Breaking the deadlock of calcified coronary artery lesions: A contemporary review.

Percutaneous coronary intervention (PCI) of severely calcified lesions is known to result in lower procedural success rates, higher complication rates, and worse long-term clinical outcomes compared to noncalcified lesions. Adequate lesion preparation through calcium modification is crucial in ensuring procedural success and reducing adverse cardiovascular outcomes. There are numerous calcium modification devices currently available whose usefulness depends on the nature of the calcific disease and its anatomical distribution. It can be challenging for the interventionists to decide which device is best suited for their patient. There is also emerging evidence for intravascular imaging in guiding selection of calcium modification devices using parameters such as calcium distribution and depth that directly impact on procedural success and clinical outcomes. In this review we aim to discuss the pathophysiology of coronary calcification, evaluate strategies and technologies of calcium modification and propose an A-M-A-S-A algorithm in managing calcified coronary lesions.

Impact of unhealthy lifestyle on cardiorespiratory fitness and heart rate recovery of medical science students.

BACKGROUND: Medical science students represent valuable labour resources for better future medicine and medical technology. However, little attention was given to the health and well-being of these early career medical science professionals. The aim of this study is to investigate the impact of lifestyle components on cardiorespiratory fitness and heart rate recovery measured after moderate exercise in this population. METHODS: Volunteers without documented medical condition were recruited randomly and continuously from the first-year medical science students during 2011-2014 at the University of Surrey, UK. Demographics and lifestyle components (the levels of smoking, alcohol intake, exercise, weekend outdoor activity and screen-time, daily sleep period, and self-assessment of fitness) were gathered through pre-exercise questionnaire. Cardiorespiratory fitness (VO2max) and heart rate recovery were determined using Åstrand-Rhyming submaximal cycle ergometry test. Data were analysed using SPSS version 25. RESULTS: Among 614 volunteers, 124 had completed both lifestyle questionnaire and the fitness test and were included for this study. Within 124 participants (20.6 ± 4 years), 46.8% were male and 53.2% were female, 11.3% were overweight and 8.9% were underweight, 8.9% were current smokers and 33.1% consumed alcohol beyond the UK recommendation. There were 34.7% of participants admitted to have < 3 h/week of moderate physical activity assessed according to UK Government National Physical Activity Guidelines and physically not fit (feeling tiredness). Fitness test showed that VO2max distribution was inversely associated with heart rate recovery at 3 min and both values were significantly correlated with the levels of exercise, self-assessed fitness and BMI. Participants who had < 3 h/week exercise, or felt not fit or were overweight had significantly lower VO2max and heart rate recovery than their peers. CONCLUSION: One in three new medical science students were physically inactive along with compromised cardiorespiratory fitness and heart rate recovery, which put them at risk of cardiometabolic diseases. Promoting healthy lifestyle at the beginning of career is crucial in keeping medical science professionals healthy.

A novel machine learning-derived radiotranscriptomic signature of perivascular fat improves cardiac risk prediction using coronary CT angiography.

BACKGROUND: Coronary inflammation induces dynamic changes in the balance between water and lipid content in perivascular adipose tissue (PVAT), as captured by perivascular Fat Attenuation Index (FAI) in standard coronary CT angiography (CCTA). However, inflammation is not the only process involved in atherogenesis and we hypothesized that additional radiomic signatures of adverse fibrotic and microvascular PVAT remodelling, may further improve cardiac risk prediction. METHODS AND RESULTS: We present a new artificial intelligence-powered method to predict cardiac risk by analysing the radiomic profile of coronary PVAT, developed and validated in patient cohorts acquired in three different studies. In Study 1, adipose tissue biopsies were obtained from 167 patients undergoing cardiac surgery, and the expression of genes representing inflammation, fibrosis and vascularity was linked with the radiomic features extracted from tissue CT images. Adipose tissue wavelet-transformed mean attenuation (captured by FAI) was the most sensitive radiomic feature in describing tissue inflammation (TNFA expression), while features of radiomic texture were related to adipose tissue fibrosis (COL1A1 expression) and vascularity (CD31 expression). In Study 2, we analysed 1391 coronary PVAT radiomic features in 101 patients who experienced major adverse cardiac events (MACE) within 5 years of having a CCTA and 101 matched controls, training and validating a machine learning (random forest) algorithm (fat radiomic profile, FRP) to discriminate cases from controls (C-statistic 0.77 [95%CI: 0.62-0.93] in the external validation set). The coronary FRP signature was then tested in 1575 consecutive eligible participants in the SCOT-HEART trial, where it significantly improved MACE prediction beyond traditional risk stratification that included risk factors, coronary calcium score, coronary stenosis, and high-risk plaque features on CCTA (Δ[C-statistic] = 0.126, P < 0.001). In Study 3, FRP was significantly higher in 44 patients presenting with acute myocardial infarction compared with 44 matched controls, but unlike FAI, remained unchanged 6 months after the index event, confirming that FRP detects persistent PVAT changes not captured by FAI. CONCLUSION: The CCTA-based radiomic profiling of coronary artery PVAT detects perivascular structural remodelling associated with coronary artery disease, beyond inflammation. A new artificial intelligence (AI)-powered imaging biomarker (FRP) leads to a striking improvement of cardiac risk prediction over and above the current state-of-the-art.

