P2Y12 inhibition in patients with NSTEMI--can later be better

Acute coronary syndrome is an umbrella term that is used to describe the abrupt reduction of blood flow to myocardial tissue, typically associated with the rupture of a coronary atherosclerotic plaque. Rupture exposes the blood to plaque contents, resulting in the deposition and activation of platelets and the formation of thrombi. Complete thrombotic occlusion produces ST-segment elevation myocardial infarction, whereas incomplete impairment of coronary blood flow results in unstable angina or, when biomarkers for myocardial injury are present, non–ST-segment elevation myocardial infarction (NSTEMI). Because the rupture of a plaque incites platelet activation and thrombosis, treatments for unstable angina and NSTEMI have focused on inhibiting platelet function and the coagulation cascade. In patients at high risk for future events (i.e., reinfarction or recurrent ischemia), an early invasive strategy of cardiac catheterization and revascularization is recommended, and in most of these patients intracoronary stents are implanted to treat the plaque rupture. Since stents can produce further plaque trauma, platelet-dependent thrombosis, and embolization into the coronary microcirculation, it is best practice to treat patients with agents that inhibit platelet activation to prevent recurrent ischemia after percutaneous coronary intervention (PCI). As a consequence, current guidelines recommend dual antiplatelet therapy with aspirin plus another agent in patients with NSTEMI who are undergoing PCI

Proof That Lower Is Better--LDL Cholesterol and IMPROVE-IT

The so-called LDL hypothesis is the concept that excess low-density lipoprotein (LDL) cholesterol is a causal factor in the development of atherosclerotic vascular disease. By extension, this hypothesis also assumes that reducing LDL cholesterol levels, regardless of the means, should produce a corresponding reduction in cardiovascular events. Considerable evidence supports the LDL hypothesis, including animal studies and epidemiologic studies involving humans, as well as clinical trials of both statins and nonstatin lipid-modifying agents. In a meta-analysis that included more than 90,000 participants in 14 randomized trials of statins, the Cholesterol Treatment Trialists’ (CTT) collaborators found that, on average, a reduction of 1 mmol per liter (38.7 mg per deciliter) in LDL cholesterol levels yields a consistent 23% reduction in the risk of major coronary events over 5 years

Joseph A. Vita, MD, 1956-2014

On November 2, 2014, our friend and colleague, Joseph Vita, died after a short but gallant struggle with lung cancer at the age of 58. Joe was never a smoker and typically appeared 10 years younger than his age; thus, it was particularly shocking to many when he became ill so suddenly and in his prime. He will be sorely missed; his contributions to cardiovascular medicine were many and diverse. He was a brilliant investigator, a superb clinician, an outstanding mentor, and an expert journal editor

Postmenopausal Hormone Therapy and Atherosclerosis--Time Is of the Essence

In this issue of the Journal, Hodis et al. provide a test of this hypothesis in the Early versus Late Intervention Trial with Estradiol (ELITE)

Short-term e-cigarette vapour exposure causes vascular oxidative stress and dysfunction: evidence for a close connection to brain damage and a key role of the phagocytic NADPH oxidase (NOX-2)

AIMS: Electronic (e)-cigarettes have been marketed as a \u27healthy\u27 alternative to traditional combustible cigarettes and as an effective method of smoking cessation. There are, however, a paucity of data to support these claims. In fact, e-cigarettes are implicated in endothelial dysfunction and oxidative stress in the vasculature and the lungs. The mechanisms underlying these side effects remain unclear. Here, we investigated the effects of e-cigarette vapour on vascular function in smokers and experimental animals to determine the underlying mechanisms. METHODS AND RESULTS: Acute e-cigarette smoking produced a marked impairment of endothelial function in chronic smokers determined by flow-mediated dilation. In mice, e-cigarette vapour without nicotine had more detrimental effects on endothelial function, markers of oxidative stress, inflammation, and lipid peroxidation than vapour containing nicotine. These effects of e-cigarette vapour were largely absent in mice lacking phagocytic NADPH oxidase (NOX-2) or upon treatment with the endothelin receptor blocker macitentan or the FOXO3 activator bepridil. We also established that the e-cigarette product acrolein, a reactive aldehyde, recapitulated many of the NOX-2-dependent effects of e-cigarette vapour using in vitro blood vessel incubation. CONCLUSIONS: E-cigarette vapour exposure increases vascular, cerebral, and pulmonary oxidative stress via a NOX-2-dependent mechanism. Our study identifies the toxic aldehyde acrolein as a key mediator of the observed adverse vascular consequences. Thus, e-cigarettes have the potential to induce marked adverse cardiovascular, pulmonary, and cerebrovascular consequences. Since e-cigarette use is increasing, particularly amongst youth, our data suggest that aggressive steps are warranted to limit their health risks

Common Statistical Pitfalls in Basic Science Research

In this review, we focused on common sources of confusion and errors in the analysis and interpretation of basic science studies. The issues addressed are seen repeatedly in the authors\u27 editorial experience, and we hope this article will serve as a guide for those who may submit their basic science studies to journals that publish both clinical and basic science research. We have discussed issues related to sample size and power, study design, data analysis, and presentation of results. We then illustrated these issues using a set of examples from basic science research studies

