OBJECTIVE—Previous studies have identified common genetic variants in 4 chromosomal regions that together account for 14% to 15% of the variance in circulating levels of protein C. To further ...characterize the genetic architecture of protein C, we obtained denser coverage at some loci, extended investigation of protein C to low-frequency and rare variants, and searched for new associations in genes known to influence protein C.
APPROACH AND RESULTS—Genetic associations with protein C antigen level were evaluated in ≤10 778 European and 3190 black participants aged 45 to 64 years. Analyses included >26 million autosomal variants available after imputation to the 1000 Genomes reference panel along with additional low-frequency and rare variants directly genotyped using the Illumina ITMAT-Broad-CARe chip and Illumina HumanExome BeadChip. Genome-wide significant associations (P<5×10) were found for common variants in the GCKR, PROC, BAZ1B, and PROCR-EDEM2 regions in whites and PROC and PROCR-EDEM2 regions in blacks, confirming earlier findings. In a novel finding, the low-density lipoprotein cholesterol–lowering allele of rs12740374, located in the CELSR2–PSRC1–SORT1 region, was associated with lower protein C level in both whites and blacks, reaching genome-wide significance in a meta-analysis combining results from both groups (P=1.4×10). To further investigate a possible link between lipid metabolism and protein C level, we conducted Mendelian randomization analyses using 185 lipid-related genetic variants as instrumental variables. The results indicated that triglycerides, and possibly low-density lipoprotein cholesterol, influence protein C levels.
CONCLUSIONS—Discovery of variants influencing circulating protein C levels in the CELSR2–PSRC1–SORT1 region may indicate a novel genetic link between lipoprotein metabolism and hemostasis.
Genome-wide association studies have identified single-nucleotide polymorphisms that are associated with an increased risk of stroke. We sought to determine whether a genetic risk score (GRS) could ...identify subjects at higher risk for ischemic stroke after accounting for traditional clinical risk factors in 5 trials across the spectrum of cardiometabolic disease.
Subjects who had consented for genetic testing and who were of European ancestry from the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation), SOLID-TIMI 52 (Stabilization of Plaques Using Darapladib), SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus), PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin), and FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) trials were included in this analysis. A set of 32 single-nucleotide polymorphisms associated with ischemic stroke was used to calculate a GRS in each patient and identify tertiles of genetic risk. A Cox model was used to calculate hazard ratios for ischemic stroke across genetic risk groups, adjusted for clinical risk factors.
In 51 288 subjects across the 5 trials, a total of 960 subjects had an ischemic stroke over a median follow-up period of 2.5 years. After adjusting for clinical risk factors, a higher GRS was strongly and independently associated with increased risk for ischemic stroke (
trend=0.009). In comparison with individuals in the lowest third of the GRS, individuals in the middle and top tertiles of the GRS had adjusted hazard ratios of 1.15 (95% CI, 0.98-1.36) and 1.24 (95% CI 1.05-1.45) for ischemic stroke, respectively. Stratification into subgroups revealed that the performance of the GRS appeared stronger in the primary prevention cohort with an adjusted hazard ratio for the top versus lowest tertile of 1.27 (95% CI, 1.04-1.53), in comparison with an adjusted hazard ratio of 1.06 (95% CI, 0.81-1.41) in subjects with previous stroke. In an exploratory analysis of patients with atrial fibrillation and CHA
DS
-VASc score of 2, high genetic risk conferred a 4-fold higher risk of stroke and an absolute risk equivalent to those with CHA
DS
-VASc score of 3.
Across a broad spectrum of subjects with cardiometabolic disease, a 32-single-nucleotide polymorphism GRS was a strong, independent predictor of ischemic stroke. In patients with atrial fibrillation but lower CHA
DS
-VASc scores, the GRS identified patients with risk comparable to those with higher CHA
DS
-VASc scores.
Atrial fibrillation (AF) affects over 33 million individuals worldwide. Genome-wide association studies have identified at least 30 AF loci, but the mechanisms through which individual variants lead ...to altered disease risk have remained unclear for the majority of these loci. At the 1q24 locus, we hypothesized that the transcription factor
could be a strong candidate gene as it is expressed in the pulmonary veins, a source of AF in many individuals. We sought to identify the molecular mechanism, whereby variation at 1q24 may lead to AF susceptibility.
We sequenced a ≈158 kb region encompassing
in 962 individuals with and without AF. We identified a broad region of association with AF at the 1q24 locus. Using in silico prediction and functional validation, we identified an enhancer that interacts with the promoter of
in cells of cardiac lineage. Within this enhancer, we identified a single-nucleotide polymorphism, rs577676, which alters enhancer activity in a mouse atrial cell line and in embryonic zebrafish and differentially regulates
expression in human left atria. We found that suppression of
in human embryonic stem cell-derived cardiomyocytes and embryonic zebrafish resulted in shortening of the atrial action potential duration, a hallmark of AF.
