Genetic Analyses of Enamel Hypoplasia in Multiethnic Cohorts.

Enamel hypoplasia causes reduction in the thickness of affected enamel and is one of the most common dental anomalies. This defect is caused by environmental and/or genetic factors that interfere with tooth formation, emphasizing the importance of investigating enamel hypoplasia on an epidemiological and genetic level. A genome-wide association of enamel hypoplasia was performed in multiple cohorts, overall comprising 7,159 individuals ranging in age from 7-82 years. Mixed-models were used to test for genetic association while simultaneously accounting for relatedness and genetic population structure. Meta-analysis was then performed. More than 5 million single-nucleotide polymorphisms were tested in individual cohorts. Analyses of the individual cohorts and meta-analysis identified association signals close to genome-wide significance (P < 510-8), and many suggestive association signals (510-8 < P < 510-6) near genes with plausible roles in tooth/enamel development. The strongest association signal (P = 1.5710-9) was observed near BMP2K in one of the individual cohorts. Additional suggestive signals were observed near genes with plausible roles in tooth development in the meta-analysis, such as SLC4A4 which can influence enamel hypoplasia. Additional human genetic studies are needed to replicate these results and functional studies in model systems are needed to validate our findings.

Even "WISE-R?"-an Update on the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation.

PURPOSE OF REVIEW: For over 20 years, the Women's Ischemia Syndrome Evaluation (WISE), a program sponsored by the National Heart, Lung, and Blood Institute, has explored diverse and important aspects of ischemic heart disease in women. RECENT FINDINGS: Women with symptoms and signs of ischemia but no significant epicardial obstructive coronary artery disease (INOCA) were documented to be at elevated risk for recurrent angina hospitalization, major adverse cardiac events, death, and health resource consumption rivaling those with obstructive coronary disease. WISE investigators have advanced our understanding of cardiovascular outcomes, systemic manifestations, psychological variables, socioeconomic factors, genetic contributions, hormonal status, advanced imaging, coronary functional findings, biomarkers, patient-reported outcomes, and treatments pertaining to women with this disease entity. This review delves into the WISE findings subsequent to a prior review1, postulates directions for future research, and asks are we "Even 'WISE-R?'".

Association between cumulative social risk, particulate matter environmental pollutant exposure, and cardiovascular disease risk.

BACKGROUND: Long-term exposure to pollution has been shown to increase risk of cardiovascular disease (CVD) and mortality, and may contribute to the increased risk of CVD among individuals with higher social risk. METHODS: Data from the community-based Heart Strategies Concentrating on Risk Evaluation (HeartSCORE) study were used to quantify Cumulative Social Risk (CSR) by assigning a score of 1 for the presence of each of 4 social risk factors: racial minority, single living, low income, and low educational status. 1-year average air pollution exposure to PM2.5 was estimated using land-use regression models. Associations with clinical outcomes were assessed using Cox models, adjusting for traditional CVD risk factors. The primary clinical outcome was combined all-cause mortality and nonfatal CVD events. RESULTS: Data were available on 1933 participants (mean age 59 years, 66% female, 44% Black). In a median follow up time of 8.3 years, 137 primary clinical outcome events occurred. PM2.5 exposure increased with higher CSR score. PM2.5 was independently associated with clinical outcome (adjusted hazard ratio [HR]: 1.19 [95% CI: 1.00, 1.41]). Participants with ≥2 CSR factors had an adjusted HR of 2.34 (1.48-3.68) compared to those with CSR = 0. The association was attenuated after accounting for PM2.5 (HR: 2.16; [1.34, 3.49]). Mediation analyses indicate that PM2.5 explained 13% of the risk of clinical outcome in individuals with CSR score ≥ 2. CONCLUSION: In a community-based cohort study, we found that the association of increasing CSR with higher CVD and mortality risks is partially accounted for by exposure to PM2.5 environmental pollutants.

Particulate Matter Air Pollution and Racial Differences in Cardiovascular Disease Risk.

