Showing papers by "David E. Newby published in 2017"

Inhaled Nanoparticles Accumulate at Sites of Vascular Disease

Abstract: The development of engineered nanomaterials is growing exponentially, despite concerns over their potential similarities to environmental nanoparticles that are associated with significant cardiorespiratory morbidity and mortality. The mechanisms through which inhalation of nanoparticles could trigger acute cardiovascular events are emerging, but a fundamental unanswered question remains: Do inhaled nanoparticles translocate from the lung in man and directly contribute to the pathogenesis of cardiovascular disease? In complementary clinical and experimental studies, we used gold nanoparticles to evaluate particle translocation, permitting detection by high-resolution inductively coupled mass spectrometry and Raman microscopy. Healthy volunteers were exposed to nanoparticles by acute inhalation, followed by repeated sampling of blood and urine. Gold was detected in the blood and urine within 15 min to 24 h after exposure, and was still present 3 months after exposure. Levels were greater following inhalati...

Myocardial Fibrosis and Cardiac Decompensation in Aortic Stenosis

Abstract: Objectives Cardiac magnetic resonance (CMR) was used to investigate the extracellular compartment and myocardial fibrosis in patients with aortic stenosis, as well as their association with other measures of left ventricular decompensation and mortality. Background Progressive myocardial fibrosis drives the transition from hypertrophy to heart failure in aortic stenosis. Diffuse fibrosis is associated with extracellular volume expansion that is detectable by T1 mapping, whereas late gadolinium enhancement (LGE) detects replacement fibrosis. Methods In a prospective observational cohort study, 203 subjects (166 with aortic stenosis [69 years; 69% male]; 37 healthy volunteers [68 years; 65% male]) underwent comprehensive phenotypic characterization with clinical imaging and biomarker evaluation. On CMR, we quantified the total extracellular volume of the myocardium indexed to body surface area (iECV). The iECV upper limit of normal from the control group (22.5 ml/m2) was used to define extracellular compartment expansion. Areas of replacement mid-wall LGE were also identified. All-cause mortality was determined during 2.9 ± 0.8 years of follow up. Results iECV demonstrated a good correlation with diffuse histological fibrosis on myocardial biopsies (r = 0.87; p Conclusions CMR detects ventricular decompensation in aortic stenosis through the identification of myocardial extracellular expansion and replacement fibrosis. This holds major promise in tracking myocardial health in valve disease and for optimizing the timing of valve replacement. (The Role of Myocardial Fibrosis in Patients With Aortic Stenosis; NCT01755936)

Long-Term Outcomes in Patients With Type 2 Myocardial Infarction and Myocardial Injury

Abstract: Background —Type 2 myocardial infarction and myocardial injury are common in clinical practice, but long-term consequences are uncertain. We aimed to define long-term outcomes and explore risk stratification in patients with type 2 myocardial infarction and myocardial injury. Methods —We identified consecutive patients (n=2,122) with elevated cardiac troponin I concentrations (≥0.05 μg/L) at a tertiary cardiac center. All diagnoses were adjudicated as per the Universal Definition of Myocardial Infarction. The primary outcome was all-cause death. Secondary outcomes included major adverse cardiovascular events (MACE; non-fatal myocardial infarction or cardiovascular death) and non-cardiovascular death. To explore competing risks, cause-specific hazard ratios were obtained using Cox regression models. Results —The adjudicated index diagnosis was type 1 or type 2 myocardial infarction or myocardial injury in 1,171 (55.2%), 429 (20.2%) and 522 (24.6%) patients, respectively. At five years, all-cause death rates were higher in those with type 2 myocardial infarction (62.5%) or myocardial injury (72.4%) compared with type 1 myocardial infarction (36.7%). The majority of excess deaths in those with type 2 myocardial infarction or myocardial injury were due to non-cardiovascular causes (HR 2.32, 95%CI 1.92-2.81, versus type 1 myocardial infarction). Despite this, the observed crude MACE rates were similar between groups (30.6% versus 32.6%), with differences apparent after adjustment for co-variates (HR 0.82, 95%CI 0.69-0.96). Coronary heart disease was an independent predictor of MACE in those with type 2 myocardial infarction or myocardial injury (HR 1.71, 95%CI 1.31-2.24). Conclusions —Despite an excess in non-cardiovascular death, patients with type 2 myocardial infarction or myocardial injury have a similar crude rate of major adverse cardiovascular events to those with type 1 myocardial infarction. Identifying underlying coronary heart disease in this vulnerable population may help target therapies that could modify future risk.

The Updated NICE Guidelines: Cardiac CT as the First-Line Test for Coronary Artery Disease.

Abstract: Purpose of Review Cost-effective care pathways are integral to delivering sustainable healthcare programmes. Due to the overestimation of coronary artery disease using traditional risk tables, non-invasive testing has been utilised to improve risk stratification and initiate appropriate management to reduce the dependence on invasive investigations. In line with recent technological improvements, cardiac CT is a modality that offers a detailed anatomical assessment of coronary artery disease comparable to invasive coronary angiography.