We have identified a functional genetic variant that alters
expression, ultimately resulting in electrophysiological alterations in atrial myocytes that may promote AF.
BACKGROUND:Atrial fibrillation (AF) may occur after an acute precipitant and subsequently resolve. Management guidelines for AF in these settings are unclear as the risk of recurrent AF and related ...morbidity is poorly understood. We examined the relations between acute precipitants of AF and long-term recurrence of AF in a clinical setting.
METHODS:From a multi-institutional longitudinal electronic medical record database, we identified patients with newly diagnosed AF between 2000 and 2014. We developed algorithms to identify acute AF precipitants (surgery, sepsis, pneumonia, pneumothorax, respiratory failure, myocardial infarction, thyrotoxicosis, alcohol, pericarditis, pulmonary embolism, and myocarditis). We assessed risks of AF recurrence in individuals with and without a precipitant and the relations between AF recurrence and heart failure, stroke, and mortality.
RESULTS:Among 10 723 patients with newly diagnosed AF (67.9±9.9 years, 41% women), 19% had an acute AF precipitant, the most common of which were cardiac surgery (22%), pneumonia (20%), and noncardiothoracic surgery (15%). The cumulative incidence of AF recurrence at 5 years was 41% among individuals with a precipitant compared with 52% in those without a precipitant (adjusted hazard ratio HR, 0.75 95% CI, 0.69–0.81; P<0.001). The lowest risk of recurrence among those with precipitants occurred with postoperative AF (5-year incidence 32% in cardiac surgery and 39% in noncardiothoracic surgery). Regardless of the presence of an initial precipitant, recurrent AF was associated with increased adjusted risks of heart failure (hazard ratio, 2.74 95% CI, 2.39–3.15; P<0.001), stroke (hazard ratio, 1.57 95% CI, 1.30–1.90; P<0.001), and mortality (hazard ratio, 2.96 95% CI, 2.70–3.24; P<0.001).
CONCLUSIONS:AF after an acute precipitant frequently recurs, although the risk of recurrence is lower than among individuals without an acute precipitant. Recurrence is associated with substantial long-term morbidity and mortality. Future studies should address surveillance and management after newly diagnosed AF in the setting of an acute precipitant.
Physical activity is regarded as favorable to health but effects across the spectrum of human disease are poorly quantified. In contrast to self-reported measures, wearable accelerometers can provide ...more precise and reproducible activity quantification. Using wrist-worn accelerometry data from the UK Biobank prospective cohort study, we test associations between moderate-to-vigorous physical activity (MVPA) - both total MVPA minutes and whether MVPA is above a guideline-based threshold of ≥150 min/week-and incidence of 697 diseases using Cox proportional hazards models adjusted for age, sex, body mass index, smoking, Townsend Deprivation Index, educational attainment, diet quality, alcohol use, blood pressure, anti-hypertensive use. We correct for multiplicity at a false discovery rate of 1%. We perform analogous testing using self-reported MVPA. Among 96,244 adults wearing accelerometers for one week (age 62 ± 8 years), MVPA is associated with 373 (54%) tested diseases over a median 6.3 years of follow-up. Greater MVPA is overwhelmingly associated with lower disease risk (98% of associations) with hazard ratios (HRs) ranging 0.70-0.98 per 150 min increase in weekly MVPA, and associations spanning all 16 disease categories tested. Overall, associations with lower disease risk are enriched for cardiac (16%), digestive (14%), endocrine/metabolic (10%), and respiratory conditions (8%) (chi-square p < 0.01). Similar patterns are observed using the guideline-based threshold of ≥150 MVPA min/week. Some of the strongest associations with guideline-adherent activity include lower risks of incident heart failure (HR 0.65, 95% CI 0.55-0.77), type 2 diabetes (HR 0.64, 95% CI 0.58-0.71), cholelithiasis (HR 0.61, 95% CI 0.54-0.70), and chronic bronchitis (HR 0.42, 95% CI 0.33-0.54). When assessed within 456,374 individuals providing self-reported MVPA, effect sizes for guideline-adherent activity are substantially smaller (e.g., heart failure HR 0.84, 95% CI 0.80-0.88). Greater wearable device-based physical activity is robustly associated with lower disease incidence. Future studies are warranted to identify potential mechanisms linking physical activity and disease, and assess whether optimization of measured activity can reduce disease risk.
BACKGROUND AND PURPOSE—Classification of stroke as cardioembolic in etiology can be challenging, particularly since the predominant cause, atrial fibrillation (AF), may not be present at the time of ...stroke. Efficient tools that discriminate cardioembolic from noncardioembolic strokes may improve care as anticoagulation is frequently indicated after cardioembolism. We sought to assess and quantify the discriminative power of AF risk as a classifier for cardioembolism in a real-world population of patients with acute ischemic stroke.