OBJECTIVE: We aimed to assess racial differences in air pollution exposures to ambient fine particulate matter (particles with median aerodynamic diameter <2.5 µm [PM2.5]) and black carbon (BC) and their association with cardiovascular disease (CVD) risk factors, arterial endothelial function, incident CVD events, and all-cause mortality. APPROACH AND RESULTS: Data from the HeartSCORE study (Heart Strategies Concentrating on Risk Evaluation) were used to estimate 1-year average air pollution exposure to PM2.5 and BC using land use regression models. Correlates of PM2.5 and BC were assessed using linear regression models. Associations with clinical outcomes were determined using Cox proportional hazards models, adjusting for traditional CVD risk factors. Data were available on 1717 participants (66% women; 45% blacks; 59±8 years). Blacks had significantly higher exposure to PM2.5 (mean 16.1±0.75 versus 15.7±0.73µg/m3; P=0.001) and BC (1.19±0.11 versus 1.16±0.13abs; P=0.001) compared with whites. Exposure to PM2.5, but not BC, was independently associated with higher blood glucose and worse arterial endothelial function. PM2.5 was associated with a higher risk of incident CVD events and all-cause mortality combined for median follow-up of 8.3 years. Blacks had 1.45 (95% CI, 1.00-2.09) higher risk of combined CVD events and all-cause mortality than whites in models adjusted for relevant covariates. This association was modestly attenuated with adjustment for PM2.5. CONCLUSIONS: PM2.5 exposure was associated with elevated blood glucose, worse endothelial function, and incident CVD events and all-cause mortality. Blacks had a higher rate of incident CVD events and all-cause mortality than whites that was only partly explained by higher exposure to PM2.5.

Association of obstructive sleep apnea with microvascular endothelial dysfunction and subclinical coronary artery disease in a community-based population.

Studies have reported an association between obstructive sleep apnea (OSA) and cardiovascular disease (CVD) morbidity and mortality. Proposed mechanisms include endothelial dysfunction and atherosclerosis. We aimed to investigate the associations of OSA with endothelial dysfunction and subclinical atherosclerotic coronary artery disease (CAD), and assess the impact of race on these associations. We used data from the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study, a community-based prospective cohort with approximately equal representation of black and white participants. OSA severity was measured in 765 individuals using the apnea-hypopnea index (AHI). Endothelial dysfunction was measured using the Endo-PAT device, expressed as Framingham reactive hyperemia index (F_RHI). Coronary artery calcium (CAC), a marker of subclinical CAD, was quantified by electron beam computed tomography. There were 498 (65%) female participants, 282 (37%) black individuals, and 204 (26%) participants with moderate/severe OSA (AHI ≥15). In univariate models, moderate/severe OSA was associated with lower F_RHI and higher CAC, as well as several traditional CVD risk factors including older age, male sex, hypertension, diabetes, higher body mass index, and lower high-density lipoprotein cholesterol levels. In a multivariable model, individuals with moderate/severe OSA had 10% lower F_RHI and 35% higher CAC, which did not reach statistical significance ( p=0.08 for both comparisons). There was no significant interaction of race on the association of OSA with F_RHI or CAC ( p-value >0.1 for all comparisons). In a community-based cohort comprised of black and white participants, moderate/severe OSA was modestly associated with endothelial dysfunction and subclinical atherosclerotic CAD. These associations did not vary by race.

Variants on chromosome 4q21 near PKD2 and SIBLINGs are associated with dental caries.

A recent genome-wide association study (GWAS) for dental caries nominated the chromosomal region 4q21 near ABCG2, PKD2 and the SIBLING (small integrin-binding ligand N-linked glycoprotein) gene family. In this investigation, we followed up and fine-mapped this region using a tag-SNP (single-nucleotide polymorphism) approach in 13 age- and race-stratified samples from 6 independent studies (N=4089). Participants were assessed for dental caries via intraoral examination and 49 tag-SNPs were genotyped capturing much of the variation in the 4q21 locus. Linear models were used to test for genetic association, while adjusting for sex, age and components of ancestry. SNPs in and near PKD2 showed significant evidence of association in individual samples of black adults (rs17013735, P-value=0.0009) and white adults (rs11938025; P-value=0.0005; rs2725270, P-value=0.003). Meta-analyses across black adult samples recapitulated the association with rs17013735 (P-value=0.003), which occurs at low frequency in non-African populations, possibly explaining the race specificity of the effect. In addition to race-specific associations, we also observed evidence of gene-by-fluoride exposure interaction effects in white adults for SNP rs2725233 upstream of PKD2 (P=0.002). Our results show evidence of regional replication, though no single variant clearly accounted for the original GWAS signal. Therefore, while we interpret our results as strengthening the hypothesis that chromosome 4q21 may impact dental caries, additional work is needed.