Persistent Long-Term Structural, Functional, and Metabolic Changes After Stress-Induced (Takotsubo) Cardiomyopathy

Abstract: BACKGROUND : Takotsubo cardiomyopathy is an increasingly recognized acute heart failure syndrome precipitated by intense emotional stress. Although there is an apparent rapid and spontaneous recovery of left ventricular ejection fraction, the long-term clinical and functional consequences of takotsubo cardiomyopathy are ill-defined. METHODS : In an observational case-control study, we recruited 37 patients with prior (>12-month) takotsubo cardiomyopathy, and 37 age-, sex-, and comorbidity-matched control subjects. Patients completed the Minnesota Living with Heart Failure Questionnaire. All participants underwent detailed clinical phenotypic characterization, including serum biomarker analysis, cardiopulmonary exercise testing, echocardiography, and cardiac magnetic resonance including cardiac 31 P-spectroscopy. RESULTS : Participants were predominantly middle-age (64±11 years) women (97%). Although takotsubo cardiomyopathy occurred 20 (range 13-39) months before the study, the majority (88%) of patients had persisting symptoms compatible with heart failure (median of 13 [range 0-76] in the Minnesota Living with Heart Failure Questionnaire) and cardiac limitation on exercise testing (reduced peak oxygen consumption, 24±1.3 versus 31±1.3 mL/kg/min, P 2 slope, 31±1 versus 26±1, P =0.002). Despite normal left ventricular ejection fraction and serum biomarkers, patients with prior takotsubo cardiomyopathy had impaired cardiac deformation indices (reduced apical circumferential strain, ‒16±1.0 versus ‒23±1.5%, P P =0.006), increased native T1 mapping values (1264±10 versus 1184±10 ms, P P CONCLUSIONS : In contrast to previous perceptions, takotsubo cardiomyopathy has long-lasting clinical consequences, including demonstrable symptomatic and functional impairment associated with persistent subclinical cardiac dysfunction. Taken together our findings demonstrate that after takotsubo cardiomyopathy, patients develop a persistent, long-term heart failure phenotype. CLINICAL TRIAL REGISTRATION : URL: https://clinicaltrials.gov. Unique identifier: NCT02989454.

Association of High-Sensitivity Cardiac Troponin I Concentration With Cardiac Outcomes in Patients With Suspected Acute Coronary Syndrome

Abstract: Importance High-sensitivity cardiac troponin I testing is widely used to evaluate patients with suspected acute coronary syndrome. A cardiac troponin concentration of less than 5 ng/L identifies patients at presentation as low risk, but the optimal threshold is uncertain. Objective To evaluate the performance of a cardiac troponin I threshold of 5 ng/L at presentation as a risk stratification tool in patients with suspected acute coronary syndrome. Data Sources Systematic search of MEDLINE, EMBASE, Cochrane, and Web of Science databases from January 1, 2006, to March 18, 2017. Study Selection Prospective studies measuring high-sensitivity cardiac troponin I concentrations in patients with suspected acute coronary syndrome in which the diagnosis was adjudicated according to the universal definition of myocardial infarction. Data Extraction and Synthesis The systematic review identified 19 cohorts. Individual patient-level data were obtained from the corresponding authors of 17 cohorts, with aggregate data from 2 cohorts. Meta-estimates for primary and secondary outcomes were derived using a binomial-normal random-effects model. Main Outcomes and Measures The primary outcome was myocardial infarction or cardiac death at 30 days. Performance was evaluated in subgroups and across a range of troponin concentrations (2-16 ng/L) using individual patient data. Results Of 11 845 articles identified, 104 underwent full-text review, and 19 cohorts from 9 countries were included. Among 22 457 patients included in the meta-analysis (mean age, 62 [SD, 15.5] years; n = 9329 women [41.5%]), the primary outcome occurred in 2786 (12.4%). Cardiac troponin I concentrations were less than 5 ng/L at presentation in 11 012 patients (49%), in whom there were 60 missed index or 30-day events (59 index myocardial infarctions, 1 myocardial infarction at 30 days, and no cardiac deaths at 30 days). This resulted in a negative predictive value of 99.5% (95% CI, 99.3%-99.6%) for the primary outcome. There were no cardiac deaths at 30 days and 7 (0.1%) at 1 year, with a negative predictive value of 99.9% (95% CI, 99.7%-99.9%) for cardiac death. Conclusions and Relevance Among patients with suspected acute coronary syndrome, a high-sensitivity cardiac troponin I concentration of less than 5 ng/L identified those at low risk of myocardial infarction or cardiac death within 30 days. Further research is needed to understand the clinical utility and cost-effectiveness of this approach to risk stratification.

Comparison of the Efficacy and Safety of Early Rule Out Pathways for Acute Myocardial Infarction

