Premorbid levels of high-sensitivity cardiac troponin T and natriuretic peptide and prognosis after incident myocardial infarction

High-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) at the time of myocardial infarction (MI) are strong predictors of prognosis. However, whether their premorbid (before MI occurrence) levels are associated with prognosis after incident MI is unknown. Methods: In 1,054 participants from the Atherosclerosis Risk in Communities Study with incident MI, we evaluated premorbid levels of hs-cTnT and NT-proBNP measured on median 5.8 (interquartile interval 3.0-11.5 [mean 5.5]) years prior to incident MI and their associations with subsequent composite and individual outcomes of all-cause mortality, cardiovascular mortality, recurrent MI, heart failure, and stroke. Results: During a median follow-up of 3.0 years after MI, 801 participants developed the composite outcome. Both hs-cTnT and NT-proBNP were independently associated with the composite outcome after incident MI. Among individual outcomes, all-cause mortality, cardiovascular mortality, and heart failure showed significant associations with both cardiac markers. Overall, NT-proBNP demonstrated a more evident relationship than hs-cTnT. Indeed, the addition of premorbid NT-proBNP alone, but not hs-cTnT alone, to conventional predictors at incident MI significantly improved risk prediction of the composite outcome after incident MI (∆c-statistic 0.013 [95% CI 0.005-0.022] from 0.691 with conventional predictors). Conclusions: Premorbid levels of hs-cTnT and NT-proBNP assessed on average 6 years prior to incident MI were associated with adverse outcomes after incident MI. These results further highlight the importance of cardiac health at an earlier stage of life

A proteomic approach for investigating the pleiotropic effects of statins in the atherosclerosis risk in communities (ARIC) study

Background: Statins are prescribed to reduce LDL-c and risk of CVD. Statins have pleiotropic effects, affecting pathophysiological functions beyond LDL-c reduction. We compared the proteome of statin users and nonusers (controls). We hypothesized that statin use is associated with proteins unrelated to lipid metabolism. Methods: Among 10,902 participants attending ARIC visit 3 (1993–95), plasma concentrations of 4955 proteins were determined using SOMAlogic's DNA aptamer-based capture array. 379 participants initiated statins within the 2 years prior. Propensity scores (PS) were calculated based on visit 2 (1990–92) LDL-c levels and visit 3 demographic/clinical characteristics. 360 statin users were PS matched to controls. Log2-transformed and standardized protein levels were compared using t-tests, with false discovery rate (FDR) adjustment for multiple comparisons. Analyses were replicated in visit 2. Results: Covariates were balanced after PS matching, except for higher visit 3 LDL-c levels among controls (125.70 vs 147.65 mg/dL; p < 0.0001). Statin users had 11 enriched and 11 depleted protein levels after FDR adjustment (q < 0.05). Proteins related and unrelated to lipid metabolism differed between groups. Results were largely replicated in visit 2. Conclusion: Proteins unrelated to lipid metabolism differed by statin use. Pending external validation, exploring their biological functions could elucidate pleiotropic effects of statins. Significance: Statins are the primary pharmacotherapy for lowering low-density lipoprotein (LDL) cholesterol and preventing cardiovascular disease. Their primary mechanism of action is through inhibiting the protein 3hydroxy-3-methylglutaryl CoA reductase (HMGCR) in the mevalonate pathway of LDL cholesterol synthesis. However, statins have pleiotropic effects and may affect other biological processes directly or indirectly, with hypothesized negative and positive effects. The present study contributes to identifying these pathways by comparing the proteome of stain users and nonusers with propensity score matching. Our findings highlight potential biological mechanisms underlying statin pleiotropy, informing future efforts to identify statin users at risk of rare nonatherosclerotic outcomes and identify health benefits of statin use independent of LDL-C reduction

Simultaneous determination of atorvastatin and ezetimibe from combined pharmaceutical products by micellar electrokinetic capillary chromatography

Abstract A rapid and sensitive micellar electrokinetic capillary chromatography method with UV photodiode-array detection was developed for the simultaneous determination of atorvastatin and ezetimibe in fixed dose drug combination. Experimental conditions such as buffer concentration and pH, surfactant concentration, system temperature, applied voltage, injection parameters were optimized in order to improve the efficiency of the separation. The best results were obtained when using fused silica capillary (48 cm length X 50 µm ID) and 25 mM borate buffer electrolyte at pH 9.3 containing 25 mM SDS, + 30 kV applied voltage, 20 ºC system temperature. The separation was achieved in approximately 2 minutes, with a resolution of 7.02, the order of migration being atorvastatin followed by ezetimibe. The analytical performance of the method was verified with regard to linearity, precision, robustness and the limit of detection and quantification were calculated