p22phox C242T Single-Nucleotide Polymorphism Inhibits Inflammatory Oxidative Damage to Endothelial Cells and Vessels.

BACKGROUND: The NADPH oxidase, by generating reactive oxygen species, is involved in the pathophysiology of many cardiovascular diseases and represents a therapeutic target for the development of novel drugs. A single-nucleotide polymorphism, C242T of the p22(phox) subunit of NADPH oxidase, has been reported to be negatively associated with coronary heart disease and may predict disease prevalence. However, the underlying mechanisms remain unknown. METHODS AND RESULTS: With the use of computer molecular modeling, we discovered that C242T single-nucleotide polymorphism causes significant structural changes in the extracellular loop of p22(phox) and reduces its interaction stability with Nox2 subunit. Gene transfection of human pulmonary microvascular endothelial cells showed that C242T p22(phox) significantly reduced Nox2 expression but had no significant effect on basal endothelial O2 (.-) production or the expression of Nox1 and Nox4. When cells were stimulated with tumor necrosis factor-α (or high glucose), C242T p22(phox) significantly inhibited tumor necrosis factor-α-induced Nox2 maturation, O2 (.-) production, mitogen-activated protein kinases and nuclear factor κB activation, and inflammation (all P<0.05). These C242T effects were further confirmed using p22(phox) short-hairpin RNA-engineered HeLa cells and Nox2(-/-) coronary microvascular endothelial cells. Clinical significance was investigated by using saphenous vein segments from non-coronary heart disease subjects after phlebotomies. TT (C242T) allele was common (prevalence of ≈22%) and, in comparison with CC, veins bearing TT allele had significantly lower levels of Nox2 expression and O2 (.-) generation in response to high-glucose challenge. CONCLUSIONS: C242T single-nucleotide polymorphism causes p22(phox) structural changes that inhibit endothelial Nox2 activation and oxidative response to tumor necrosis factor-α or high-glucose stimulation. C242T single-nucleotide polymorphism may represent a natural protective mechanism against inflammatory cardiovascular diseases.

Molecular insights of p47phox phosphorylation dynamics in the regulation of NADPH oxidase activation and superoxide production.

Phagocyte superoxide production by a multicomponent NADPH oxidase is important in host defense against microbial invasion. However inappropriate NADPH oxidase activation causes inflammation. Endothelial cells express NADPH oxidase and endothelial oxidative stress due to prolonged NADPH oxidase activation predisposes many diseases. Discovering the mechanism of NADPH oxidase activation is essential for developing novel treatment of these diseases. The p47(phox) is a key regulatory subunit of NADPH oxidase; however, due to the lack of full protein structural information, the mechanistic insight of p47(phox) phosphorylation in NADPH oxidase activation remains incomplete. Based on crystal structures of three functional domains, we generated a computational structural model of the full p47(phox) protein. Using a combination of in silico phosphorylation, molecular dynamics simulation and protein/protein docking, we discovered that the C-terminal tail of p47(phox) is critical for stabilizing its autoinhibited structure. Ser-379 phosphorylation disrupts H-bonds that link the C-terminal tail to the autoinhibitory region (AIR) and the tandem Src homology 3 (SH3) domains, allowing the AIR to undergo phosphorylation to expose the SH3 pocket for p22(phox) binding. These findings were confirmed by site-directed mutagenesis and gene transfection of p47(phox-/-) coronary microvascular cells. Compared with wild-type p47(phox) cDNA transfected cells, the single mutation of S379A completely blocked p47(phox) membrane translocation, binding to p22(phox) and endothelial O2(·-) production in response to acute stimulation of PKC. p47(phox) C-terminal tail plays a key role in stabilizing intramolecular interactions at rest. Ser-379 phosphorylation is a molecular switch which initiates p47(phox) conformational changes and NADPH oxidase-dependent superoxide production by cells.