Abstract: Background: High-sensitivity cardiac troponin assays enable myocardial infarction to be ruled out earlier, but the optimal approach is uncertain. We compared the European Society of Cardiology rule-out pathway with a pathway that incorporates lower cardiac troponin concentrations to risk stratify patients. Methods: Patients with suspected acute coronary syndrome (n=1218) underwent high-sensitivity cardiac troponin I measurement at presentation and 3 and 6 or 12 hours. We compared the European Society of Cardiology pathway (<99th centile at presentation or at 3 hours if symptoms <6 hours) with a pathway developed in the High-STEACS study (High-Sensitivity Troponin in the Evaluation of Patients With Acute Coronary S yndrome) population (<5 ng/L at presentation or change <3 ng/L and <99th centile at 3 hours). The primary outcome was a comparison of the negative predictive value of both pathways for index type 1 myocardial infarction or type 1 myocardial infarction or cardiac death at 30 days. We evaluated the primary outcome in prespecified subgroups stratified by age, sex, time of symptom onset, and known ischemic heart disease. Results: The primary outcome occurred in 15.7% (191 of 1218) patients. In those less than the 99th centile at presentation, the European Society of Cardiology pathway ruled out myocardial infarction in 28.1% (342 of 1218) and 78.9% (961 of 1218) at presentation and 3 hours, respectively, missing 18 index and two 30-day events (negative predictive value, 97.9%; 95% confidence interval, 96.9–98.7). The High-STEACS pathway ruled out 40.7% (496 of 1218) and 74.2% (904 of 1218) at presentation and 3 hours, missing 2 index and two 30-day events (negative predictive value, 99.5%; 95% confidence interval, 99.0–99.9; P <0.001 for comparison). The negative predictive value of the High-STEACS pathway was greater than the European Society of Cardiology pathway overall ( P <0.001) and in all subgroups, including those presenting early or known to have ischemic heart disease. Conclusions: Use of the High-STEACS pathway incorporating low high-sensitivity cardiac troponin concentrations rules out myocardial infarction in more patients at presentation and misses 5-fold fewer index myocardial infarctions than guideline-approved pathways based exclusively on the 99th centile. Clinical Trial Registration: URL: . Unique identifier: [NCT01852123][1]. # Clinical Perspective {#article-title-31} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01852123&atom=%2Fcirculationaha%2F135%2F17%2F1586.atom

Patient selection for high sensitivity cardiac troponin testing and diagnosis of myocardial infarction: prospective cohort study.

Abstract: Objective To evaluate how selection of patients for high sensitivity cardiac troponin testing affects the diagnosis of myocardial infarction across different healthcare settings.Design Prospective study of three independent consecutive patient populations presenting to emergency departments.Setting Secondary and tertiary care hospitals in the United Kingdom and United States.Participants High sensitivity cardiac troponin I concentrations were measured in 8500 consecutive patients presenting to emergency departments: unselected patients in the UK (n=1054) and two selected populations of patients in whom troponin testing was requested by the attending clinician in the UK (n=5815) and the US (n=1631). The final diagnosis of type 1 or type 2 myocardial infarction or myocardial injury was independently adjudicated.Main outcome measures Positive predictive value of an elevated cardiac troponin concentration for a diagnosis of type 1 myocardial infarction.Results Cardiac troponin concentrations were elevated in 13.7% (144/1054) of unselected patients, with a prevalence of 1.6% (17/1054) for type 1 myocardial infarction and a positive predictive value of 11.8% (95% confidence interval 7.0% to 18.2%). In selected patients, in whom troponin testing was guided by the attending clinician, the prevalence and positive predictive value were 14.5% (843/5815) and 59.7% (57.0% to 62.2%) in the UK and 4.2% (68/1631) and 16.4% (13.0% to 20.3%) in the US. Across both selected patient populations, the positive predictive value was highest in patients with chest pain, with ischaemia on the electrocardiogram, and with a history of ischaemic heart disease.Conclusions When high sensitivity cardiac troponin testing is performed widely or without previous clinical assessment, elevated troponin concentrations are common and predominantly reflect myocardial injury rather than myocardial infarction. These observations highlight how selection of patients for cardiac troponin testing varies across healthcare settings and markedly influences the positive predictive value for a diagnosis of myocardial infarction.

18F-Fluoride and 18F-Fluorodeoxyglucose Positron Emission Tomography After Transient Ischemic Attack or Minor Ischemic Stroke: Case-Control Study.

Abstract: Dr Vesey and the study were funded by program grants from the British Heart Foundation (PG12/8/29371) and Chest Heart and Stroke Scotland (R13/A147). Dr Jenkins, Vesey, Dweck, and Newby are supported by the British Heart Foundation (FS/14/78/31020, CH/09/002) and the Wellcome Trust (WT103782AIA). Dr Dweck is the recipient of the Sir Jules Thorn Biomedical Research Award 2015. The Wellcome Trust Clinical Research Facility and the Clinical Research Imaging Centre are supported by National Health Service (NHS) Research Scotland (NRS) through NHS Lothian. Dr Beek is supported by the Scottish Imaging Network—a Platform of Scientific Excellence (SINAPSE). Dr Rudd is part-supported by the National Institute for Health Research Cambridge Biomedical Research Centre, the British Heart Foundation, and the Wellcome Trust.