Differences in Hospital Risk-standardized Mortality Rates for Acute Myocardial Infarction When Assessed Using Transferred and Nontransferred Patients.

BACKGROUND: One in 5 patients with acute myocardial infarction (AMI) are transferred between hospitals. However, current hospital performance measures based on AMI mortality exclude these patients from the evaluation of referral hospitals. OBJECTIVE: To determine the relationship between risk-standardized mortality for transferred and nontransferred patients at referral hospitals. RESEARCH DESIGN: This is a retrospective cohort study. SUBJECTS: Fee-for-service Medicare claims from 2011 for patients hospitalized with a primary diagnosis of AMI, at hospitals admitting at least 15 patients in transfer. MEASURES: Hospital-specific risk-standardized 30-day mortality rates (RSMRs) for 2 groups of patients: those admitted through transfer from another hospital, and those natively admitted without a preceding or subsequent interhospital transfer. RESULTS: There were 304 hospitals admitting at least 15 patients in transfer. These hospitals cared for 77,711 natively admitted patients (median, 254; interquartile range, 162-321), and 11,829 patients admitted in transfer (median, 26; interquartile range, 19-46). Risk-standardized mortality rates were higher for natively admitted patients than for those admitted in transfer (mean, 11.5%±1.2% vs. 7.2%±1.1%). There was weak correlation between hospital performance as assessed by RSMR for patients natively admitted versus those admitted in transfer (Pearson r=0.24, P<0.001); when performance was arrayed by quartile, 102 hospitals (33.6%) differed at least 2 quartiles of performance across the 2 patient groups. CONCLUSIONS: For Medicare patients with AMI, hospital-specific RSMRs for natively admitted patients are only weakly associated with RSMRs for patients transferred in from another hospital. Current AMI performance metrics may fail to provide guidance about hospital quality for transferred patients.

Association of cumulative social risk with mortality and adverse cardiovascular disease outcomes.

BACKGROUND: Quantifying the cumulative effect of social risk factors on cardiovascular disease (CVD) risk can help to better understand the sources of disparities in health outcomes. METHOD AND RESULTS: Data from the Heart Strategies Concentrating on Risk Evaluation (HeartSCORE) study were used to create an index of cumulative social risk (CSR) and quantify its association with incident CVD and all-cause mortality. CSR was defined by assigning a score of 1 for the presence of each of 4 social factors: i) racial minority status (Black race), ii) single living status, iii) low income, and iv) low educational level. Hazard ratios (HRs) were computed using Cox-regression models, adjusted for CVD risk factors. Over a median follow-up period of 8.3 years, 127 incident events were observed. The incidence of the primary outcome for subgroups of participants with 0, 1, and ≥2 CSR scores was 5.31 (95% CI, 3.40-7.22), 10.32 (7.16-13.49) and 17.80 (12.94-22.67) per 1000 person-years, respectively. Individuals with CSR score of 1 had an adjusted HR of 1.85 (1.15-2.97) for incident primary outcomes, compared to those with score of 0. The corresponding HR for individuals with CSR score of 2 or more was 2.58 (1.60-4.17). CONCLUSION: An accumulation of social risk factors independently increased the likelihood of CVD events and deaths in a cohort of White and Black individuals.

Airflow Limitation and Endothelial Dysfunction. Unrelated and Independent Predictors of Atherosclerosis.