Applicability and Cost Implications for Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors Based on the ODYSSEY Outcomes Trial: Insights From the Department of Veterans Affairs

In the recently presented ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab trial, alirocumab use in patients with acute coronary syndrome (ACS) and low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL (or non–high-density lipoprotein cholesterol ≥100 mg/dL or apolipoprotein B ≥80 mg/dL) resulted in a 15% relative (1.6% absolute) reduction in the risk of major adverse cardiovascular events. We evaluated what proportion of patients in the VA Health Care System would qualify for alirocumab on the basis of ODYSSEY Outcomes criteria, how they are currently treated with LDL-C–lowering medications, and the cost implications if other evidence-based medications were used first before a proprotein convertase subtilisin/kexin type 9 inhibitor was considered

Very High-Risk ASCVD and Eligibility for Nonstatin Therapies Based on the 2018 AHA/ACC Cholesterol Guidelines

The 2018 American Heart Association/American College of Cardiology Multisociety Cholesterol Guidelines recommend risk stratification among patients with atherosclerotic cardiovascular disease (ASCVD) to identify “very high-risk ASCVD patients.” These patients have characteristics associated with a higher risk of recurrent ASCVD events; consequently, they derive a higher net absolute benefit from addition of ezetimibe and/or a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) to statin therapy. From a clinical and payer’s perspective, we assessed the proportion of patients with ASCVD who will qualify as very high-risk based on the guideline criteria, their current lipid management, and how this will change with maximizing statin therapy and stepwise use of ezetimibe before consideration for a PCSK9i, as recommended by the 2018 cholesterol guideline

The ARIC (Atherosclerosis Risk In Communities) Study: JACC Focus Seminar 3/8

ARIC (Atherosclerosis Risk In Communities) initiated community-based surveillance in 1987 for myocardial infarction and coronary heart disease (CHD) incidence and mortality and created a prospective cohort of 15,792 Black and White adults ages 45 to 64 years. The primary aims were to improve understanding of the decline in CHD mortality and identify determinants of subclinical atherosclerosis and CHD in Black and White middle-age adults. ARIC has examined areas including health disparities, genomics, heart failure, and prevention, producing more than 2,300 publications. Results have had strong clinical impact and demonstrate the importance of population-based research in the spectrum of biomedical research to improve health

BNP and obesity in acute decompensated heart failure with preserved vs. reduced ejection fraction: The Atherosclerosis Risk in Communities Surveillance Study

Background Levels of B-type natriuretic peptide (BNP), a prognostic marker in patients with heart failure (HF), are lower among HF patients with obesity or preserved Left Ventricular Ejection Fraction (LVEF). We examined the distribution and prognostic value of BNP across BMI categories in acute decompensated heart failure (ADHF) patients with preserved vs. reduced LVEF. Methods We analyzed data from the Atherosclerosis Risk in Communities (ARIC) HF surveillance study which sampled and adjudicated ADHF hospitalizations in patients aged ≥ 55 years from 4 US communities (2005–2009). We examined 5 BMI categories: underweight (< 18.5 kg/m2), normal weight (18.5–<25), overweight (25–<30), obese (30–<40) and morbidly obese (≥ 40) in HF with preserved LVEF (HFpEF) and reduced LVEF (HFrEF). The outcome was 1-year mortality from admission. We used ANCOVA to model log BNP and logistic regression for 1-year mortality, both adjusted for demographics and clinical characteristics. Results The cohort included 9820 weighted ADHF hospitalizations (58% HFrEF; 42% HFpEF). BNP levels were lower in HFpEF compared to HFrEF (p < 0.001) and decreased as BMI increased within the LVEF groups (p < 0.001). After adjustment for covariates, log10 BNP independently predicted 1-year mortality (adjusted OR 1.62 (95% CI 1.17–2.24)) with no significant interaction by BMI or LVEF groups. Conclusions BNP levels correlated inversely with BMI, and were higher in HFrEF compared to HFpEF. Obese patients with HFpEF and ADHF had a significant proportion with BNP levels below clinically accepted thresholds. Nevertheless, BNP was a predictor of mortality in ADHF across groups of BMI in HFpEF and HFrEF

NuSTAR J033202-2746.8: Direct Constraints on the Compton Reflection in a Heavily Obscured Quasar at z ≈ 2