The Global Threat of Outdoor Ambient Air Pollution to Cardiovascular Health: Time for Intervention

Abstract: Anthropogenic ambient fine particulate matter less than 2.5 μm (PM2.5) air pollution from fossil fuel combustion (eg, coal-fired power plants and traffic) ranks among the leading causes of worldwide morbidity and mortality.1 In agreement with figures from the World Health Organization (http://www.who.int/topics/global _burden_of_disease/en/), estimations indicate that approximately 3.15 million deaths per year are attributable to PM2.5. This alarming figure exceeds that of many more widely recognized risk factors (eg, hypercholesterolemia) and unfortunately is estimated to double by 2050.1 However, perhaps underappreciated by health care professionals and the general populace alike is that the largest portion of ambient PM2.5–induced health effects are owing to cardiovascular events. Short-term elevations in PM2.5 increase the risk for myocardial infarctions, strokes, heart failure, arrhythmias, and cardiac death.2,3 Longer-term exposures synergistically increase this acute risk and can even potentiate the development of chronic cardiometabolic conditions including diabetes and hypertension. As such, both the American Heart Association and European Society of Cardiology have formally recognized ambient PM2.5 as a major cardiovascular risk factor.2,3 While nearly all of humanity is adversely affected, the public health burden of ambient PM2.5 is disproportionately felt by rapidly developing countries.1,4 More than 99% of individuals living in east and south Asia are chronically exposed to PM2.5 levels exceeding annual World Health Organization Air Quality Guidelines (<10 μg/m3) compared with less than 20% in North America.4 On top of this prevailing poor air quality, daily concentrations routinely exceed 100 μg/m3 (5to 10-fold greater than those across the United States) in megacities such as New Delhi, India, and Beijing, China. Unfortunately, extreme air pollution episodes (greater than 750-1000 μg/m3) lasting several weeks per year are becoming all too routine (eg, the Chinese “airpocalypse”). While improvements in air quality in the United States during the past few decades, largely owing to governmental National Ambient Air Quality Standards, have translated into significant improvements in life expectancy,5,6 the opposite trend continues throughout much of Asia.4 Successful widespread pollutioncontrol measures and advancements in using “green” technologies face numerous (eg, economic, infrastructure, and political) near-term barriers.7 A substantial reduction from annual PM2.5 levels in India and China (mean of 59 μg/m3 and 41 μg/m3, respectively) require a major paradigm shift in human activity, and at the present rate of development, solving the worsening societal air pollution problem appears to be a long-term goal for the next generations. In the meantime, hundreds of millions of individuals will continue to face unhealthy ambient PM2.5 concentrations far exceeding World Health Organization Air Quality Guidelines.1,4 Given this sobering reality, are there opportunities to intervene to reduce exposures, and what should individuals do to protect themselves? These questions are important to resolve for the benefit of millions of atrisk patients with cardiovascular diseases living in Asia, the Middle East, and Africa who face extraordinarily poor air quality both indoors and outdoors for the foreseeable future.1,4 Unfortunately, there are few evidencebased solutions that are immediately available. While lifestyle changes (eg, dietary-nutritional supplements or medications such as statins) might be viable approaches, accruing evidence supports several low-risk inexpensive interventions capable of reducing “personallevel” PM2.5 exposures and improving surrogate markers of cardiovascular health.5,6 Air purifiers with high-efficiency particulate arrestance filters can lower in-home PM2.5 levels by roughly half, leading to improvements in blood pressure as well as markers of inflammation, thrombosis, and vascular function.5 Of particular relevance to heavily polluted regions are N95 respirators. These facemasks are validated to block greater than 95% of PM2.5 inhalation and are more effective than simple surgical or cloth masks more typically worn across Asia. Indeed, N95 facemasks have shown to provide some degree of cardiovascular protection (eg, lower blood pressure and prevent STdepression) during outdoor activity.5,6 While acknowledging these preliminary (but encouraging) findings, neither the American Heart Association nor the European Society of Cardiology provided formal recommendations regarding the usage of any personalized interventions.2,3 As members of both expert panels, we concurred with the fundamental reasoning underlying these decisions: there have been no randomized clinical studies with hard cardiovascular end points to conclusively support or refute their health benefits. Here, we make an emphatic call for just such a definitive trial. While protocol details, formal statistical power/sample size calculations, and plans to overcome logistical implementation barriers (eg, funding sources and compliance with interventions) surely require much deliberation, we believe it is nonetheless important to bring to the attention of the medical community the urgent need for and the potential global public health implications of an interventional outcome study. Several possible designs and intervention(s) may be equally VIEWPOINT

Cardiac αVβ3 integrin expression following acute myocardial infarction in humans.

Abstract: The study and MRD, WJ and DEN are supported by the British Heart Foundation (FS/12/84, FS/10/026, CH/09/002, R M/13/2/30158, RE/13/3/30183). DEN is the recipient of a Wellcome Trust Senior Investigator Award (WT103782AIA). JHFR is part-funded by the NIHR Cambridge Biomedical Research Centre. The Wellcome Trust Clinical Research Facility and Clinical Research Imaging Centre are supported by NHS Research Scotland (NRS) through NHS Lothian.

PAR4 (Protease-Activated Receptor 4) Antagonism With BMS-986120 Inhibits Human Ex Vivo Thrombus Formation.

Abstract: Objective—BMS-986120 is a novel first-in-class oral PAR4 (protease-activated receptor 4) antagonist with potent and selective antiplatelet effects. We sought to determine for the first time, the ef...