Short-Term Exposure to Air Pollution and Biomarkers of Oxidative Stress: The Framingham Heart Study

BACKGROUND: Short-term exposure to elevated air pollution has been associated with higher risk of acute cardiovascular diseases, with systemic oxidative stress induced by air pollution hypothesized as an important underlying mechanism. However, few community-based studies have assessed this association. METHODS AND RESULTS: Two thousand thirty-five Framingham Offspring Cohort participants living within 50 km of the Harvard Boston Supersite who were not current smokers were included. We assessed circulating biomarkers of oxidative stress including blood myeloperoxidase at the seventh examination (1998-2001) and urinary creatinine-indexed 8-epi-prostaglandin F2alpha (8-epi-PGF2alpha) at the seventh and eighth (2005-2008) examinations. We measured fine particulate matter (PM2.5), black carbon, sulfate, nitrogen oxides, and ozone at the Supersite and calculated 1-, 2-, 3-, 5-, and 7-day moving averages of each pollutant. Measured myeloperoxidase and 8-epi-PGF2alpha were loge transformed. We used linear regression models and linear mixed-effects models with random intercepts for myeloperoxidase and indexed 8-epi-PGF2alpha, respectively. Models were adjusted for demographic variables, individual- and area-level measures of socioeconomic position, clinical and lifestyle factors, weather, and temporal trend. We found positive associations of PM2.5 and black carbon with myeloperoxidase across multiple moving averages. Additionally, 2- to 7-day moving averages of PM2.5 and sulfate were consistently positively associated with 8-epi-PGF2alpha. Stronger positive associations of black carbon and sulfate with myeloperoxidase were observed among participants with diabetes than in those without. CONCLUSIONS: Our community-based investigation supports an association of select markers of ambient air pollution with circulating biomarkers of oxidative stress

Regulation of ROS signal transduction by NADPH oxidase 4 localization

Reactive oxygen species (ROS) function as intracellular signaling molecules in a diverse range of biological processes. However, it is unclear how freely diffusible ROS dictate specific cellular responses. In this study, we demonstrate that nicotinamide adenine dinucleotide phosphate reduced oxidase 4 (Nox4), a major Nox isoform expressed in nonphagocytic cells, including vascular endothelium, is localized to the endoplasmic reticulum (ER). ER localization of Nox4 is critical for the regulation of protein tyrosine phosphatase (PTP) 1B, also an ER resident, through redox-mediated signaling. Nox4-mediated oxidation and inactivation of PTP1B in the ER serves as a regulatory switch for epidermal growth factor (EGF) receptor trafficking and specifically acts to terminate EGF signaling. Consistent with this notion, PTP1B oxidation could also be modulated by ER targeting of antioxidant enzymes but not their untargeted counterparts. These data indicate that the specificity of intracellular ROS-mediated signal transduction may be modulated by the localization of Nox isoforms within specific subcellular compartments

Effects of tobacco cigarettes, e-cigarettes, and waterpipe smoking on endothelial function and clinical outcomes

Tobacco smoking is a leading cause of non-communicable disease globally and is a major risk factor for cardiovascular disease (CVD) and lung disease. Importantly, recent data by the World Health Organizations (WHO) indicate that in the last two decades global tobacco use has significantly dropped, which was largely driven by decreased numbers of female smokers. Despite such advances, the use of e-cigarettes and waterpipes (shisha, hookah, narghile) is an emerging trend, especially among younger generations. There is growing body of evidence that e-cigarettes are not a harm-free alternative to tobacco cigarettes and there is considerable debate as to whether e-cigarettes are saving smokers or generating new addicts. Here, we provide an updated overview of the impact of tobacco/waterpipe (shisha) smoking and e-cigarette vaping on endothelial function, a biomarker for early, subclinical, atherosclerosis from human and animal studies. Also their emerging adverse effects on the proteome, transcriptome, epigenome, microbiome, and the circadian clock are summarized. We briefly discuss heat-not-burn tobacco products and their cardiovascular health effects. We discuss the impact of the toxic constituents of these products on endothelial function and subsequent CVD and we also provide an update on current recommendations, regulation and advertising with focus on the USA and Europe. As outlined by the WHO, tobacco cigarette, waterpipe, and e-cigarette smoking/vaping may contribute to an increased burden of symptoms due to coronavirus disease 2019 (COVID-19) and to severe health consequences

Suppression of ischemia in arterial occlusive disease by JNK-promoted native collateral artery development

Arterial occlusive diseases are major causes of morbidity and mortality. Blood flow to the affected tissue must be restored quickly if viability and function are to be preserved. We report that disruption of the mixed-lineage protein kinase (MLK) - cJun NH2-terminal kinase (JNK) signaling pathway in endothelial cells causes severe blockade of blood flow and failure to recover in the murine femoral artery ligation model of hindlimb ischemia. We show that the MLK-JNK pathway is required for the formation of native collateral arteries that can restore circulation following arterial occlusion. Disruption of the MLK-JNK pathway causes decreased Dll4/Notch signaling, excessive sprouting angiogenesis, and defects in developmental vascular morphogenesis. Our analysis demonstrates that the MLK-JNK signaling pathway is a key regulatory mechanism that protects against ischemia in arterial occlusive disease