RATIONALE: Lower FEV1 is associated with increased prevalence of atherosclerosis; however, causal mechanisms remain elusive. OBJECTIVES: To determine if systemic endothelial dysfunction mediates the association between reduced FEV1 and increased atherosclerosis. METHODS: Brachial artery endothelial function, pulmonary function, coronary artery calcium, and carotid plaque were assessed in 231 Pittsburgh SCCOR (Specialized Centers for Clinically Oriented Research) study participants; peripheral arterial endothelial function, pulmonary function, and coronary artery calcium were assessed in 328 HeartSCORE (Heart Strategies Concentrating on Risk Evaluation) study participants. MEASUREMENTS AND MAIN RESULTS: Lower FEV1 was independently associated with increased atherosclerosis in both cohorts (per 25% lower % predicted FEV1: odds ratio [OR], 1.76; 95% confidence interval [CI], 1.30-2.40; P < 0.001 for carotid plaque in SCCOR participants) (per 25% lower % predicted FEV1: OR, 1.35; 95% CI, 1.02-1.77; P = 0.03 for coronary artery calcium in HeartSCORE participants). Similarly, reduced endothelial function was independently associated with increased atherosclerosis in both cohorts (per SD lower endothelial function: OR, 1.30; 95% CI, 1.01-1.67; P = 0.04 for carotid plaque in SCCOR participants) (per SD lower endothelial function: OR, 1.38; 95% CI, 1.09-1.76; P = 0.008 and OR, 1.41; 95% CI, 1.07-1.86; P = 0.01 for coronary artery calcium in SCCOR and HeartSCORE participants, respectively). However, there was no association between endothelial dysfunction and FEV1, FEV1/FVC, low-attenuation area/visual emphysema, and diffusing capacity in SCCOR participants, and between endothelial dysfunction and FEV1 or FEV1/FVC in HeartSCORE participants (all P > 0.05). Adjusting the association between FEV1 and atherosclerosis for endothelial dysfunction had no impact. CONCLUSIONS: Endothelial dysfunction does not mediate the association between airflow limitation and atherosclerosis. Instead, airflow limitation and endothelial dysfunction seem to be unrelated and mutually independent predictors of atherosclerosis.

Renal Protection Using Remote Ischemic Peri-Conditioning During Inter-Facility Helicopter Transport of Patients With ST-Segment Elevation Myocardial Infarction: A Retrospective Study.

OBJECTIVE: To assess the impact of remote ischemic peri-conditioning (RIPC) during inter-facility air medical transport of ST-segment elevation myocardial infarction (STEMI) patients on the incidence of acute kidney injury (AKI) following primary percutaneous coronary intervention (pPCI). BACKGROUND: STEMI patients who receive pPCI have an increased risk of AKI for which there is no well-defined prophylactic therapy in the setting of emergent pPCI. METHODS: Using the ACTION Registry-GWTG, we evaluated the impact of RIPC applied during inter-facility helicopter transport of STEMI patients from non-PCI capable hospitals to 2 PCI-hospitals in the United States between March, 2013 and September, 2015 on the incidence of AKI following pPCI. AKI was defined as ≥0.3 mg/dL increase in creatinine within 48-72 hours after pPCI. RESULTS: Patients who received RIPC (n = 127), compared to those who did not (n = 92), were less likely to have AKI (11 of 127 patients [8.7%] vs. 17 of 92 patients [18.5%]; adjusted odds ratio = 0.32, 95% CI 0.12-0.85, P = 0.023) and all-cause in-hospital mortality (2 of 127 patients [1.6%] vs. 7 of 92 patients [7.6%]; adjusted odds ratio = 0.14, 95% CI 0.02-0.86, P = 0.034) after adjusting for socio-demographic and clinical characteristics. There was no difference in hospital length of stay (3 days [interquartile range, 2-4] vs. 3 days [interquartile range, 2-5], P = 0.357) between the 2 groups. CONCLUSION: RIPC applied during inter-facility helicopter transport of STEMI patients for pPCI is associated with lower incidence of AKI and in-hospital mortality. The use of RIPC for renal protection in STEMI patients warrants further in depth investigation.

Effect of Two Work-to-Rest Ratios on Cardiovascular, Thermal, and Perceptual Responses During Fire Suppression and Recovery.

OBJECTIVE: Fire suppression is a physically demanding occupation that often results in significant heat stress and hypohydration. Guidelines for the number of work intervals allowed before a structured recovery were consensus derived and have not been tested. METHODS: Apparently healthy firefighters were recruited for this field study. Subjects were assigned to two or three bouts of live fire training prior to 20 minutes of structured recovery to provide rehydration and cooling. After recovery, the subjects completed a timed test of firefighting skills. RESULTS: Extending the fire suppression interval from two to three work periods before a structured recovery period increased core temperature and the time required to perform a high intensity circuit of firefighting skills immediately following recovery. A mild hypotension was noted during recovery but the groups did not differ for blood pressure, heart rate, or firefighter perception of thermal strain or exertion. CONCLUSIONS: This is the first study to examine the physiologic effects of structural firefighting work intervals on recovery and subsequent performance. Both groups experienced maximal cardiovascular strain during fire suppression but extending the work interval worsened heat stress and negatively affected certain aspects of performance immediately following the recovery period.

