Alexander Sirker

NADPH oxidases in cardiovascular disease: insights from in vivo models and clinical studies

NADPH oxidase family enzymes (or NOXs) are the major sources of reactive oxygen species (ROS) that are implicated in the pathophysiology of many cardiovascular diseases. These enzymes appear to be especially important in the modulation of redox-sensitive signalling pathways that underlie key cellular functions such as growth, differentiation, migration and proliferation. Seven distinct members of the family have been identified of which four (namely NOX1, 2, 4 and 5) may have cardiovascular functions. In this article, we review our current understanding of the roles of NOX enzymes in several common cardiovascular disease states, with a focus on data from genetic studies and clinical data where available.

Acid-base physiology: the 'traditional' and the 'modern' approaches

Summary The interpretation and understanding of acid–base dysfunction has recently been revisited. The ‘traditional’ approach developed from the pioneering work of Henderson and Hasselbalch and is still the most widely used in clinical practice. There are a number of problems identified with this approach, however. The ‘modern’ approach derives from Stewarts work in physical chemistry. In this review we describe the origins of the traditional approach and discusses related concepts. We then describe Stewarts approach, including how it is derived and how it may be used to classify acid–base derangements. The applications of Stewarts approach to clinical scenarios in intensive care is then discussed briefly before we examine some published clinical studies based on his work.

Involvement of NADPH Oxidases in Cardiac Remodelling and Heart Failure

Cardiac remodelling occurs in response to stress, such as chronic hypertension or myocardial infarction, and forms the substrate for subsequent development of heart failure. Key pathophysiological features include ventricular hypertrophy, interstitial fibrosis, contractile dysfunction, and chamber dilatation. Although the molecular mechanisms are complex and not fully defined, substantial evidence now implicates increased oxidative stress as being important. The NADPH oxidase (‘Nox’) enzymes are a particularly important source of reactive oxygen species that are implicated in redox signalling. This article reviews the evidence for an involvement of NADPH oxidases in different aspects of adverse cardiac remodelling. A better understanding of the roles of this complex enzyme family may define novel therapeutic targets for the prevention of heart failure.

Late gadolinium enhancement of acute myocardial infarction in mice at 7T: Cine-FLASH versus inversion recovery

To investigate myocardial infarction (MI), late gadolinium (Gd) enhancement (LGE), cardiovascular magnetic resonance imaging (CMRI) is used as the current gold standard for the in vivo diagnosis in patients and preclinical studies. While inversion recovery (IR) fast gradient echo LGE imaging is the preferred technique at clinical field strengths it remains to be investigated which is the best sequence at higher field strength. We therefore compared the IR technique against cine fast low shot angle (cine‐FLASH) for the quantification of MI size in mice at 7T in vivo.

High-frequency speckle tracking echocardiography in the assessment of left ventricular function and remodeling after murine myocardial infarction.

The objectives of this study were to assess the feasibility and accuracy of high-frequency speckle tracking echocardiography (STE) in a murine model of myocardial infarction (MI). STE is used clinically to quantify global and regional cardiac function, but its application in mice is challenging because of the small cardiac size and rapid heart rates. A high-frequency micro-ultrasound system with STE (Visualsonics Vevo 2100) was compared against magnetic resonance imaging (MRI) for the assessment of global left ventricular (LV) size and function after murine MI. Animals subjected to coronary ligation (n = 46) or sham ligation (n = 27) were studied 4 wk postoperatively. Regional and global deformation were also assessed. STE-derived LV ejection fraction (EF) and mass correlated well with MRI indexes (r = 0.93, 0.77, respectively; P < 0.001), as did STE-derived mass with postmortem values (r = 0.80, P < 0.001). Higher STE-derived volumes correlated positively with MRI-derived infarct size (P < 0.01). Global strain parameters were significantly reduced after MI (all P < 0.001) and strongly correlated with LV mass and MRI-derived infarct size as promising surrogates for the extent of remodeling and infarction, respectively (both P < 0.05). Regional strain analyses showed that radial strain and strain rate were relatively preserved in anterior basal segments after MI compared with more apical segments (P < 0.001); however, longitudinal strain and strain rate were significantly impaired both basally and distally (P < 0.001). Strain-derived parameters of dyssynchrony were significantly increased in the MI group (P < 0.01). Analysis time for STE was 210 ± 45 s with acceptable inter- and intraobserver variability. In conclusion, high-frequency STE enables quantitative assessment of regional and global function in the remodeling murine LV after MI.