Endothelial cell-specific reactive oxygen species production increases susceptibility to aortic dissection.

BACKGROUND: Increased production of reactive oxygen species (ROS) throughout the vascular wall is a feature of cardiovascular disease states, but therapeutic strategies remain limited by our incomplete understanding of the role and contribution of specific vascular cell ROS to disease pathogenesis. To investigate the specific role of endothelial cell (EC) ROS in the development of structural vascular disease, we generated a mouse model of endothelium-specific Nox2 overexpression and tested the susceptibility to aortic dissection after angiotensin II (Ang II) infusion. METHODS AND RESULTS: A specific increase in endothelial ROS production in Nox2 transgenic mice was sufficient to cause Ang II-mediated aortic dissection, which was never observed in wild-type mice. Nox2 transgenic aortas had increased endothelial ROS production, endothelial vascular cell adhesion molecule-1 expression, matrix metalloproteinase activity, and CD45(+) inflammatory cell infiltration. Conditioned media from Nox2 transgenic ECs induced greater Erk1/2 phosphorylation in vascular smooth muscle cells compared with wild-type controls through secreted cyclophilin A (CypA). Nox2 transgenic ECs (but not vascular smooth muscle cells) and aortas had greater secretion of CypA both at baseline and in response to Ang II stimulation. Knockdown of CypA in ECs abolished the increase in vascular smooth muscle cell Erk1/2 phosphorylation conferred by EC conditioned media, and preincubation with CypA augmented Ang II-induced vascular smooth muscle cell ROS production. CONCLUSIONS: These findings demonstrate a pivotal role for EC-derived ROS in the determination of the susceptibility of the aortic wall to Ang II-mediated aortic dissection. ROS-dependent CypA secretion by ECs is an important signaling mechanism through which EC ROS regulate susceptibility of structural components of the aortic wall to aortic dissection.

Managing Ventricular Wall Rupture as a Complication of Late Presentation MI in a Complex Patient with Ankylosing Spondylitis.

Ventricular free wall rupture is an infrequent but serious complication of myocardial infarction with high mortality despite surgical intervention. In recent years with the COVID-19 pandemic, observational studies have reported a rise in this complication most likely due to patient hesitation in seeking urgent medical assistance for fear of contracting COVID-19 in a hospital setting. This case report highlights the early recognition and diagnosis of ventricular wall rupture by the heart team with a good surgical outcome in a complex patient with ankylosing spondylitis. Ventricular rupture should be considered in deteriorating patients presenting with suspicion of late presentation myocardial infarction. Clinicians in the post-COVID-19 era should expect to see these complications more frequently.

Divergent effects of p47(phox) phosphorylation at S303-4 or S379 on tumor necrosis factor-α signaling via TRAF4 and MAPK in endothelial cells.

OBJECTIVE: To define the mechanism of p47(phox) phosphorylation in regulating endothelial cell response to tumor necrosis factor-α (TNFα) stimulation. METHODS AND RESULTS: We replaced 11 serines (303-4, 310, 315, 320, 328, 345, 348, 359, 370, and 379) with alanines and investigated their effects on TNFα (100 U/mL, 30 minutes)-induced acute O(2)(.-) production and mitogen-activated protein kinase phosphorylation in endothelial cells. Seven constructs, S303-4A (double), S310A, S315A, S328A, S345A, S370A, and S379A, significantly reduced the O(2)(.-) production, and 4 of them (S328A, S345A, S370A, and S379A) also inhibited TNFα-induced extracellular-signal-regulated kinase (ERK) 1/2 phosphorylation. Blocking the phosphorylation of S303-4 and S379 inhibited most effectively TNFα-induced O(2)(.-) production. However, phosphorylation of S303-4 was not required for TNFα-induced p47(phox) membrane translocation and binding to TNF receptor-associated factor 4, ERK1/2 activation, and subsequent vascular cell adhesion molecule-1 expression. Knockout of p47(phox) or knockdown of TNF receptor-associated factor 4 using siRNA abolished TNFα-induced ERK1/2 phosphorylation, and inhibition of ERK1/2 activation significantly reduced the TNFα-induced vascular cell adhesion molecule-1 expression. CONCLUSIONS: Phosphorylation of p47(phox) at different serine sites plays distinct roles in endothelial cell response to TNFα stimulation. Double serine (S303-4) phosphorylation is crucial for acute O(2)(.-) production, but is not involved in TNFα signaling through TNF receptor-associated factor 4 and ERK1/2. p47(phox) requires serine phosphorylation at distinct sites to support specific signaling events in response to TNFα.