METHODS—We performed a cross-sectional analysis of a multi-institutional sample of patients with acute ischemic stroke. We systematically adjudicated stroke subtype and examined associations between AF risk using CHA2DS2-VASc, Cohorts for Heart and Aging Research in Genomic Epidemiology-AF score, and the recently developed Electronic Health Record–Based AF score, and cardioembolic stroke using logistic regression. We compared the ability of AF risk to discriminate cardioembolism by calculating C statistics and sensitivity/specificity cutoffs for cardioembolic stroke.
RESULTS—Of 1431 individuals with ischemic stroke (age, 65±15; 40% women), 323 (22.6%) had cardioembolism. AF risk was significantly associated with cardioembolism (CHA2DS2-VAScodds ratio OR per SD, 1.69 95% CI, 1.49–1.93; Cohorts for Heart and Aging Research in Genomic Epidemiology-AF scoreOR, 2.22 95% CI, 1.90–2.60; electronic Health Record–Based AFOR, 2.55 95% CI, 2.16–3.04). Discrimination was greater for Cohorts for Heart and Aging Research in Genomic Epidemiology-AF score (C index, 0.695 95% CI, 0.663–0.726) and Electronic Health Record–Based AF score (0.713 95% CI, 0.681–0.744) versus CHA2DS2-VASc (C index, 0.651 95% CI, 0.619–0.683). Examination of AF scores across a range of thresholds indicated that AF risk may facilitate identification of individuals at low likelihood of cardioembolism (eg, negative likelihood ratios for Electronic Health Record–Based AF score ranged 0.31–0.10 at sensitivity thresholds 0.90–0.99).
CONCLUSIONS—AF risk scores associate with cardioembolic stroke and exhibit moderate discrimination. Utilization of AF risk scores at the time of stroke may be most useful for identifying individuals at low probability of cardioembolism. Future analyses are warranted to assess whether stroke subtype classification can be enhanced to improve outcomes in undifferentiated stroke.
This study investigated the relationship of the catch rates (CRs) of Spanish mackerel (
Scomberomorus commerson
) with oceanographic factors in the waters around Taiwan by using high-resolution ...fishery and environmental data for the period 2011–2016. The investigation results revealed that trammel nets accounted for 69.79% of the total catch of
S. commerson
and were operated mostly in the Taiwan Strait (TS). We noted seasonal variations in the distribution of high CRs. These CRs were observed in the southwestern TS, including the waters along the southwestern coast of Taiwan and around the Penghu Islands, and extended to the Taiwan Bank during autumn; they increased in winter. To predict the spatial and temporal patterns of Spanish mackerel density and their relationship with oceanographic and spatiotemporal variables, generalized additive models were used. These models explained 48.4% of the total deviance, which was consistent with the assumed Gaussian distribution. Moreover, all variables examined were significant CR predictors (
p <
0.05). Latitude and longitude were the key factors influencing the spatiotemporal distribution of
S. commerson
, and sea surface chlorophyll
a
concentration was a key oceanographic factor. Observing projected changes in El Niño/Southern Oscillation events for
S. commerson
revealed that CRs were higher and distributed further southward during La Niña events than during other events. We inferred that the
S. commerson
distribution gradually moved toward the southwest with the northeast monsoon, which was enhanced during La Niña in winter.
Background: Remote ischemic preconditioning (RIPC) has cardioprotective effects. This study was designed to evaluate the effectiveness and potential influencing factors of RIPC for myocardial ...ischemia-reperfusion injury (MIRI) in rats and mice. Methods: The PubMed, Web of Science, Embase, and Cochrane Library databases were searched to identify animal model studies that explored the effect of RIPC on MIRI. The primary outcome was myocardial infarct size, and secondary outcomes included serum cardiac markers, vital signs, hemodynamic parameters, and TUNEL-positive cells. Quality was assessed using SYRCLE’s Risk of Bias Tool. Results: This systematic review and meta-analysis included 713 male animals from 37 studies. RIPC significantly protected against MIRI in small animal models by reducing infarct size, decreasing serum myocardial marker levels and cell death, and improving cardiac function. Subgroup analysis indicated that RIPC duration and sites influence the protective effect of RIPC on MIRI. Meta-regression suggested that study type and staining method might be sources of heterogeneity. The funnel plot, Egger’s test, and Begg’s test suggested the existence of publication bias, but results of the sensitivity analysis and nonparametric trim-and-fill method showed that the overall effect of RIPC on MIRI infarct size was robust. Conclusions: RIPC significantly protected against MIRI in small animal models by reducing infarct size, decreasing serum myocardial markers and limiting cell death, and improving cardiac function. RIPC duration and site influence the protective effect of RIPC on MIRI, which contributes in reducing confounding factors and determines the best approach for human studies.