Bivalirudin, glycoprotein inhibitor, and heparin use and association with outcomes of primary percutaneous coronary intervention in the United Kingdom.

AIMS The HORIZONS trial reported a survival advantage for bivalirudin over heparin-with-glycoprotein inhibitors (GPIs) in primary PCI for ST elevation myocardial infarction. This drove an international shift in clinical practice. Subsequent studies have produced divergent findings on mortality benefits with bivalirudin. We investigated this issue in a larger population than studied in any of these trials, using the United Kingdom national PCI registry. METHODS AND RESULTS 61 136 primary PCI procedures were performed between January 2008 and January 2012. Demographic and procedural data were obtained from the registry. Mortality information was obtained through the UK Office of National Statistics. Multivariable logistic regression and propensity analysis modelling were utilized to study the association of different anti-thrombotic strategies with outcomes. Unadjusted data demonstrated near-identical survival curves for bivalirudin and heparin-plus-GPI groups. Significantly higher early and late mortality was found in patients treated with heparin alone ( ITALIC! P < 0.0001) but this group had a markedly higher baseline risk. After propensity matching, the bivalirudin vs. heparin-plus-GPI groups still demonstrated very similar adjusted mortality (odds ratio 1.00 at 30 days, and 0.96 at 1 year). Patients treated with heparin alone continued to show higher mortality after adjustment, although effect size was considerably diminished (odds ratio vs. other groups 1.17-1.24 at 30 days). CONCLUSIONS Analysis of recent UK data showed no significant difference in short- or medium-term mortality between ST elevation myocardial infarction patients treated with bivalirudin vs. heparin-plus-GPI at primary PCI.

MRI-based prediction of adverse cardiac remodeling after murine myocardial infarction

Myocardial infarction (MI) results in adverse cardiac remodeling leading to heart failure and increased mortality. Experimental mouse models of MI are extensively used to identify mechanisms underlying adverse remodeling, but the extent of remodeling that occurs may be highly variable and can limit the utility to discover new disease pathways. The ability to predict the development of significant late post-MI remodeling would be invaluable in conducting such studies by increasing throughput and efficiency. This study aimed to identify potential thresholds of cardiac magnetic resonance imaging (MRI) parameters measured early after murine MI that would predict the development of significant adverse remodeling at 4 wk. MI was achieved by permanent coronary ligation and animals (n = 84) were followed up for 4 wk subsequently. MRI was used to assess left ventricular (LV) volumes, mass and ejection fraction, as well as infarct size (IS). Late gadolinium enhancement cine-MRI was performed at 2 days with standard cine-MRI at 30 days post-MI. Utilizing multiple logistic regression, we found that IS >36%, at 2 days post-MI, was the overall best single predictor of adverse remodeling at 30 days (sensitivity 80.7%, specificity 88.9%; C-statistic of 0.939 from receiver-operating curve analysis). LV end-systolic volume (LVESV) >32 μl was also an excellent predictor comparable to IS. The combination of IS >36% and/or LVESV >32 μl provided the highest predictive values for late adverse remodeling among multiple predictors. This study demonstrates that MRI-based estimation of IS and ESV during the acute phase of murine MI are good predictors of subsequent adverse remodeling that may aid experimental design.