Intra-coronary physiology in contemporary percutaneous coronary intervention and anginal therapy with a focus on microvascular disease.

Coronary physiological measurements have transformed the treatment of coronary artery disease (CAD), with increasing evidence supporting the use of pressure wire guided revascularisation. Advances in microvascular assessment have enabled clinicians to discern angina aetiology even in patients without obstructive epicardial coronary artery disease, paving the way for more effective tailored therapy. In this article, the authors will examine pressure wire indices, their role in influencing clinical outcomes and future directions.

Improving use of proton pump inhibitors with dual antiplatelet therapy in patients admitted with acute coronary syndrome.

Acute coronary syndrome (ACS) is one of the leading causes of morbidity and mortality with a major impact on healthcare resources and expenditure. Dual antiplatelet therapy (DAPT) is recommended for the treatment of ACS. DAPT is associated with an increased risk of gastrointestinal (GI) bleeding, which is seen in 1.2%-2.4% of patients on DAPT and associated with fivefold increase in mortality at 30 days and fourfold increase at 1 year. European Society of Cardiology guidelines recommend that patients on DAPT should also be prescribed a proton pump inhibitor (PPI) to reduce the risk of GI bleeding.We assessed compliance with this recommendation on the cardiology ward of our tertiary cardiac unit. At baseline, only 56% of patients on DAPT were coprescribed a PPI. We subsequently devised and delivered a service improvement project (three completed audit cycles) to improve concomitant prescription of PPI, with the aim of achieving 100% compliance with the guidelines. We introduced low-cost interventions that included educational sessions for junior doctors, cardiac nursing staff and pharmacists, as well as posters which served as visual prompts for discharging doctors. We also initiated a protocol that the pharmacy team clarify with the discharging doctor whether a patient on DAPT should also be on PPI, before the discharge summary is finalised.Consequently, 100% of patients on DAPT were coprescribed PPI within fourteen weeks of the onset of our intervention. This improvement was sustained across a subsequent cohort of junior doctors. Our interventions should help to reduce the risk of GI bleeding in this population.

Inhibition of endothelial Nox2 activation by LMH001 protects mice from angiotensin II-induced vascular oxidative stress, hypertension and aortic aneurysm.

Endothelial oxidative stress and inflammation attributable to the activation of a Nox2-NADPH oxidase are key features of many cardiovascular diseases. Here, we report a novel small chemical compound (LMH001, MW = 290.079), by blocking phosphorylated p47phox interaction with p22phox, inhibited effectively angiotensin II (AngII)-induced endothelial Nox2 activation and superoxide production at a small dose (IC50 = 0.25 µM) without effect on peripheral leucocyte oxidative response to pathogens. The therapeutic potential of LMH001 was tested using a mouse model (C57BL/6J, 7-month-old) of AngII infusion (0.8 mg/kg/d, 14 days)-induced vascular oxidative stress, hypertension and aortic aneurysm. Age-matched littermates of p47phox knockout mice were used as controls of Nox2 inhibition. LMH001 (2.5 mg/kg/d, ip. once) showed no effect on control mice, but inhibited completely AngII infusion-induced excess ROS production in vital organs, hypertension, aortic walls inflammation and reduced incidences of aortic aneurysm. LMH001 effects on reducing vascular oxidative stress was due to its inhibition of Nox2 activation and was abrogated by knockout of p47phox. LMH001 has the potential to be developed as a novel drug candidate to treat oxidative stress-related cardiovascular diseases.

p47phox-Dependent Oxidant Signalling through ASK1, MKK3/6 and MAPKs in Angiotensin II-Induced Cardiac Hypertrophy and Apoptosis.

