolation. A fully glaciated Greenland comparable to its present-day ice volume is modelled only during glacial maxima after 2.7 Ma and more continuously after 2.5 Ma

Assessing risk prediction models using individual participant data from multiple studies

Individual participant time-to-event data from multiple prospective epidemiologic studies enable detailed investigation into the predictive ability of risk models. Here we address the challenges in appropriately combining such information across studies. Methods are exemplified by analyses of log C-reactive protein and conventional risk factors for coronary heart disease in the Emerging Risk Factors Collaboration, a collation of individual data from multiple prospective studies with an average follow-up duration of 9.8 years (dates varied).We derive risk prediction models using Cox proportional hazards regression analysis stratified by study and obtain estimates of risk discrimination, Harrell’s concordance index, and Royston’s discrimination measure within each study; we then combine the estimates across studies using aweighted meta-analysis. Various weighting approaches are compared and lead us to recommend using the number of events in each study. We also discuss the calculation of measures of reclassification for multiple studies. We further show that comparison of differences in predictive ability across subgroups should be based only on within-study information and that combining measures of risk discrimination from casecontrol studies and prospective studies is problematic. The concordance index and discrimination measure gave qualitatively similar results throughout. While the concordance index was very heterogeneous between studies, principally because of differing age ranges, the increments in the concordance index from adding log C-reactive protein to conventional risk factors were more homogeneous.Lisa Pennells, Stephen Kaptoge, Ian R. White, Simon G. Thompson, Angela M. Wood and the Emerging Risk Factors Collaboration (Debbie A. Lawlor

Natriuretic peptides and integrated risk assessment for cardiovascular disease. an individual-participant-data meta-analysis

BACKGROUND: Guidelines for primary prevention of cardiovascular diseases focus on prediction of coronary heart disease and stroke. We assessed whether or not measurement of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration could enable a more integrated approach than at present by predicting heart failure and enhancing coronary heart disease and stroke risk assessment. METHODS: In this individual-participant-data meta-analysis, we generated and harmonised individual-participant data from relevant prospective studies via both de-novo NT-proBNP concentration measurement of stored samples and collection of data from studies identified through a systematic search of the literature (PubMed, Scientific Citation Index Expanded, and Embase) for articles published up to Sept 4, 2014, using search terms related to natriuretic peptide family members and the primary outcomes, with no language restrictions. We calculated risk ratios and measures of risk discrimination and reclassification across predicted 10 year risk categories (ie, <5%, 5% to <7·5%, and ≥7·5%), adding assessment of NT-proBNP concentration to that of conventional risk factors (ie, age, sex, smoking status, systolic blood pressure, history of diabetes, and total and HDL cholesterol concentrations). Primary outcomes were the combination of coronary heart disease and stroke, and the combination of coronary heart disease, stroke, and heart failure. FINDINGS: We recorded 5500 coronary heart disease, 4002 stroke, and 2212 heart failure outcomes among 95 617 participants without a history of cardiovascular disease in 40 prospective studies. Risk ratios (for a comparison of the top third vs bottom third of NT-proBNP concentrations, adjusted for conventional risk factors) were 1·76 (95% CI 1·56-1·98) for the combination of coronary heart disease and stroke and 2·00 (1·77-2·26) for the combination of coronary heart disease, stroke, and heart failure. Addition of information about NT-proBNP concentration to a model containing conventional risk factors was associated with a C-index increase of 0·012 (0·010-0·014) and a net reclassification improvement of 0·027 (0·019-0·036) for the combination of coronary heart disease and stroke and a C-index increase of 0·019 (0·016-0·022) and a net reclassification improvement of 0·028 (0·019-0·038) for the combination of coronary heart disease, stroke, and heart failure. INTERPRETATION: In people without baseline cardiovascular disease, NT-proBNP concentration assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention

Rate of telomere shortening and cardiovascular damage: a longitudinal study in the 1946 British Birth Cohort.

