As the major regulator of vascular homeostasis, the endothelium exerts a number of vasoprotective effects, such as vasodilation, suppression of smooth muscle cell growth, and inhibition of ...inflammatory responses. Many of these effects are largely mediated by nitric oxide, the most potent endogenous vasodilator. Nitric oxide opposes the effects of endothelium-derived vasoconstrictors and inhibits oxidation of low-density lipoprotein. A defect in the production or activity of nitric oxide leads to endothelial dysfunction, signaled by impaired endothelium-dependent vasodilation. Accumulating evidence suggests that endothelial dysfunction is an early marker for atherosclerosis and can be detected before structural changes to the vessel wall are apparent on angiography or ultrasound. Many of the risk factors that predispose to atherosclerosis can also cause endothelial dysfunction, and the presence of multiple risk factors has been found to predict endothelial dysfunction. A number of clinical trials have shown that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) improve endothelial dysfunction in patients with coronary risk factors beyond what could be attributed to their impact on plasma lipids. Studies have elucidated several possible mechanisms by which statin therapy may improve endothelial dysfunction, including upregulation of nitric oxide production or activity and reduction of oxidative stress.
Proteins are effector molecules that mediate the functions of genes
and modulate comorbidities
, behaviors and drug treatments
. They represent an enormous potential resource for personalized, ...systemic and data-driven diagnosis, prevention, monitoring and treatment. However, the concept of using plasma proteins for individualized health assessment across many health conditions simultaneously has not been tested. Here, we show that plasma protein expression patterns strongly encode for multiple different health states, future disease risks and lifestyle behaviors. We developed and validated protein-phenotype models for 11 different health indicators: liver fat, kidney filtration, percentage body fat, visceral fat mass, lean body mass, cardiopulmonary fitness, physical activity, alcohol consumption, cigarette smoking, diabetes risk and primary cardiovascular event risk. The analyses were prospectively planned, documented and executed at scale on archived samples and clinical data, with a total of ~85 million protein measurements in 16,894 participants. Our proof-of-concept study demonstrates that protein expression patterns reliably encode for many different health issues, and that large-scale protein scanning
coupled with machine learning is viable for the development and future simultaneous delivery of multiple measures of health. We anticipate that, with further validation and the addition of more protein-phenotype models, this approach could enable a single-source, individualized so-called liquid health check.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
HIV-seropositive patients are at higher risk for atherosclerosis than HIV-seronegative persons. This has been variably attributed to antiretroviral drug toxicity, immunodeficiency, and/or ...HIV-associated inflammation. To evaluate the contributions of these factors to HIV-associated atherosclerosis, we assessed carotid artery intima-media thickness in a diverse cohort of HIV-seronegative and seropositive adults, including a unique group of HIV-infected patients who were untreated, had undetectable viral loads, and had preserved CD4 T-cell counts (HIV controllers).
Carotid intima-media thickness was measured in 494 participants, including 33 HIV controllers and 93 HIV-seronegative controls. HIV controllers had higher intima-media thickness than seronegative controls even after adjustment for traditional risk factors (P = 0.003). Intima-media thickness in controllers was similar to antiretroviral-untreated patients with detectable viremia. Across all participants, intima-media thickness was strongly associated with the presence of HIV disease rather than viral load or CD4 T-cell count. C-reactive protein was higher in HIV controllers than HIV-seronegative persons. Antiretroviral drug exposure was also associated with higher intima-media thickness.
Increased atherosclerosis with HIV infection can occur in the absence of antiretroviral therapy, detectable viremia, or overt immunodeficiency. Chronic inflammation - which is higher in controllers than in HIV-uninfected persons - may account for early atherosclerosis in these patients.
To assess the effects of empagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, on broad biological systems through proteomics.
Aptamer-based proteomics was used to quantify ...3,713 proteins in 144 paired plasma samples obtained from 72 participants across the spectrum of glucose tolerance before and after 4 weeks of empagliflozin 25 mg/day. The biology of the plasma proteins significantly changed by empagliflozin (at false discovery rate-corrected
< 0.05) was discerned through Ingenuity Pathway Analysis.