The p47phox is a key regulatory subunit of Nox2-containing NADPH oxidase (Nox2) that by generating reactive oxygen species (ROS) plays an important role in Angiotensin II (AngII)-induced cardiac hypertrophy and heart failure. However, the signalling pathways of p47phox in the heart remains unclear. In this study, we used wild-type (WT) and p47phox knockout (KO) mice (C57BL/6, male, 7-month-old, n = 9) to investigate p47phox-dependent oxidant-signalling in AngII infusion (0.8 mg/kg/day, 14 days)-induced cardiac hypertrophy and cardiomyocyte apoptosis. AngII infusion resulted in remarkable high blood pressure and cardiac hypertrophy in WT mice. However, these AngII-induced pathological changes were significantly reduced in p47phox KO mice. In WT hearts, AngII infusion increased significantly the levels of superoxide production, the expressions of Nox subunits, the expression of PKCα and C-Src and the activation of ASK1 (apoptosis signal-regulating kinase 1), MKK3/6, ERK1/2, p38 MAPK and JNK signalling pathways together with an elevated expression of apoptotic markers, i.e., γH2AX and p53 in the cardiomyocytes. However, in the absence of p47phox, although PKCα expression was increased in the hearts after AngII infusion, there was no significant activation of ASK1, MKK3/6 and MAPKs signalling pathways and no increase in apoptosis biomarker expression in cardiomyocytes. In conclusion, p47phox-dependent redox-signalling through ASK1, MKK3/6 and MAPKs plays a crucial role in AngII-induced cardiac hypertrophy and cardiomyocyte apoptosis.

Intravascular imaging-guided intracoronary lithotripsy: First real-world experience.

BACKGROUND AND AIMS: Coronary calcification remains a significant challenge for the contemporary interventional cardiologist. We aim to describe the use of intravascular lithotripsy (IVL) in a range of real-world settings. METHODS: A retrospective two-center analysis of patients treated with IVL between June 2018 and November 2019. Technical and procedural success, as well as procedural complications and 30-day outcomes (death, myocardial infarction, or repeat target vessel revascularization), was recorded. RESULTS: Sixty-five patients underwent IVL: 80% were male and the mean age was 70.1 ± 12.0 years. 54% of patients presented with acute coronary syndrome (ACS) and 68% of patients had intracoronary imaging. Twelve patients required IVL within pre-existing stents, and 12 underwent IVL in the left main stem. All balloons were successfully delivered with 98.5% procedural success. There was a significant gain in MLA post PCI of 261.9 ± 100% following IVL. There were two procedural complications. At 30-day follow-up, there was one death, and one patient required a repeat procedure due to stent underexpansion. CONCLUSIONS: In this largest real-world series of imaging-guided IVL for calcified lesions to date, we demonstrate that IVL is deliverable, safe, and effective at calcium modification especially when intracoronary imaging is used.

Knockout of p47 phox uncovers a critical role of p40 phox in reactive oxygen species production in microvascular endothelial cells.

OBJECTIVE: p40(phox) is an important regulatory subunit of NADPH oxidase, but its role in endothelial reactive oxygen species (ROS) production remains unknown. METHODS AND RESULTS: Using coronary microvascular endothelial cells isolated from wild-type and p47(phox) knockout mice, we found that knockout of p47(phox) increased the level of p40(phox) expression, whereas depletion of p40(phox) in wild-type cells increased p47(phox) expression. In both cases, the basal ROS production (without agonist stimulation) was well preserved. Double knockout of p40(phox) and p47(phox) dramatically reduced (approximately 65%) ROS production and cells started to die. The transcriptional regulation of p40(phox) and p47(phox) expressions involves HBP1. p40(phox) was prephosphorylated in resting cells. PMA stimulation induced p40(phox) swift dephosphorylation (within 1 minute) in parallel with the start of p47(phox) phosphorylation. p40(phox) was then rephosphorylated, and this was accompanied with an increase in ROS production. Depletion of p40(phox) resulted in approximately 67% loss in agonist-induced ROS production despite the presence of p47(phox). These were further supported by experiments on mouse aortas stimulated with angiotensin II. CONCLUSIONS: p40(phox) is prephosphorylated in resting endothelial cells and can compensate p47(phox) in keeping basal ROS production. Dephosphorylation of p40(phox) is a prerequisite for agonist-induced p47(phox) phosphorylation, and p40(phox) through its dynamic dephosphorylation and rephosphorylation is involved in the regulation of agonist-induced ROS production.

In vivo and in silico characterization of apocynin in reducing organ oxidative stress: A pharmacokinetic and pharmacodynamic study.