High-Sensitivity Cardiac Troponin and the Risk Stratification of Patients with Renal Impairment Presenting with Suspected Acute Coronary Syndrome

Abstract: Background —High-sensitivity cardiac troponin testing may improve the risk-stratification and diagnosis of myocardial infarction, but concentrations can be challenging to interpret in patients with renal impairment and the effectiveness of testing in this group is uncertain. Methods —In a prospective multi-center study of consecutive patients with suspected acute coronary syndrome, we evaluated the performance of high-sensitivity cardiac troponin I in those with and without renal impairment (estimated glomerular filtration rate 2 ). The negative predictive value (NPV) and sensitivity of troponin concentrations below the risk stratification threshold (5ng/L) at presentation were reported for a primary outcome of index type 1 myocardial infarction, or type 1 myocardial infarction or cardiac death at 30 days. The positive predictive value (PPV) and specificity at the 99 th centile diagnostic threshold (16ng/L in women, 34ng/L in men) was determined for index type 1 myocardial infarction. Subsequent type 1 myocardial infarction and cardiac death were reported at 1 year. Results —Of 4,726 patients identified, 904 (19%) had renal impairment. Troponin concentrations th centile were lower in patients with renal impairment at 50.0% (95%CI 45.2-54.8%) and 70.9% (95%CI 67.5-74.2%) respectively, compared to 62.4% (95%CI 58.8-65.9%) and 92.1% (95%CI 91.2-93.0%) in those without. At 1 year, patients with troponin concentrations >99 th centile and renal impairment were at greater risk of subsequent myocardial infarction or cardiac death than those with normal renal function (24% vs. 10%, adjusted hazard ratio 2.19, 95%CI 1.54-3.11). Conclusions —In suspected acute coronary syndrome, high-sensitivity cardiac troponin identified fewer patients with renal impairment as low-risk and more as high-risk, but with lower specificity for type 1 myocardial infarction. Irrespective of diagnosis, patients with renal impairment and elevated cardiac troponin concentrations had two-fold greater risk of a major cardiac event compared to those with normal renal function, and should be considered for further investigation and treatment. Clinical Trial Registration —URL: https://clinicaltrials.gov Unique Identifier: NCT01852123

MR/PET Imaging of the Cardiovascular System

Abstract: Cardiovascular imaging has largely focused on identifying structural, functional, and metabolic changes in the heart. The ability to reliably assess disease activity would have major potential clinical advantages, including the identification of early disease, differentiating active from stable conditions, and monitoring disease progression or response to therapy. Positron emission tomography (PET) imaging now allows such assessments of disease activity to be acquired in the heart, whereas magnetic resonance (MR) scanning provides detailed anatomic imaging and tissue characterization. Hybrid MR/PET scanners therefore combine the strengths of 2 already powerful imaging modalities. Simultaneous acquisition of the 2 scans also provides added benefits, including improved scanning efficiency, motion correction, and partial volume correction. Radiation exposure is lower than with hybrid PET/computed tomography scanning, which might be particularly beneficial in younger patients who may need repeated scans. The present review discusses the expanding clinical literature investigating MR/PET imaging, highlights its advantages and limitations, and explores future potential applications.

Fire Simulation and Cardiovascular Health in Firefighters.

Abstract: Background:Rates of myocardial infarction in firefighters are increased during fire suppression duties, and are likely to reflect a combination of factors including extreme physical exertion and he...

BioPARR: A software system for estimating the rupture potential index for abdominal aortic aneurysms.

Abstract: An abdominal aortic aneurysm (AAA) is a permanent and irreversible dilation of the lower region of the aorta. It is a symptomless condition that, if left untreated, can expand until rupture. Despite ongoing efforts, an efficient tool for accurate estimation of AAA rupture risk is still not available. Furthermore, a lack of standardisation across current approaches and specific obstacles within computational workflows limit the translation of existing methods to the clinic. This paper presents BioPARR (Biomechanics based Prediction of Aneurysm Rupture Risk), a software system to facilitate the analysis of AAA using a finite element analysis based approach. Except semi-automatic segmentation of the AAA and intraluminal thrombus (ILT) from medical images, the entire analysis is performed automatically. The system is modular and easily expandable, allows the extraction of information from images of different modalities (e.g. CT and MRI) and the simulation of different modelling scenarios (e.g. with/without thrombus). The software uses contemporary methods that eliminate the need for patient-specific material properties, overcoming perhaps the key limitation to all previous patient-specific analysis methods. The software system is robust, free, and will allow researchers to perform comparative evaluation of AAA using a standardised approach. We report preliminary data from 48 cases.

Effect of Fluticasone Furoate and Vilanterol on Exacerbations of Chronic Obstructive Pulmonary Disease in Patients with Moderate Airflow Obstruction.

Abstract: Rationale: Inhaled corticosteroids have been shown to decrease exacerbations in patients with moderate to severe chronic obstructive pulmonary disease (COPD). Their effects in patients with milder airflow obstruction remain unclear.Objectives: This was an analysis of exacerbations in the SUMMIT (Study to Understand Mortality and Morbidity) study.Methods: In a double-blind, randomized controlled trial, once-daily inhaled placebo, fluticasone furoate (FF; 100 μg), vilanterol (VI; 25 μg), or the combination of FF/VI was administered. The primary outcome was all-cause mortality. Exacerbations of COPD were an additional predefined endpoint. A total of 1,368 centers in 43 countries and 16,485 patients with moderate COPD and heightened cardiovascular risk were included in the study.Measurements and Main Results: Compared with placebo, FF/VI reduced the rate of moderate and/or severe exacerbations by 29% (95% confidence interval [CI], 22–35; P < 0.001) and the rate of hospitalized exacerbations by 27% (95% CI, 13...