Empagliflozin significantly affected levels of 43 proteins, 6 related to cardiomyocyte function (fatty acid-binding protein 3 and 4 FABPA, neurotrophic receptor tyrosine kinase, renin, thrombospondin 4, and leptin receptor), 5 to iron handling (ferritin heavy chain 1, transferrin receptor protein 1, neogenin, growth differentiation factor 2 GDF2, and β2-microglobulin), and 1 to sphingosine/ceramide metabolism (neutral ceramidase), a known pathway of cardiovascular disease. Among the protein changes achieving the strongest statistical significance, insulin-like binding factor protein-1 (IGFBP-1), transgelin-2, FABPA, GDF15, and sulphydryl oxidase 2 precursor were increased, while ferritin, thrombospondin 3, and Rearranged during Transfection (RET) were decreased by empagliflozin administration.
SGLT2 inhibition is associated, directly or indirectly, with multiple biological effects, including changes in markers of cardiomyocyte contraction/relaxation, iron handling, and other metabolic and renal targets. The most significant differences were detected in protein species (GDF15, ferritin, IGFBP-1, and FABP) potentially related to the clinical and metabolic changes that were actually measured in the same patients. These novel results may inform further studies using targeted proteomics and a prospective design.
Primary and primordial prevention of cardiovascular disease (CVD) requires not only identification of risk factors, but also appropriate and timely therapy. In order to prevent the expected increase ...in prevalence of CVD, it is essential that clinicians are aware of behavioral cardiovascular risk factors. A basic review is critical to clarify the difference between physical activity and fitness, as well as to discuss the role each plays in cardiovascular outcomes. We discuss observational epidemiological studies and randomized control trials that have examined the effect of physical activity and cardiorespiratory fitness on CVD. (Circ J 2016; 80: 34–43)
Statins have pleiotropic effects, reducing not only low-density lipoprotein cholesterol levels, but also the levels of C-reactive protein (CRP), an inflammatory marker. This study found that the ...effects of statin therapy on the progression or regression of coronary atherosclerosis are related to both their lipid-lowering effect and their CRP-lowering effect. These results provide additional support for the concept that part of the beneficial effect of statins is due to the lowering of CRP.
The effects of statin therapy on the progression or regression of coronary atherosclerosis are related to both their lipid-lowering effect and their CRP-lowering effect.
Two recent trials demonstrated that intensive lipid-lowering therapy with statins improved clinical outcomes
1
and reduced the progression of atherosclerosis.
2
Many authorities attributed the greater benefits of intensive statin therapy, as compared with moderate statin therapy, to greater reductions in the levels of atherogenic lipoproteins, particularly low-density lipoprotein (LDL) cholesterol.
3
However, statins have a wide range of biologic effects in addition to lipid lowering, including reductions in the levels of C-reactive protein (CRP), a phenomenon commonly termed a “pleiotropic effect.”
4
–
6
In both recent comparisons, at the conclusion of the trials, CRP levels were 30 to 40 percent lower after intensive . . .
Objectives This study was designed to determine whether erectile dysfunction (ED) predicts cardiovascular disease (CVD) beyond traditional risk factors. Background Both ED and CVD share ...pathophysiological mechanisms and often co-occur. It is unknown whether ED improves the prediction of CVD beyond traditional risk factors. Methods This was a prospective, population-based study of 1,709 men (of 3,258 eligible) age 40 to 70 years. The ED data were measured by self-report. Subjects were followed for CVD for an average follow-up of 11.7 years. The association between ED and CVD was examined using the Cox proportional hazards regression model. The discriminatory capability of ED was examined using C statistics. The reclassification of CVD risk associated with ED was assessed using a method that quantifies net reclassification improvement. Results Of the prospective population, 1,057 men with complete risk factor data who were free of CVD and diabetes at baseline were included. During follow-up, 261 new cases of CVD occurred. We found ED was associated with CVD incidence controlling for age (hazard ratio HR: 1.42, 95% confidence interval CI: 1.05 to 1.90), age and traditional CVD risk factors (HR: 1.41, 95% CI: 1.05 to 1.90), as well as age and Framingham risk score (HR: 1.40, 95% CI: 1.04 to 1.88). Despite these significant findings, ED did not significantly improve the prediction of CVD incidence beyond traditional risk factors. Conclusions Independent of established CVD risk factors, ED is significantly associated with increased CVD incidence. Nonetheless, ED does not improve the prediction of who will and will not develop CVD beyond that offered by traditional risk factors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts
Submitted 6 October 2005
; accepted in final form 11 April 2006
Measurement of the increase in digital pulse volume ...amplitude (PVA) during reactive hyperemia relative to baseline (PVA-RH) is being applied widely as a convenient test of nitric oxide bioavailability. However, evidence linking digital PVA-RH to nitric oxide is currently lacking. Accordingly, we investigated whether nitric oxide is responsible for the increase in digital PVA. During reactive hyperemia, we used a peripheral arterial tonometer to record digital PVA at baseline and during reactive hyperemia. The role of nitric oxide in these responses was investigated in 19 healthy subjects by inhibiting nitric oxide synthesis with N G -nitro- L -arginine methyl ester ( L -NAME). Ten subjects underwent the identical protocol with saline and five with phenylephrine, a nonspecific vasoconstrictor, instead of L -NAME. The change in digital PVA after drug administration was compared between the three groups. Relative to the response with saline (5 ± 2%), baseline PVA was unchanged by L -NAME infusion (10 ± 2%), but it decreased significantly with phenylephrine (50 ± 12%; P = 0.003). PVA-RH increased slightly with saline infusion (9 ± 4%). In comparison, PVA-RH was significantly blunted by L -NAME administration (46 ± 21%; P = 0.002) and was relatively unchanged by phenylephrine (20 ± 9%). The present study establishes a central role for nitric oxide in the augmentation of PVA during reactive hyperemia. The measurement of digital PVA-RH may indeed provide a simple means of assessing endothelial function in humans.