Increased Radial Access Is Not Associated With Worse Femoral Outcomes for Percutaneous Coronary Intervention in the United Kingdom

Background— The radial artery is increasingly adopted as the primary access site for cardiac catheterization because of patient preference, lower bleeding rates, cost effectiveness, and reduced risk of mortality in high-risk patient groups. Concerns have been expressed that operators/centers have become increasingly unfamiliar with transfemoral access. The aim of this study was to assess whether a change in access site practice toward transradial access nationally has led to worse outcomes in percutaneous coronary intervention procedures performed through the transfemoral access approach. Methods and Results— Using the British Cardiovascular Intervention Society (BCIS) database, a retrospective analysis of 235 250 transfemoral access percutaneous coronary intervention procedures was undertaken in all 92 centers in England and Wales between 2007 and 2013. Recent femoral proportion and recent femoral volume were determined, and in-hospital vascular complications and 30-day mortality were evaluated. After case-mix adjustment, no independent association was observed between 30-day mortality for cases undertaken through the transfemoral access and center femoral proportion, the risk-adjusted odds ratio for recent femoral proportion was nonsignificant (odds ratio, 0.99; 95% confidence interval, 0.97–1.02; P=0.472 per 0.1 increase in proportion), and similarly recent femoral volume (per 100 procedures) was not found to be significant (odds ratio, 1.00; 95% confidence interval, 0.98–1.01; P=0.869). The in-hospital vascular complication rate was 1.0%, and this outcome was not significantly associated with recent femoral proportion after risk-adjustment (odds ratio, 0.97; 95% confidence interval, 0.94–1.00; P=0.060 per 0.1 increase in proportion). Conclusions— The outcome gains achieved by the national adoption of radial access are not associated with a loss of femoral proficiency, and centers should be encouraged to continue to adopt radial access as the default access site for percutaneous coronary intervention wherever possible in line with current best evidence.

Acute myocardial infarction following tranexamic acid use in a low cardiovascular risk setting.

James Doecke Peter N. Mollee Devinder S. Gill Debra Norris David W. Johnson Maher K. Gandhi Department of Haematology, Princess Alexandra Hospital, Woolloongabba, Qld, Department of Cancer and Population Studies, Queensland Institute of Medical Research, Herston, Qld, Department of Pathology, Queensland Medical Laboratories, Qld, Department of Renal Medicine, Princess Alexandra Hospital, Woolloongabba, Qld, and Clinical Immunohaematology Lab, Queensland Institute of Medical Research, Herston, Qld, Australia. E-mail: Maher.Gandhi@qimr.edu.au

Cell-specific effects of Nox2 on the acute and chronic response to myocardial infarction

Background Increased reactive oxygen species (ROS) production is involved in the process of adverse cardiac remodeling and development of heart failure after myocardial infarction (MI). NADPH oxidase-2 (Nox2) is a major ROS source within the heart and its activity increases after MI. Furthermore, genetic deletion of Nox2 is protective against post-MI cardiac remodeling. Nox2 levels may increase both in cardiomyocytes and endothelial cells and recent studies indicate cell-specific effects of Nox2, but it is not known which of these cell types is important in post-MI remodeling. Methods and results We have generated transgenic mouse models in which Nox2 expression is targeted either to cardiomyocytes (cardio-Nox2TG) or endothelial cells (endo-Nox2TG). We here studied the response of cardio-Nox2TG mice, endo-Nox2TG mice and matched wild-type littermates (WT) to MI induced by permanent left coronary artery ligation up to 4 weeks. Initial infarct size assessed by magnetic resonance imaging (MRI) and cardiac dysfunction were similar among groups. Cardiomyocyte hypertrophy and interstitial fibrosis were augmented in cardio-Nox2TG compared to WT after MI and post-MI survival tended to be worse whereas endo-Nox2TG mice showed no significant difference compared to WT. Conclusions These results indicate that cardiomyocyte rather than endothelial cell Nox2 may have the more important role in post-MI remodeling.