AIM: Cross-sectional studies reported associations between short leucocyte telomere length (LTL) and measures of vascular and cardiac damage. However, the contribution of LTL dynamics to the age-related process of cardiovascular (CV) remodelling remains unknown. In this study, we explored whether the rate of LTL shortening can predict CV phenotypes over 10-year follow-up and the influence of established CV risk factors on this relationship. METHODS AND RESULTS: All the participants from the MRC National Survey of Health and Development (NSHD) with measures of LTL and traditional CV risk factors at 53 and 60-64 years and common carotid intima-media thickness (cIMT), cardiac mass and left ventricular function at 60-64 years were included. LTL was measured by real-time polymerase chain reaction and available at both time points in 1033 individuals. While LTL at 53 years was not linked with any CV phenotype at 60-64 years, a negative association was found between LTL and cIMT at 60-64 years (β = -0.017, P = 0.015). However, the strongest association was found between rate of telomere shortening between 53 and 60-64 years and values of cIMT at 60-64 years (β = -0.020, P = 0.006). This association was not affected by adjustment for traditional CV risk factors. Cardiac measurements were not associated with cross-sectional or longitudinal measures of LTL. CONCLUSION: These findings suggest that the rate of progression of cellular ageing in late midlife (reflected by the rate of LTL attrition) relates to vascular damage, independently from contribution of CV risk factor exposure

Targeting inflammation to reduce cardiovascular disease risk: a realistic clinical prospect?

Data from basic science experiments is overwhelmingly supportive of the causal role of immune-inflammatory response(s) at the core of atherosclerosis, and therefore the theoretical potential to manipulate the inflammatory response to prevent cardiovascular events. However, extrapolation to humans requires care and we still lack definitive evidence to show that interfering in immune-inflammatory processes may safely lessen clinical atherosclerosis. In this review, we discuss key therapeutic targets in the treatment of vascular inflammation, placing basic research in to a wider clinical perspective, as well as identifying outstanding questions

Risk of multiple myeloma is associated with polymorphisms within telomerase genes and telomere length

Compelling biological and epidemiological evidences point to a key role of genetic variants of the TERT and TERC genes in cancer development. We analyzed the genetic variability of these two gene regions using samples of 2,267 multiple myeloma (MM) cases and 2,796 healthy controls. We found that a TERT variant, rs2242652, is associated with reduced MM susceptibility (OR?=?0.81; 95% CI: 0.72-0.92; p?=?0.001). In addition we measured the leukocyte telomere length (LTL) in a subgroup of 140 cases who were chemotherapy-free at the time of blood donation and 468 controls, and found that MM patients had longer telomeres compared to controls (OR?=?1.19; 95% CI: 0.63-2.24; ptrend ?=?0.01 comparing the quartile with the longest LTL versus the shortest LTL). Our data suggest the hypothesis of decreased disease risk by genetic variants that reduce the efficiency of the telomerase complex. This reduced efficiency leads to shorter telomere ends, which in turn may also be a marker of decreased MM risk.Grant sponsor: Polish Ministry of Science and Higher Education; Grant number: NN402178334; Grant sponsors: Research Fund at Region Sjaelland, DK; Baden-Wurttemberg State Ministry of Science, Research and Arts; CRIS Foundatio

The importance of snow albedo for ice sheet evolution over the last glacial cycle

The surface energy and mass balance of ice sheets strongly depends on the amount of solar radiation absorbed at the surface, which is mainly controlled by the albedo of snow and ice. Here, using an Earth system model of intermediate complexity, we explore the role played by surface albedo for the simulation of glacial cycles. We show that the evolution of the Northern Hemisphere ice sheets over the last glacial cycle is very sensitive to the representation of snow albedo in the model. It is well known that the albedo of snow depends strongly on snow grain size and the content of light-absorbing impurities. Excluding either the snow aging effect or the dust darkening effect on snow albedo leads to an excessive ice build-up during glacial times and consequently to a failure in simulating deglaciation. While the effect of snow grain growth on snow albedo is well constrained, the albedo reduction due to the presence of dust in snow is much more uncertain because the light-absorbing properties of dust vary widely as a function of dust mineral composition. We also show that assuming slightly different optical properties of dust leads to very different ice sheet and climate evolutions in the model. Conversely, ice sheet evolution is less sensitive to the choice of ice albedo in the model. We conclude that a proper representation of snow albedo is a fundamental prerequisite for a successful simulation of glacial cycles