We report Nuclear Spectroscopic Telescope Array (NuSTAR) observations of NuSTAR J033202-2746.8, a heavily obscured, radio-loud quasar detected in the Extended Chandra Deep Field-South, the deepest layer of the NuSTAR extragalactic survey (~400 ks, at its deepest). NuSTAR J033202-2746.8 is reliably detected by NuSTAR only at E > 8 keV and has a very flat spectral slope in the NuSTAR energy band ($\Gamma =0.55^{+0.62}_{-0.64}$; 3-30 keV). Combining the NuSTAR data with extremely deep observations by Chandra and XMM-Newton (4 Ms and 3 Ms, respectively), we constrain the broad-band X-ray spectrum of NuSTAR J033202-2746.8, indicating that this source is a heavily obscured quasar ($N_{\rm H}=5.6^{+0.9}_{-0.8}\times 10^{23}$ cm–2) with luminosity L 10-40 keV ≈ 6.4 × 1044 erg s–1. Although existing optical and near-infrared (near-IR) data, as well as follow-up spectroscopy with the Keck and VLT telescopes, failed to provide a secure redshift identification for NuSTAR J033202-2746.8, we reliably constrain the redshift z = 2.00 ± 0.04 from the X-ray spectral features (primarily from the iron K edge). The NuSTAR spectrum shows a significant reflection component ($R=0.55^{+0.44}_{-0.37}$), which was not constrained by previous analyses of Chandra and XMM-Newton data alone. The measured reflection fraction is higher than the R ~ 0 typically observed in bright radio-loud quasars such as NuSTAR J033202-2746.8, which has L 1.4 GHz ≈ 1027 W Hz–1. Constraining the spectral shape of active galactic nuclei (AGNs), including bright quasars, is very important for understanding the AGN population, and can have a strong impact on the modeling of the X-ray background. Our results show the importance of NuSTAR in investigating the broad-band spectral properties of quasars out to high redshift

NuSTAR unveils a Compton-thick type 2 quasar in MrK 34

We present Nuclear Spectroscopic Telescope Array (NuSTAR) 3-40 keV observations of the optically selected Type 2 quasar (QSO2) SDSS J1034+6001 or Mrk 34. The high-quality hard X-ray spectrum and archival XMM-Newton data can be fitted self-consistently with a reflection-dominated continuum and a strong Fe K? fluorescence line with equivalent width &gt;1 keV. Prior X-ray spectral fitting below 10 keV showed the source to be consistent with being obscured by Compton-thin column densities of gas along the line of sight, despite evidence for much higher columns from multiwavelength data. NuSTAR now enables a direct measurement of this column and shows that N H lies in the Compton-thick (CT) regime. The new data also show a high intrinsic 2-10 keV luminosity of L 2-10 ~ 1044 erg s–1, in contrast to previous low-energy X-ray measurements where L 2-10 lesssim 1043 erg s–1 (i.e., X-ray selection below 10 keV does not pick up this source as an intrinsically luminous obscured quasar). Both the obscuring column and the intrinsic power are about an order of magnitude (or more) larger than inferred from pre-NuSTAR X-ray spectral fitting. Mrk 34 is thus a "gold standard" CT QSO2 and is the nearest non-merging system in this class, in contrast to the other local CT quasar NGC 6240, which is currently undergoing a major merger coupled with strong star formation. For typical X-ray bolometric correction factors, the accretion luminosity of Mrk 34 is high enough to potentially power the total infrared luminosity. X-ray spectral fitting also shows that thermal emission related to star formation is unlikely to drive the observed bright soft component below ~3 keV, favoring photoionization instead

Lowering water table reduces carbon sink strength and carbon stocks in northern peatlands

Peatlands at high latitudes have accumulated >400 Pg carbon (C) because saturated soil and cold temperatures suppress C decomposition. This substantial amount of C in Arctic and Boreal peatlands is potentially subject to increased decomposition if the water table (WT) decreases due to climate change, including permafrost thaw-related drying. Here, we optimize a version of the Organizing Carbon and Hydrology In Dynamic Ecosystems model (ORCHIDEE-PCH4) using site-specific observations to investigate changes in CO2 and CH4 fluxes as well as C stock responses to an experimentally manipulated decrease of WT at six northern peatlands. The unmanipulated control peatlands, with the WT 2 kg C m−2 over 100 years when WT is lowered by 50 cm, while permafrost peatlands temporally switched from C sinks to sources. These results highlight that reductions in C storage capacity in response to drying of northern peatlands are offset in part by reduced CH4 emissions, thus slightly reducing the positive carbon climate feedbacks of peatlands under a warmer and drier future climate scenario