End stage renal disease-induced hypercalcemia may promote aortic valve calcification via Annexin VI enrichment of valve interstitial cell derived-matrix vesicles.

Abstract: Patients with end-stage renal disease (ESRD) have elevated circulating calcium (Ca) and phosphate (Pi), and exhibit accelerated progression of calcific aortic valve disease (CAVD). We hypothesized that matrix vesicles (MVs) initiate the calcification process in CAVD. Ca induced rat valve interstitial cells (VICs) calcification at 4.5 mM (16.4-fold; p < 0.05) whereas Pi treatment alone had no effect. Ca (2.7 mM) and Pi (2.5 mM) synergistically induced calcium deposition (10.8-fold; p < 0.001) in VICs. Ca treatment increased the mRNA of the osteogenic markers Msx2, Runx2, and Alpl (p < 0.01). MVs were harvested by ultracentrifugation from VICs cultured with control or calcification media (containing 2.7 mM Ca and 2.5 mM Pi) for 16 hr. Proteomics analysis revealed the marked enrichment of exosomal proteins, including CD9, CD63, LAMP-1, and LAMP-2 and a concomitant up-regulation of the Annexin family of calcium-binding proteins. Of particular note Annexin VI was shown to be enriched in calcifying VIC-derived MVs (51.9-fold; p < 0.05). Through bioinformatic analysis using Ingenuity Pathway Analysis (IPA), the up-regulation of canonical signaling pathways relevant to cardiovascular function were identified in calcifying VIC-derived MVs, including aldosterone, Rho kinase, and metal binding. Further studies using human calcified valve tissue revealed the co-localization of Annexin VI with areas of MVs in the extracellular matrix by transmission electron microscopy (TEM). Together these findings highlight a critical role for VIC-derived MVs in CAVD. Furthermore, we identify calcium as a key driver of aortic valve calcification, which may directly underpin the increased susceptibility of ESRD patients to accelerated development of CAVD.

Effects of Diesel Exhaust on Cardiovascular Function and Oxidative Stress.

Abstract: Significance: Air pollution is a major global health concern with particulate matter (PM) being especially associated with increases in cardiovascular morbidity and mortality Diesel exhaust emissions are a particularly rich source of the smallest sizes of PM (“fine” and “ultrafine”) in urban environments, and it is these particles that are believed to be the most detrimental to cardiovascular health Recent Advances: Controlled exposure studies to diesel exhaust in animals and man demonstrate alterations in blood pressure, heart rate, vascular tone, endothelial function, myocardial perfusion, thrombosis, atherogenesis, and plaque stability Oxidative stress has emerged as a highly plausible pathobiological mechanism by which inhalation of diesel exhaust PM leads to multiple facets of cardiovascular dysfunction Critical Issues: Diesel exhaust inhalation promotes oxidative stress in several biological compartments that can be directly associated with adverse cardiovascular effects Future Directi

Ferumoxytol-enhanced Magnetic Resonance Imaging assessing inflammation after Myocardial Infarction

Abstract: Objectives Macrophages play a central role in the cellular inflammatory response to myocardial infarction (MI) and predict subsequent clinical outcomes. We aimed to assess temporal changes in cellular inflammation and tissue oedema in patients with acute MI using ultrasmallsuperparamagnetic particles of iron oxide (USPIO)-enhanced MRI. Methods Thirty-one patients were recruited following acute MI and followed up for 3 months with repeated T2 and USPIO-enhanced T2*-mapping MRI. Regions of interest were categorised into infarct, peri-infarct and remote myocardial zones, and compared with control tissues. Results Following a single dose, USPIO enhancement was detected in the myocardium until 24 hours (p Conclusion Myocardial macrophage activity can be detected using USPIO-enhanced MRI in the first 2 weeks following acute MI. This observed pattern of cellular inflammation is distinct, and provides complementary information to the more prolonged myocardial oedema detectable using T2 mapping. This imaging technique holds promise as a non-invasive method of assessing and monitoring myocardial cellular inflammation with potential application to diagnosis, risk stratification and assessment of novel anti-inflammatory therapeutic interventions. Trial registration number Trial registration number: 14663. Registered on UK Clinical Research Network (http://public.ukcrn.org.uk) and also ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT02319278?term=DECIFER&rank=2).

Cardiovascular outcomes with an inhaled beta2-agonist/corticosteroid in patients with COPD at high cardiovascular risk