Pilot Study Examining the Effects of Atropine on Performance during Uncompensable Heat Stress.

UNLABELLED: In many operational scenarios, hypohydration can be corrected with oral rehydration following the work interval. Although rare, there are potential situations that require extended intervals of uncompensable heat stress exposure while working in personal protective equipment (PPE). Under these conditions, retention of body water may be valuable to preserve work capacity and reduce cardiovascular strain. We conducted a pilot study comparing intramuscular atropine sulfate versus saline placebo to establish the safety profile of the protocol and to provide pilot data for future investigations. Five, healthy, heat-acclimated subjects completed this crossover design laboratory study. Each subject performed up to one hour of exertion in a hot environment while wearing a chemical resistant coverall. Atropine sulfate (0.02 mg/kg) or an equivalent volume of sterile saline was administered by intramuscular injection. Core temperature, heart rate, perceptual measures, and changes in body mass were measured. All five subjects completed the acclimation period and both protocols. No adverse events occurred, and no pharmacologically induced delirium was identified. Change in body mass was less following exercise influenced by atropine sulfate (p = 0.002). Exertion time tended to be longer in the atropine sulfate arm (p = 0.08). Other measures appeared similar between groups. Intramuscular atropine sulfate reduced sweating and tended to increase the work interval under uncompensable heat stress when compared to saline placebo. Heart rate and temperature changes during exertion were similar in both conditions suggesting that the influence of an anticholinergic agent on thermoregulation may be minimal during uncompensable heat stress. KEY WORDS: thermoregulation; cholinolytic; anticholinergic; reaction time.

Effects of enamel matrix genes on dental caries are moderated by fluoride exposures.

Dental caries (tooth decay) is the most common chronic disease, worldwide, affecting most children and adults. Though dental caries is highly heritable, few caries-related genes have been discovered. We investigated whether 18 genetic variants in the group of non-amelogenin enamel matrix genes (AMBN, ENAM, TUFT1, and TFIP11) were associated with dental caries experience in 13 age- and race-stratified samples from six parent studies (N = 3,600). Linear regression was used to model genetic associations and test gene-by-fluoride interaction effects for two sources of fluoride: daily tooth brushing and home water fluoride concentration. Meta-analysis was used to combine results across five child and eight adult samples. We observed the statistically significant association of rs2337359 upstream of TUFT1 with dental caries experience via meta-analysis across adult samples (p < 0.002) and the suggestive association for multiple variants in TFIP11 across child samples (p < 0.05). Moreover, we discovered two genetic variants (rs2337359 upstream of TUFT1 and missense rs7439186 in AMBN) involved in gene-by-fluoride interactions. For each interaction, participants with the risk allele/genotype exhibited greater dental caries experience only if they were not exposed to the source of fluoride. Altogether, these results confirm that variation in enamel matrix genes contributes to individual differences in dental caries liability, and demonstrate that the effects of these genes may be moderated by protective fluoride exposures. In short, genes may exert greater influence on dental caries in unprotected environments, or equivalently, the protective effects of fluoride may obviate the effects of genetic risk alleles.

Effect of aspirin on acute changes in peripheral arterial stiffness and endothelial function following exertional heat stress in firefighters: The factorial group results of the Enhanced Firefighter Rehab Trial.

Peripheral arterial stiffness and endothelial function, which are independent predictors of cardiac events, are abnormal in firefighters. We examined the effects of aspirin on peripheral arterial stiffness and endothelial function in firefighters. Fifty-two firefighters were randomized to receive daily 81 mg aspirin or placebo for 14 days before treadmill exercise in thermal protection clothing, and a single dose of 325 mg aspirin or placebo immediately following exertion. Peripheral arterial augmentation index adjusted for a heart rate of 75 (AI75) and reactive hyperemia index (RHI) were determined immediately before, and 30, 60, and 90 minutes after exertion. Low-dose aspirin was associated with lower AI75 (-15.25±9.25 vs -8.08±10.70, p=0.014) but not RHI. On repeated measures analysis, treatment with low-dose aspirin before, but not single-dose aspirin after exertion, was associated with lower AI75 following exertional heat stress (p=0.018). Low-dose aspirin improved peripheral arterial stiffness and wave reflection but not endothelial function in firefighters.

