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. Copyright © 2007 S. Karger AG.

NADPH oxidase and heart failure

Reactive oxygen species play important roles in the pathophysiology of chronic heart failure secondary to chronic left ventricular hypertrophy or myocardial infarction. Reactive oxygen species influence several components of the phenotype of the failing heart, including contractile function, interstitial fibrosis, endothelial dysfunction and myocyte hypertrophy. Recent studies implicate the production of reactive oxygen species by a family of NADPH oxidases in these effects. NADPH oxidases are activated in an isoform-specific manner by many pathophysiological stimuli and exert distinct downstream effects. Understanding NADPH oxidase activation and regulation, and their downstream effectors, could help to develop novel therapeutic targets.

NADPH oxidase-dependent redox signalling in cardiac hypertrophy, remodelling and failure

Markers of increased oxidative stress are known to be elevated following acute myocardial infarction and in the context of chronic left ventricular hypertrophy or heart failure, and their levels may correlate with the degree of contractile dysfunction or cardiac deficit. An obvious pathological mechanism that may account for this correlation is the potential deleterious effects of increased oxidative stress through the induction of cellular dysfunction, energetic deficit or cell death. However, reactive oxygen species have several much more subtle effects in the remodelling or failing heart that involve specific redox-regulated modulation of signalling pathways and gene expression. Such redox-sensitive regulation appears to play important roles in the development of several components of the phenotype of the failing heart, for example cardiomyocyte hypertrophy, interstitial fibrosis and chamber remodelling. In this article, we review the evidence supporting the involvement of reactive oxygen species and redox signalling pathways in the development of cardiac hypertrophy and heart failure, with a particular focus on the NADPH oxidase family of superoxide-generating enzymes which appear to be especially important in redox signalling.

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 4weeks. 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.

The development and investigation of a novel pulsatile heart assist device

Cardiovascular diseases (CVD) contributed to almost 30% of worldwide mortality; with heart failure being one class of CVD. One popular and widely available treatment for heart failure is the intra-aortic balloon pump (IABP). This heart assist device is used in counterpulsation to improve myocardial function by increasing coronary perfusion, and decreasing aortic end-diastolic pressure (i.e. the resistance to blood ejection from the heart). However, this device can only be used acutely, and patients are bedridden. The subject of this research is a novel heart assist treatment called the Chronic Intermittent Mechanical Support (CIMS) which was conceived to offer advantages of the IABP device chronically, whilst overcoming its disadvantages. The CIMS device comprises an implantable balloon pump, a percutaneous drive line, and a wearable driver console. The research here aims to determine the haemodynamic effect of balloon pump activation under in vitro conditions. A human mock circulatory loop (MCL) with systemic and coronary perfusion was constructed, capable of simulating various degrees of heart failure. Two prototypes of the CIMS balloon pump were made with varying stiffness. Several experimental factors (balloon inflation/deflation timing, Helium gas volume, arterial compliance, balloon pump stiffness and heart valve type) form the factorial design experiments. A simple modification to the MCL allowed flow visualisation experiments using video recording. Suitable statistical tests were used to analyse the data obtained from all experiments. Balloon inflation and deflation in the ascending aorta of the MCL yielded favourable results. The sudden balloon deflation caused the heart valve to open earlier, thus causing longer valve opening duration in a cardiac cycle. It was also found that pressure augmentation in diastole was significantly correlated with increased cardiac output and coronary flowrate. With an optimum combination (low arterial compliance and low balloon pump stiffness), systemic and coronary perfusions were increased by 18% and 21% respectively, while the aortic end-diastolic pressure (forward flow resistance) decreased by 17%. Consequently, the ratio of oxygen supply and demand to myocardium (endocardial viability ratio, EVR) increased between 33% and 75%. The increase was mostly attributed to diastolic augmentation rather than systolic unloading.

Monocyte subpopulation counts and TNF alpha associations with clinical outcome post ST elevation myocardial infarction

Background Monocytes are implicated in the initiation and progression of the atherosclerotic plaque contributing to its instability and rupture. Although peripheral monocytosis has been related to poor clinical outcome post ST elevation myocardial infarction (STEMI), only scarce information is available of mechanisms of this association. Tumour necrosis factor alpha (TNFα) is a key cytokine in the acute phase inflammatory response, and it is predominantly produced by inflammatory macrophages. Little is known about TNFα association with circulating monocyte subpopulations post STEMI. Method A total of 142 STEMI patients (mean age 62±13 years; 72% male) treated with percutaneous revascularization were recruited with blood samples obtained within first 24 hours from the onset and on day 10-14. Peripheral blood monocyte subpopulations were enumerated and characterized using flow cytometry after staining for CD14, CD16 and CCR2 and were defined as: CD14++CD16-CCR2+ (Mon1), CD14++CD16+CCR+ (Mon2) and CD14+CD16++CCR2- (Mon3) cells. Plasma levels of TNFα were measured by enzyme-linked immunosorbent assay (ELISA, Peprotec system, UK). Major adverse cardiac events (MACE), defined as recurrent STEMI, new diagnosis of heart failure and death were recorded at follow up, mean of 164±134 days. Results TNFα levels were significantly higher 24 hours post STEMI, compared to day 14 (paired t-test, p <0.001) with day 1 levels weakly correlated with total monocyte count as well as Mon1 (Spearman’s correlation, r=0.19, p=0.02 and r=0.22, p=0.01, respectively). There was no correlation between TNFα and Mon2 or Mon3 subpopulations. TNFα levels were significantly higher in patients with a recorded MACE (n=28, Mann-Whitney test, p<0.001) (figure 1).⇓