Apocynin has been widely used in vivo as a Nox2-contaninig nicotinamide adenine dinucleotide phosphate oxidase inhibitor. However, its time-dependent tissue distribution and inhibition on organ reactive oxygen species (ROS) production remained unclear. In this study, we examined apocynin pharmacokinetics and pharmacodynamics (PKPD) after intravenous (iv) injection (bolus, 5 mg/kg) of mice (CD1, 12-week). Apocynin was detected using a HPLC coupled to a linear ion-trap tandem mass spectrometer. Apocynin peak concentrations were detected in plasma at 1 minute (5494 ± 400 ng/mL) (t1/2  = 0.05 hours, clearance = 7.76 L/h/kg), in urine at 15 minutes (14 942 ± 5977 ng/mL), in liver at 5 minutes (2853 ± 35 ng/g), in heart at 5 minutes (3161 ± 309 ng/g) and in brain at 1 minute (4603 ± 208 ng/g) after iv injection. These were accompanied with reduction of ROS production in the liver, heart and brain homogenates. Diapocynin was not detected in these samples. Therapeutic effect of apocynin was examined using a mouse model (C57BL/6J) of high-fat diet (HFD, 16 weeks)-induced obesity and accelerated aging. Apocynin (5 mmol/L) was supplied in drinking water during the HFD period and was detected at the end of treatment in the brain (5369 ± 1612 ng/g), liver (4818 ± 1340 ng/g) and heart (1795 ± 1487 ng/g) along with significant reductions of ROS production in these organs. In conclusion, apocynin PKPD is characterized by a short half-life, rapid clearance, good distribution and inhibition of ROS production in major organs. Diapocynin is not a metabolite of apocynin in vivo. Apocynin crosses easily the blood-brain barrier and reduces brain oxidative stress associated with metabolic disorders and aging.

Exploration of Alcohol Consumption Behaviours and Health-Related Influencing Factors of Young Adults in the UK.

Hazardous alcohol consumption is ranked above illicit drug use with regards to health deterioration and social and economic burden. This study sought to clarify the factors influencing alcohol consumption and its prevalence in young adults. Demographics, alcohol consumption and lifestyle information were gathered via anonymous questionnaires during 2011-2019, crossing Reading, Surrey and Farnborough universities, UK. Controlling for confounders, a multinomial logistic regression was performed using SAS® 9.4 software. A total of 1440 students (43.5% males, 56.5% females; 54.4% Caucasians) with a mean (SD) age of 19.9 (2.73) were included. Among them, 68.9% consumed alcohol frequently and 31.7% had ≥12 units/week. Statistical analysis revealed that males consumed twice more alcohol than females, odds ratio (OR) 1.67 (95% confidence interval (CI) = 1.34-2.09), p-value < 0.01. Caucasians consumed up to five times more alcohol than other ethnicities, OR 4.55 (3.57-5.56), p-value < 0.01. Smokers consumed three times more alcohol than non-smokers, OR 2.69 (1.82, 3.99), p-value < 0.01. In general, the levels of alcohol consumption were positively associated with the levels of physical activity, OR 2.00 (1.17-3.42), p-value < 0.05 and negatively associated with recreational sedentary screen-time activities in males, OR 0.31 (0.12-0.86), p-value = 0.03. Focusing alcohol interventions toward Caucasians, smokers and physically active students, particularly males, may guide university strategies to reduce alcohol-related societal harm and risks of morbidity and mortality.

Nox2 dependent redox-regulation of microglial response to amyloid-ß stimulation and microgliosis in aging.

Microglia express constitutively a Nox2 enzyme that is involved in neuroinflammation by the generation of reactive oxygen species (ROS). Amyloid ß (Aß) plays a crucial role in Alzheimer's disease. However, the mechanism of Aß-induced microglial dysfunction and redox-regulation of microgliosis in aging remains unclear. In this study, we examined Nox2-derived ROS in mediating microglial response to Aß peptide 1-42 (Aß42) stimulation in vitro, in aging-associated microgliosis in vivo and in post-mortem human samples. Compared to controls, Aß42 markedly induced BV2 cell ROS production, Nox2 expression, p47phox and ERK1/2 phosphorylation, cell proliferation and IL-1ß secretion. All these changes could be inhibited to the control levels in the presence of Nox2 inhibitor or superoxide scavenger. Compared to young (3-4 months) controls, midbrain tissues from wild-type aging mice (20-22 months) had significantly higher levels of Nox2-derived ROS production, Aß deposition, microgliosis and IL-1ß production. However, these aging-related changes were reduced or absent in Nox2 knockout aging mice. Clinical significance of aging-associated Nox2 activation, microgliosis and IL-1ß production was investigated using post-mortem midbrain tissues of humans at young (25-38 years) and old age (61-85 years). In conclusion, Nox2-dependent redox-signalling is crucial in microglial response to Aß42 stimulation and in aging-associated microgliosis and brain inflammation.