The effects of ice slurry ingestion before exertion in Wildland firefighting gear.

PURPOSE: To investigate the effect of ice slurry ingestion precooling on body core temperature (Tc) during exertion in wildland firefighting garments in uncompensable heat stress. METHODS: On two separate trials, 10 males ingested 7.5 g·kg(-1) of either an ice slurry (0.1°C) or control beverage (20°C) during seated rest for 30 minutes prior to simulating the U.S. Forest Service Pack Test on a treadmill in wildland firefighting garments in a hot environment (38.8 ± 1.2°C, 17.5 ± 1.4% relative humidity). Deep gastric temperature, mean skin temperature (Tsk), and heart rate (HR) were recorded. Ratings of perceived exertion, thermal sensation, comfort, and sweating were assessed. RESULTS: Compared with ingestion of a temperate beverage, precooling with ice slurry before exertion in a hot environment reduced Tc during the first 30 minutes of the exercise bout. Exercise time and distance completed were not different between treatments. Skin temperature, heart rate, and perceptual responses rose in both conditions during exercise but did not differ by condition. CONCLUSION: Pretreatment with ice slurry prior to exertion in wildland firefighting garments results in a modest reduction in Tc during the first 30 minutes of exercise when compared to pretreatment with control beverage but the ice slurry precooling advantage did not persist throughout the 45-minute exercise protocol.

Risk of cardiovascular events in survivors of severe sepsis.

RATIONALE: The risk of cardiovascular events after severe sepsis is not known, and these events may explain increased long-term mortality in survivors of severe sepsis. OBJECTIVES: To determine whether survivors of severe sepsis hospitalization have high long-term risk of cardiovascular events. We examined whether higher risk is due to severe sepsis hospitalization or poor prehospitalization health status, and if the higher risk is also observed in patients hospitalized for infectious and noninfectious reasons, and in other critically ill patients. METHODS: Unmatched and matched-cohort analyses of Medicare beneficiaries. For unmatched analysis, we compared patients with severe sepsis admitted to the intensive care unit (ICU) and survived hospitalization (n = 4,179) to unmatched population control subjects (n = 819,283). For matched analysis, we propensity-score-matched each patient with severe sepsis to four control subjects (population, hospitalized, non-severe sepsis ICU control subjects, and infection hospitalization). Primary outcome was 1-year incidence rate of hospitalization for cardiovascular events. MEASUREMENTS AND MAIN RESULTS: Cardiovascular events were common among patients discharged alive after severe sepsis hospitalization (29.5%; 498.2 events/1,000 person-years). Survivors of severe sepsis had a 13-fold higher risk of cardiovascular events compared with unmatched control subjects (498.2 vs. 36 events/1,000 person-years; P < 0.0001), and a 1.9-fold higher risk compared with matched-population control subjects (P < 0.0001). Survivors of severe sepsis had 1.1-fold higher risk compared with matched hospitalized patients and infection hospitalizations (P = 0.002 and 0.001) and similar risk compared with matched-ICU control subjects. CONCLUSIONS: Survivors of severe sepsis have high risk of cardiovascular events. The higher risk is mainly due to poor prehospitalization health status, and is also seen in a broader population of acutely ill patients.

A randomized controlled trial of aspirin and exertional heat stress activation of platelets in firefighters during exertion in thermal protective clothing.