Abstract: Objectives Cardiovascular disease (CVD) and chronic obstructive pulmonary disease (COPD) often coexist. We assessed the effect of inhaled COPD treatments on CVD outcomes and safety in patients with COPD and at heightened CVD risk. Methods The SUMMIT (Study to Understand Mortality and MorbidITy) was a multicentre, randomised, double-blind, placebo-controlled, event-driven trial in 16 485 patients with moderate COPD who had or were at high risk of CVD. Here, we assessed the prespecified secondary endpoint of time to first on-treatment composite CVD event (CVD death, myocardial infarction, stroke, unstable angina or transient ischaemic attack (TIA)) by Cox regression and by clinician-reported CVD adverse events across the four groups: once-daily inhaled placebo (n=4111), long-acting beta2-agonist (vilanterol (VI) 25 µg; n=4118), corticosteroid (fluticasone furoate (FF) 100 µg; n=4135) and combination therapy (FF/VI; n=4121). Results Participants were predominantly middle-aged (mean 65 (SD 8) years) men (75%) with overt CVD (66%). The composite CVD endpoint occurred in 688 patients (first event: sudden death (35%), acute coronary syndrome (37%) and stroke or TIA (23%), and was not reduced in any treatment group versus placebo: VI (HR 0.99, 95% CI 0.80 to 1.22), FF (HR 0.90, 95% CI 0.72 to 1.11) and their combination (HR 0.93, 95% CI 0.75 to 1.14). Outcomes were similar among all subgroups. Adverse events, including palpitations and arrhythmias, did not differ by treatment. Conclusions In patients with COPD with moderate airflow limitation and heightened CVD risk, treatment with inhaled VI, FF or their combination has an excellent safety profile and does not impact CVD outcomes. Trial registration number NCT01313676.

Duration of dual antiplatelet therapy in acute coronary syndrome.

Abstract: Despite a large volume of evidence supporting the use of dual antiplatelet therapy in patients with acute coronary syndrome, there remains major uncertainty regarding the optimal duration of therapy. Clinical trials have varied markedly in the duration of therapy, both across and within trials. Recent systematic reviews and meta-analyses suggest that shorter durations of dual antiplatelet therapy are superior because the avoidance of atherothrombotic events is counterbalanced by the greater risks of excess major bleeding with apparent increases in all-cause mortality with longer durations. These findings did not show significant heterogeneity according to whether patients had stable or unstable coronary heart disease. Moreover, the potential hazards and benefits may differ when applied to the general broad population of patients encountered in everyday clinical practice who have markedly higher bleeding and atherothrombotic event rates. Clinicians lack definitive information regarding the duration of therapy in patients with acute coronary syndrome and risk scores do not appear to be sufficiently robust to address these concerns. We believe that there is a pressing need to undertake a broad inclusive safety trial of shorter durations of therapy in real world populations of patients with acute coronary syndrome. The clinical evidence would further inform future research into strategies for personalised medicine.

Symptoms and quality of life in patients with suspected angina undergoing CT coronary angiography: a randomised controlled trial.

Abstract: Background In patients with suspected angina pectoris, CT coronary angiography (CTCA) clarifies the diagnosis, directs appropriate investigations and therapies, and reduces clinical events. The effect on patient symptoms is currently unknown. Methods In a prospective open-label parallel group multicentre randomised controlled trial, 4146 patients with suspected angina due to coronary heart disease were randomised 1:1 to receive standard care or standard care plus CTCA. Symptoms and quality of life were assessed over 6 months using the Seattle Angina Questionnaire and Short Form 12. Results Baseline scores indicated mild physical limitation (74±0.4), moderate angina stability (44±0.4), modest angina frequency (68±0.4), excellent treatment satisfaction (92±0.2) and moderate impairment of quality of life (55±0.3). Compared with standard care alone, CTCA was associated with less marked improvements in physical limitation (difference −1.74 (95% CIs, −3.34 to −0.14), p=0.0329), angina frequency (difference −1.55 (−2.85 to −0.25), p=0.0198) and quality of life (difference −3.48 (−4.95 to −2.01), p Conclusions While improving diagnosis, treatment and outcome, CTCA is associated with a small attenuation of the improvements in symptoms and quality of life due to the detection of moderate non-obstructive coronary artery disease. Trial registration number: NCT01149590.

High-Sensitivity Cardiac Troponin I and the Diagnosis of Coronary Artery Disease in Patients With Suspected Angina Pectoris.

Abstract: Background: We determined whether high-sensitivity cardiac troponin I can improve the estimation of the pretest probability for obstructive coronary artery disease (CAD) in patients with suspected stable angina. Methods and Results: In a prespecified substudy of the SCOT-HEART trial (Scottish Computed Tomography of the Heart), plasma cardiac troponin was measured using a high-sensitivity single-molecule counting assay in 943 adults with suspected stable angina who had undergone coronary computed tomographic angiography. Rates of obstructive CAD were compared with the pretest probability determined by the CAD Consortium risk model with and without cardiac troponin concentrations. External validation was undertaken in an independent study population from Denmark comprising 487 patients with suspected stable angina. Higher cardiac troponin concentrations were associated with obstructive CAD with a 5-fold increase across quintiles (9%–48%; P P =0.004; χ 2 =16.8 [ P =0.032] to 14.3 [ P =0.074]). The updated model also improved classification of the American College of Cardiology/American Heart Association pretest probability risk categories (net reclassification improvement, 0.062; 95% confidence interval, 0.035–0.089). The revised model achieved similar improvements in discrimination and calibration when applied in the external validation cohort. Conclusions: High-sensitivity cardiac troponin I concentration is an independent predictor of obstructive CAD in patients with suspected stable angina. Use of this test may improve the selection of patients for further investigation and treatment. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01149590.