The toxicity of gadolinium-based contrast agents (GBCAs) has drawn a lot of attention. Nephrogenic systemic fibrosis (NSF), a lethal disease related to the use of GBCAs, is still not understood. ...Recently, gadolinium retention is found in brain tissues after repeated use of GBCAs in magnetic resonance imaging (MRI). However, most of the works investigating the toxicity of GBCAs are focusing on its high-concentration (0.5–10 mM) part, which is not reflective of the physiological conditions in human beings. Macrophages play a regulatory role in immune responses and are responsible for the fibrosis process. Their role in gadolinium retention and the pathogenesis of NSF, however, has seldom been investigated. This study aimed to evaluate the immune response generated by macrophages (RAW 264.7) exposing to low levels of GBCAs. The incubation concentration of GBCAs, including Omniscan®, Primovist®, Magnevist®, and Gadovist®, is proportional to the level of gadolinium uptake when detected via inductively coupled plasma mass spectrometry (ICP-MS) and imaged by MRI, whereas Primovist® treatment groups have highest gadolinium uptake among all of the tested concentrations. Low-concentration (2.5 μmol/L) Gd chloride or GBCAs exposure promoted the reactive production of oxygen species (ROS), nitrate/nitrite, prostaglandin E2 (PGE2), and suppressed the potential of mitochondrial membrane. There was higher ROS, nitrate/nitrite, and PGE2 production in the Primovist®, Omniscan®, and Magnevist® groups compared to the Gadovist® group. In face of lipopolysaccharide (LPS) stimulation, Primovist®, Omniscan®, and Magnevist® groups exhibited elevated nitrite/nitrate and suppressed IL-1β secretion and IL-6 and IL-10 secretion. Moreover, upon LPS stimulation, there is decreased TNF-α secretion 4 hours after Primovist® or Omiscan® exposure but the TNF-α secretion increased at 24 hours. Our data suggest that there is upregulated inflammation even in the presence of low levels of GBCAs, even similar to the physiological condition in murine macrophage. Further investigation of GBCAs on the human macrophage or in vivo animal study may clarify the role of macrophage on the pathogenesis of NSF and other GBCAs-related disease.
This study sought to determine whether the risk of atrial fibrillation AF can be estimated accurately by using routinely ascertained features in the electronic health record (EHR) and whether AF risk ...is associated with stroke.
Early diagnosis of AF and treatment with anticoagulation may prevent strokes.
Using a multi-institutional EHR, this study identified 412,085 individuals 45 to 95 years of age without prevalent AF between 2000 and 2014. A prediction model was derived and validated for 5-year AF risk by using split-sample validation and model performance was compared with other methods of AF risk assessment.
Within 5 years, 14,334 individuals developed AF. In the derivation sample (7,216 AF events of 206,042 total), the optimal risk model included sex, age, race, smoking, height, weight, diastolic blood pressure, hypertension, hyperlipidemia, heart failure, coronary heart disease, valvular disease, prior stroke, peripheral arterial disease, chronic kidney disease, hypothyroidism, and quadratic terms for height, weight, and age. In the validation sample (7,118 AF events of 206,043 total) the AF risk model demonstrated good discrimination (C-statistic: 0.777; 95% confidence interval CI: 0.771 to 0.783) and calibration (0.99; 95% CI: 0.96 to 1.01). Model discrimination and calibration were superior to CHARGE-AF (Cohorts for Heart and Aging Research in Genomic Epidemiology AF) (C-statistic: 0.753; 95% CI: 0.747 to 0.759; calibration slope: 0.72; 95% CI: 0.71 to 0.74), C2HEST (Coronary artery disease / chronic obstructive pulmonary disease; Hypertension; Elderly age ≥75 years; Systolic heart failure; Thyroid disease hyperthyroidism) (C-statistic: 0.754; 95% CI: 0.747 to 0.762; calibration slope: 0.44; 95% CI: 0.43 to 0.45), and CHA2DS2-VASc (Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Prior stroke, transient ischemic attack TIA, or thromboembolism, Vascular disease, Age 65–74 years, Sex category female) scores (C-statistic: 0.702; 95% CI: 0.693 to 0.710; calibration slope: 0.37; 95% CI: 0.36 to 0.38). AF risk discriminated incident stroke (n = 4,814; C-statistic: 0.684; 95% CI: 0.677 to 0.692) and stroke within 90 days of incident AF (n = 327; C-statistic: 0.789; 95% CI: 0.764 to 0.814).
A model developed from a real-world EHR database predicted AF accurately and stratified stroke risk. Incorporating AF prediction into EHRs may enable risk-guided screening for AF.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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