Chronic cocaine-induced cardiac oxidative stress and mitogen-activated protein kinase activation: the role of Nox2 oxidase.

Chronic cocaine exposure is associated with severe cardiac complications, but the mechanisms of cocaine cardiotoxicity remain unclear, and current therapies are unsatisfactory. We investigated the hypothesis of oxidative stress-mediated cardiotoxicity and the role of NADPH oxidase in this process in a mouse model of chronic escalating "binge" cocaine administration (milligrams per kilogram): days 1 to 4 at 3 x 15 mg, days 5 to 8 at 3 x 20 mg, days 9 to 12 at 3 x 25 mg, and days 13 to 14 at 3 x 30 mg. Compared with vehicle controls, chronic binge cocaine administration significantly increased the cardiac NADPH-dependent O(2)(.) production (1.96- +/- 0.4-fold) as detected by tiron (an O(2)(.) scavenger)-inhibitable lucigenin chemiluminescence and dihydroethidium fluorescence. Cocaine-induced reactive oxygen species (ROS) production was associated with significant increases ( approximately 2-fold) in the protein expressions of Nox2 (an isoform of NADPH oxidase) and its regulatory subunits: p22(phox), p67(phox), p47(phox), p40(phox), and Rac1, and in p47(phox) phosphorylation as detected by immunoblotting (all p < 0.03). Increased Nox2 activity was accompanied by the activation of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase (MAPK), and c-Jun NH(2)-terminal kinase, notably in the cardiomyocytes. Cell culture experiments revealed that cocaine-induced ROS production was primarily a direct action of cocaine on cardiac myocytes, which caused severe oxidative damage to myocytes and cell death as detected by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. These could be inhibited by inhibitors to protein kinase C (bisindolymaleimide) or by depletion of Nox2 using small interfering RNA. In conclusion, chronic cocaine administration directly causes severe myocardial oxidative stress through the activation of Nox2 oxidase. Increased ROS production contributes to MAPK activation and the subsequent myocyte damage. Inhibitors to NADPH oxidase or antioxidants may have therapeutic potential in the treatment of cocaine cardiotoxicity.

One-Hour High Sensitivity Troponin Testing: A Safe and Effective Triage Tool for the Emergency Department.

The latest European Society of Cardiology guideline on the management of acute coronary syndromes without persistent ST-elevation stipulates several acceptable pathways through which patients presenting with chest pain can be assessed for unstable coronary disease. This article reviews the data behind the "rule-in and rule-out algorithm," which can exclude acute myocardial infarction within 1 hour of presentation through the use of fifth generation high-sensitivity troponin assays.

Quantification of Ischemia As a Prognostic Mandate for Coronary Revascularization in Asymptomatic Patients: How Much Is Enough?

The aim of this study was to investigate whether asymptomatic patients with known coronary artery disease and demonstrable myocardial ischemia warrant revascularization on prognostic grounds. A Medline and PubMed search was performed, including 7 trials with data discussed and concise reviews of prominent articles in the field. The magnitude of inducible ischemia in those with known coronary disease correlates closely with poor cardiovascular outcomes in terms of death, myocardial infarction, hospitalization, and revascularization. Patients with ≥10% inducible ischemia experience a survival advantage when revascularized with a reduction in mortality of greater than 50% regardless of symptoms (P < 0.00001). Evidence also suggests that left ventricular function remains preserved in those who are revascularized when compared with medical therapy alone; left ventricular ejection fraction 53.9% versus 48.8% (P < 0.001). Silent ischemia is a useful prognostic marker in those with known coronary disease. It is recommended that asymptomatic patients with known coronary disease be revascularized on prognostic grounds if ≥10% ischemia can be demonstrated on nuclear or myocardial perfusion scan, ≥3 segments of regional wall motion abnormality on stress echocardiography/cardiac magnetic resonance imaging, or ≥2 segments with perfusion deficits on stress perfusion cardiac magnetic resonance imaging.