Correction to“Inhaled Nanoparticles Accumulate at Sites of Vascular Disease”

Abstract: The authors submit the following corrections. A mislabeling of the units was found in Figure 2D. The y-axes of both graphs should read: "concentration of gold (ng gold/L)" not "(ng gold/mL)". Similarly, in Supplementary Figure S4 the urine concentration on the yaxis should also read: "concentration of gold (ng gold/L)". This error affects the estimate of % mass translocation in the Discussion, which also contained inconsistencies. We have now corrected these errors and refined our exposure estimates for this calculation. Thus, we would like to revise the following text on page 4546: "Based on the exposure characteristics of our first study (2 h exposure of ∼116 μg/m3 under light exercise), we calculate the total inhaled dose of particulate to be ∼690 mg. If ∼80 μg of gold was cleared by the kidneys over 24 h (average volume of urine collected: 2.4 L containing 35 ng/mL), and, therefore, if this was the sole route of clearance, we estimate that at least 0.2% of inhaled gold nanoparticles translocated from the lung into circulation". This should be replaced with: "Based on the exposure characteristics of our first study (2 h exposure of ∼116 μg/m3 intermittent rest [6 L/min for 4 × 15 min] and moderate exercise [47.5 L/min for 4 × 15 min]), we calculate the total inhaled dose of the particulate to be ∼383 μg. If ∼84 ng of gold was cleared by the kidney over 24 h (average volume or urine collected: 2.4 L containing 35 ng/L; Figure 1D), we estimate that at least 0.02% of inhaled gold nanoparticles translocated from the lung into the circulation". We emphasize that this calculation is for illustrative purposes and represents only a defined 24 h period in time. The estimate is likely to be conservative and does not take into account the proportion of alveolar deposition and the slow return of respiratory rate to resting levels after exercise and is based on the assumption that the urine is the sole route of clearance. While this estimate is an order of magnitude lower than that stated in the original manuscript, the proportion of translocated particles still fits with prior findings. Early studies in rodents provided rough estimates that <1% mass of nanoparticles with a diameter of <50 nm will translocate.1 Subsequent studies broadened this range from 0.01 to 10%, although estimates are most frequently around 0.3% or less for a given tissue at 24 h post-exposure.2-11 Studies in man are hampered by technical limitations,12,13 although, on the assumption that translocation can occur in man, current findings suggest a very low rate of translocation.14-16 Thus, the estimate of 0.02% translocation in the present study concurs with that of previous work. Differences in the species, method of exposure, particle size, particle physicochemistry, post-exposure sampling period, method of measurement and tissue sample(s) used, all make direct comparisons between these studies challenging. In most instances (especially where values are close to the threshold of detection), the relative amount of gold in exposed versus nonexposed tissues (within the same study) has arguably greater value than the actual concentration of gold per se. However, the calculation has qualitative value in that it confirms or strengthens several key messages about the translocation process: (1) A very low proportion of nanoparticles translocate from the lung to the blood in both animals and man. (2) The body has several routes of clearance of translocated nanoparticles (including, but not limited to, the urine and via the liver) that will affect systemic levels of nanoparticles. Nevertheless, translocated nanoparticles accumulate in several tissues. The individual biokinetics of these routes requires further research. (3) Particles are retained in the lung for long periods of time, thus, there appears to be an ongoing slow translocation of low amounts of nanoparticles into the blood (from the lung and/or other organs they may have originally accumulated in). These corrections do not affect any other findings of the paper or the conclusions drawn. The important observation in the current study is that translocated nanoparticles reach and accumulate at areas of disease that may be most susceptible to their physicochemical properties. Thus, the preferential accumulation in regions of susceptibility suggests that translocated nanoparticles could cause significant biological actions that promote the disease process.

Myocardial inflammation, injury and infarction during on-pump coronary artery bypass graft surgery.

Abstract: Myocardial inflammation and injury occur during coronary artery bypass graft (CABG) surgery. We aimed to characterise these processes during routine CABG surgery to inform the diagnosis of type 5 myocardial infarction. We assessed 87 patients with stable coronary artery disease who underwent elective CABG surgery. Myocardial inflammation, injury and infarction were assessed using plasma inflammatory biomarkers, high-sensitivity cardiac troponin I (hs-cTnI) and cardiac magnetic resonance imaging (CMR) using both late gadolinium enhancement (LGE) and ultrasmall superparamagnetic particles of iron oxide (USPIO). Systemic humoral inflammatory biomarkers (myeloperoxidase, interleukin-6, interleukin-8 and c-reactive protein) increased in the post-operative period with C-reactive protein concentrations plateauing by 48 h (median area under the curve (AUC) 7530 [interquartile range (IQR) 6088 to 9027] mg/L/48 h). USPIO-defined cellular myocardial inflammation ranged from normal to those associated with type 1 myocardial infarction (median 80.2 [IQR 67.4 to 104.8] /s). Plasma hs-cTnI concentrations rose by ≥50-fold from baseline and exceeded 10-fold the upper limit of normal in all patients. Two distinct patterns of peak cTnI release were observed at 6 and 24 h. After CABG surgery, new LGE was seen in 20% (n = 18) of patients although clinical peri-operative type 5 myocardial infarction was diagnosed in only 9% (n = 8). LGE was associated with the delayed 24-h peak in hs-cTnI and its magnitude correlated with AUC plasma hs-cTnI concentrations (r = 0.33, p 10-fold the 99th centile upper limit of normal that is not attributable to inflammatory or ischemic injury alone. Peri-operative type 5 myocardial infarction is often unrecognised and is associated with a delayed 24-h peak in plasma hs-cTnI concentrations.