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Background Little clinical research on new-generation heat-not-burn cigarettes ( HNBC ) in comparison with electronic vaping cigarettes ( EVC ) and traditional tobacco combustion cigarettes ( TC ) has been reported. We aimed to appraise the acute effects of single use of HNBC , EVC, and TC in healthy smokers. Methods and Results This was an independent, cross-over, randomized trial in 20 TC smokers, with allocation to different cycles of HNBC , EVC , and TC . All participants used all types of products, with an intercycle washout of 1 week. End points were oxidative stress, antioxidant reserve, platelet activation, flow-mediated dilation, blood pressure, and satisfaction scores. Single use of any product led to an adverse impact on oxidative stress, antioxidant reserve, platelet function, flow-mediated dilation, and blood pressure. HNBC had less impact than EVC and TC on soluble Nox2-derived peptide (respectively, P=0.004 and 0.001), 8-iso-prostaglandin F2α- III ( P=0.004 and <0.001), and vitamin E ( P=0.018 and 0.044). HNBC and EVC were equally less impactful than TCs on flow-mediated dilation ( P=0.872 for HNBC versus EVC ), H 2 O 2 ( P=0.522), H 2 O 2 breakdown activity ( P=0.091), soluble CD 40 ligand ( P=0.849), and soluble P-selectin ( P=0.821). The effect of HNBC and, to a lesser extent EVC , on blood pressure was less evident than that of TC , whereas HNBC appeared more satisfying than EVC (all P<0.05). Conclusions Acute effects of HNBC , EVC, and TC are different on several oxidative stress, antioxidant reserve, platelet function, cardiovascular, and satisfaction dimensions, with TCs showing the most detrimental changes in clinically relevant features. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 03301129.

The phagocytic cell enzyme NADPH oxidase-2 (Nox2) is critical for killing micro-organisms via production of reactive oxygen species and thus is a key element of the innate immune system. Nox2 is also detectable in endothelial cells and platelets where it has vasoconstrictive and aggregating properties, respectively. Patients with X-linked chronic granulomatous disease with hereditary Nox2 deficiency not only have impaired bacterial killing but, in association with loss of Nox2 function, also have enhanced carotid artery dilation, impaired platelet-related thrombosis, and reduced carotid atherosclerotic burden. Experimental studies corroborated these reports in chronic granulomatous disease by demonstrating (1) Nox2 is upregulated in atherosclerotic plaque, and this upregulation significantly correlates with oxidative stress and (2) pharmacological inhibition of Nox2 is associated with a delayed atherosclerotic progression in animal models. Furthermore, the role of Nox2 in platelet-associated thrombosis was substantiated by experiments showing impaired platelet activation in animals treated with a Nox2 inhibitor or impaired platelet aggregation along with reduced platelet-related thrombosis in the mouse knockout model of Nox2. Interestingly, in chronic granulomatous disease patients and in the mouse knockout model of Nox2, no defects of primary hemostasis were detected. This review analyses experimental and clinical data suggesting Nox2 is a potential target for counteracting the atherothrombotic process., (© 2016 American Heart Association, Inc.)

Nonalcoholic fatty liver disease (NAFLD) has a high prevalence in the general population. Brachial artery flow-mediated dilation (FMD) is a surrogated marker of early atherosclerosis. Few data investigating the relation between FMD, NAFLD, and cardiovascular (CV) risk are available. We recruited 367 consecutive outpatients with cardiometabolic risk factors who underwent ultrasound scanning for liver steatosis and FMD. Mean age was 54.2 ± 12.2 years, and 37% were women. NAFLD was present in 281 patients (77%). Median FMD was 5.1%. FMD was significantly reduced in patients with NAFLD (p <0.001), diabetes (p = 0.001), history of coronary heart disease (p = 0.034), and metabolic syndrome (p = 0.050) and in those taking antihypertensive drugs (p = 0.022). Women disclosed greater FMD than males (p = 0.033). Moreover, FMD inversely correlated with age (Spearman rank correlation test [Rs], -0.171; p = 0.001), waist circumference (Rs, -0.127; p = 0.016), fasting blood glucose (Rs, -0.204; p <0.001), and gamma-glutamyl transpeptidase (Rs, -0.064; p = 0.234). At multivariate regression analysis, fasting blood glucose (β, -0.148; p = 0.008), age (β, -0.158; p = 0.005), and the presence of NAFLD (β, -0.132; p = 0.016) inversely correlated with FMD, whereas female gender predicted a better FMD (β, 0.125; p = 0.022). FMD and Framingham Risk Score (FRS) were inversely correlated (Rs, -0.183; p <0.001). After dividing patients into low (FRS <10; FMD, 5.5% [3.1% to 8.9%]), intermediate (FRS 10 to 20; FMD, 4.9% [2.7% to 7.5%]), and high (FRS >20; FMD, 3.3% [1.7% to 4.5%]) risk, FMD significantly decreased across risk classes of FRS (p = 0.003). At multivariate regression analysis, both FRS (β, -0.129; p = 0.016) and NAFLD (β, -0.218; p <0.001) were variables independently associated with FMD. In conclusion, the presence of NAFLD and FRS inversely correlated with FMD., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: NADPH oxidase, one of the most important enzymes producing reactive oxidant species, is suggested to play a role in experimental atherosclerosis, but its role in human atherosclerosis is still unclear. We hypothesized that a reduced activity of NADPH oxidase might be linked to a reduced atherosclerotic burden., Methods and Results: Thirty-one women carriers of hereditary deficiency of NOX2, the catalytic subunit of NADPH oxidase, were matched for sex and age with 31 controls and 31 obese women. Flow-mediated dilation and intima-media thickness, 2 surrogate markers of atherosclerosis, serum activity of NOX2, urinary isoprostanes, serum levels of nitrite/nitrate, and platelet production of isoprostanes and nitrite/nitrate were determined. Compared with controls (5.7±3.0% and 0.60±0.11 mm), carriers of NOX2 deficiency had higher flow-mediated dilation (9.2±5.0%; P<0.001) and lower intima-media thickness (0.50±0.11 mm; P=0.002), whereas obese women had lower flow-mediated dilation (3.2±2.1%; P=0.007) and higher intima-media thickness (0.71±0.15 mm; P<0.001). Compared with controls, carriers of NOX2 deficiency had lower urinary isoprostanes (132.6±87.3 versus 82.3±46.0 pg/mg creatinine; P=0.007) and serum NOX2 activity (24.9±19.3 versus 12.8±11.9 pg/mL; P=0.004) and higher serum nitrite/nitrate (23.8±7.6 versus 30.5±6.3 µmol/L; P<0.001), whereas obese women had higher urinary isoprostanes (132.6±87.3 versus 182.2±84.6 pg/mg creatinine; P=0.008) and serum NOX2 activity (24.9±19.3 versus 36.1±18.6 pg/mL; P=0.008) and lower serum nitrite/nitrate (23.8±7.6 versus 12.6±4.2 µmol/L; P<0.001). Flow-mediated dilation correlated with intima-media thickness (r=-0.433; P<0.001), serum NOX2 activity (r=-325; P<0.001), and urinary isoprostanes (r=-0.314; P=0.002). Ex vivo study showed that, compared with controls, platelets from carriers of NOX2 deficiency had lower isoprostanes (P<0.001) and higher nitrite/nitrate (P<0.001), whereas platelets from obese women had higher isoprostanes (P<0.001) and lower nitrite/nitrate (P=0.013)., Conclusions: The study shows reduced atherosclerotic burden in carriers of NOX2 deficiency, suggesting that oxidative stress generated by this enzymatic pathway is implicated in human atherosclerosis.