endothelium; vasodilation; reactive hyperemia
Address for reprint requests and other correspondence: A. Nohria, Cardiovascular Div., Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115 (e-mail: anohria{at}partners.org )
Patients with kidney failure suffer high mortality, and we currently lack markers for risk stratification for these patients. We carried out a quality control study of a modified aptamer assay ...(SomaScan v.4.0) that measures ~ 5000 proteins, in preparation for a larger study using this platform in cohorts with kidney failure.
Forty participants from the Cardiac, Endothelial Function and Arterial Stiffness in End-Stage Renal Disease (CERES study) were selected to analyze technical and short-term biological variability, orthogonal correlations and differential protein expression in plasma from patients who died during 2.5 year follow-up. Long-term (one year) variability was studied in 421 participants in the Chronic Renal Insufficiency Cohort. We evaluated 4849 aptamers (4607 unique proteins) using data formats including raw data and data formatted using Adaptive Normalization by Maximum Likelihood (ANML), an algorithm developed for SomaScan data in individuals with normal kidney function.
In ANML format, medianIQR intra-assay coefficient of variation (CV) was 2.38%1.76, 3.40 and inter-assay CV was 7.38%4.61, 13.12. Short-term within-subject CV was 5.76% 3.35, 9.72; long-term CV was 8.71%5.91, 13.37. Spearman correlations between aptamer and traditional assays for PTH, NT-proBNP, FGF-23 and CRP were all > 0.7. Fold-change (FC) in protein levels among non-survivors, significant after Bonferroni correction, included SVEP1 (FC95% CI 2.14 1.62, 2.82), keratocan (1.74 1.40, 2.15) and LanC-like protein 1 (0.56 0.45, 0.70). Compared to raw aptamer data, technical and short-term biological variability in paired samples was lower in ANML-formatted data. ANML formatting had minimal impact on orthogonal correlations with traditional assays or the associations of proteins with the phenotype of mortality.
SomaScan had excellent technical variability and low within-subject short-term variability. ANML formatting could facilitate comparison of biomarker results with other studies that utilize this format. We expect SomaScan to provide novel and reproducible information in patients with kidney failure on dialysis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract The Princeton Consensus (Expert Panel) Conference is a multispecialty collaborative tradition dedicated to optimizing sexual function and preserving cardiovascular health. The third ...Princeton Consensus met November 8 to 10, 2010, and had 2 primary objectives. The first objective focused on the evaluation and management of cardiovascular risk in men with erectile dysfunction (ED) and no known cardiovascular disease (CVD), with particular emphasis on identification of men with ED who may require additional cardiologic work-up. The second objective focused on reevaluation and modification of previous recommendations for evaluation of cardiac risk associated with sexual activity in men with known CVD. The Panel's recommendations build on those developed during the first and second Princeton Consensus Conferences, first emphasizing the use of exercise ability and stress testing to ensure that each man's cardiovascular health is consistent with the physical demands of sexual activity before prescribing treatment for ED, and second highlighting the link between ED and CVD, which may be asymptomatic and may benefit from cardiovascular risk reduction.
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