PURPOSE: Platelet aggregation is enhanced in firefighters following short bouts of work in thermal protective clothing (TPC). We sought to determine if aspirin therapy before and/or following exertion in TPC prevents platelet activation. METHODS: In a double-blind, placebo-controlled study, 102 firefighters were randomized to receive daily therapy (81 mg aspirin or placebo) for 14 days before and a single dose (325 mg aspirin or placebo) following exercise in TPC resulting in four potential assignments: aspirin before and after exercise (AA), placebo before and after exercise (PP), aspirin before and placebo after exercise (AP), and placebo before and aspirin after exercise (PA). Platelet closure time (PCT) was measured with a platelet function analyzer before the 2-week treatment, after the 2 week treatment period, immediately after exercise, and 30, 60, and 90 minutes later. RESULTS: Baseline PCT did not differ between groups. PCT changed over time in all four groups (p < 0.001) rising to a median of >300 seconds [IQR 99, 300] in AA and >300 [92, 300] in AP prior to exercise. Following exercise, median PCT decreased to in all groups. Median PCT returned to >300 seconds 30 minutes later in AA and AP and rose to 300 seconds in PA 60 minutes after exercise. CONCLUSIONS: Daily aspirin therapy blunts platelet activation during exertional heat stress and single-dose aspirin therapy following exertional heat stress reduces platelet activation within 60 minutes.

Elevated high-density lipoprotein cholesterol and adverse outcomes in women with symptoms of ischemic heart disease.

Background: Emerging data in the general population and those with coronary artery disease demonstrate higher risk of adverse outcomes with high (>70 mg/dL) HDL-C levels. There are limited data on the risk of adverse outcomes in women with suspected ischemic heart disease. Objective: To investigate relationships between high (>70 mg/dL), average (50-70 mg/dL), and low (<50 mg/dL) HDL-C levels with major adverse cardiac events (MACE) (death, myocardial infarction, stroke, and heart failure hospitalization), and all-cause mortality in women referred for coronary angiography for suspected myocardial ischemia. Methods: A total of 607 women enrolled in the Women's Ischemia Syndrome Evaluation (WISE) original cohort (NCT00000554) with available HDL-C values were included in this analysis. Associations between HDL-C level and outcomes were evaluated using both multivariate Cox proportional hazard regression and spline regression analysis. Results: The mean age was 59 ± 12 years, 62 % had 3 or more cardiac risk factors, and 66 (10.9 %) had a high HDL-C. High and low HDL-C were both associated with higher MACE risk compared to average HDL-C after adjusting for demographic and clinical characteristics (HR 1.80, CI 1.03-3.14, p = 0.038; HR 1.63, CI 1.09-2.42, p = 0.016, respectively). Similarly, high, and low HDL-C were associated with higher risk of all-cause mortality (HR 3.64, CI 1.84-7.20, p < 0.001; HR 2.81, CI 1.67-4.71, p < 0.001, respectively). Conclusions: High and low HDL-C levels are both independently associated with higher MACE and all-cause mortality in women with suspected ischemia undergoing coronary angiography.

Sex-Based Utilization of Guideline Recommended Statin Therapy and Cardiovascular Disease Outcomes: A Primary Prevention Healthcare Network Registry.

Background: In the US, women have similar cardiovascular death rates than men. Less is known about sex differences in statin use for primary prevention and associated atherosclerotic cardiovascular disease (ASCVD) outcomes. Methods: Statin prescriptions using electronic health records were examined in patients without ASCVD (myocardial infarction (MI), revascularization or ischemic stroke) between 2013-2019. Guideline-directed statin intensity (GDSI) at index and follow-up visits were compared among sexes across ASCVD risk groups, defined by pooled-cohort equation. Cox regression hazard ratios (HR) [95% CI] were calculated for statin use and outcomes (myocardial infarction, stroke/transient ischemic attack (TIA), and all-cause mortality) stratified by sex. Interaction terms (statin and sex) were applied. Results: Among 282,298 patients, (mean age ∼ 50 years) 17.1% women and 19.5% men were prescribed any statin at index visit. Time to GDSI was similar between sexes, but the proportion of high-risk women on GDSI at follow-ups was lower compared to high-risk men (2-years: 27.7 vs 32.0%, and 5-years: 47.2 vs 55.2%, p<0.05). When compared to GDSI, no statin use was associated with higher risk of MI and ischemic stroke/TIA amongst both sexes. High-risk women on GDSI had a lower risk of mortality (HR=1.39 [1.22-1.59]) versus men (HR=1.67 [1.50-1.86]) of similar risk (p value interaction=0.004). Conclusion: In a large contemporary healthcare system, there was underutilization of statins across both sexes in primary prevention. High-risk women were less likely to be initiated on GDSI compared with high-risk men. GDSI significantly improved the survival in both sexes regardless of ASCVD risk group. Future strategies to ensure continued use of GDSI, specifically among women, should be explored.