Maqsood M. Elahi

Oxidative Stress as a Mediator of Cardiovascular Disease

During physiological processes molecules undergo chemical changes involving reducing and oxidizing reactions. A molecule with an unpaired electron can combine with a molecule capable of donating an electron. The donation of an electron is termed as oxidation whereas the gaining of an electron is called reduction. Reduction and oxidation can render the reduced molecule unstable and make it free to react with other molecules to cause damage to cellular and sub-cellular components such as membranes, proteins and DNA. In this paper, we have discussed the formation of reactive oxidant species originating from a variety of sources such as nitric oxide (NO) synthase (NOS), xanthine oxidases (XO), the cyclooxygenases, nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase isoforms and metal-catalyzed reactions. In addition, we present a treatise on the physiological defences such as specialized enzymes and antioxidants that maintain reduction-oxidation (redox) balance. We have also given an account of how enzymes and antioxidants can be exhausted by the excessive production of reactive oxidant species (ROS) resulting in oxidative stress/nitrosative stress, a process that is an important mediator of cell damage. Important aspects of redox imbalance that triggers the activity of a number of signaling pathways including transcription factors activity, a process that is ubiquitous in cardiovascular disease related to ischemia/reperfusion injury have also been presented.

Tracing the origins of postoperative atrial fibrillation: the concept of oxidative stress-mediated myocardial injury phenomenon

Background Atrial fibrillation (AF) is the most common arrhythmia associated with coronary artery surgery and is an important factor contributing to postoperative morbidity and mortality. Recently, there is growing evidence that dysregulation of the oxidant-antioxidant balance, inflammatory factors and discordant alteration of energy metabolites may play a significant role in its pathogenesis. Design We evaluated the link between postoperative atrial fibrillation with inflammatory factors and oxidative stress. Methods We searched all databases in Medline, Pubmed, ISI, the Cochrane database, and Embase. We identified more than 100 trials, multiple meta-analyses, and three sets of practice guidelines for the prevention of PAF in cardiac surgery. Results Mechanisms of postoperative AF are likely to be multifactorial and are influenced by preoperative, intraoperative and postoperative factors including a genetic basis. Electrical remodelling is thought to be related to the generation of reactive oxidant species and inflammatory factors during the ischemia-reperfusion phase of cardiac surgery. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase was found to be the primary source of superoxide within the human atrial myocardium (in patients in sinus rhythm and in those with AF) and linked with paroxysmal and chronic AF. Reactive oxidant species cause lipid peroxidation, breakdown of cell membrane, decreased mitochondrial function, calcium overload and apoptosis. This affect was shown to be reversed by exogenous nitric oxide/donors (sodium nitroprusside). Inflammatory factors such as the rise in white blood cell count, C-reactive proteins were implicated in the pathogenesis of AF. In contrast, new evidence identifies statins as having both antioxidant and anti-inflammatory properties and that their use reduces the incidence of postoperative AF (57% in the control vs. 35% in the atorvastatin group). Other antiinflammatory strategies include steroids with one study showing postoperative AF occurred in 21% in the steroid group compared with 51% in the placebo group although their use resulted in an increase in other complications. The mainstay of therapy however, remains to be beta-blockers alone which impart a modest influence on overall rates of AF with a reduction from 33.7 to 16.9% (OR: 0.37, 95% CI: 0.29–0.48). Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers has been shown in one study to reduce the risk of developing new-onset AF by nearly 50%, although this has not been adequately evaluated in cardiac surgery. Conclusion Inflammatory factors and oxidative stress play a major role in the pathogenesis of postoperative AF. This review provides an analysis of current evidence in support of efforts directed at antiinflammatory and antioxidant agents as interventions. Eur J Cardiovasc Prev Rehabil 15:735–741

Acute kidney injury following cardiac surgery: impact of early versus late haemofiltration on morbidity and mortality

Various forms of renal replacement therapies (RRT) are available to treat acute kidney injury (AKI) after cardiac surgery. The objective of this review is to assess the incidence of postoperative AKI that necessitates the application of haemofiltration in adult patients undergoing cardiac operations with cardiopulmonary bypass (CPB), to determine the factors that influence the outcome in these patients. In addition, the review aims to assess the outcomes of postoperative early haemofiltration as compared to late intensive haemofiltration. Different forms of RRT such as intermittent haemodialysis, continuous haemofiltration, or hybrid forms which combine advantages of both are now available for application in cardiac surgery patients, and will be discussed in this article. The underlying disease, its severity and stage, the aetiology of AKI, clinical and haemodynamic status of the patient, the resources available, and different costs of therapy may all influence the choice of the RRT strategy. AKI, with its risk of uraemic complications, represents an independent risk factor for adverse outcomes in critically ill patients after cardiac surgery. Whether early initiation of RRT is associated with improved survival is unknown, and also clear guidelines on RRT durations are still lacking. In particular, it remains unclear whether haemodynamically unstable patients who develop septic shock pre- and postoperatively can benefit from early RRT initiation. In addition, it is not known whether in AKI patients undergoing cardiac surgery RRT modalities can eliminate significant amounts of clinically relevant inflammatory mediators. This review gives an update of information available in the literature on possible mechanisms underlying AKI and the recent developments in continuous renal replacement treatment modalities.

Nitric oxide in blood

There is growing evidence that altered production and/or spatio‐temporal distribution of reactive oxidant species and reactive nitrosative species in blood creates oxidative and/or nitrosative stresses in the failing myocardium and endothelium. This contributes to the abnormal cardiac and vascular phenotypes that characterize cardiovascular disease. These derangements at the system level can now be interpreted at the integrated cellular and molecular levels in terms of effects on signaling elements in the heart and vasculature. The end results of nitric oxide/redox disequilibrium have implications for cardiac and vascular homeostasis and may result in the development of atherosclerosis, myocardial tissue remodelling and hypertrophy. Reactive oxygen species/reactive nitrogen species generation is also attributed to the transit from hypertrophic to apoptotic phenotypes, a possible mechanism of myocardial failure. In this review, we highlight the possible roles of altered production and/or spatio‐temporal distribution of reactive oxidant species and reactive nitrosative species in blood on the pathogenesis of the failing cardiovascular system.

Direct Complications of Repeat Median Sternotomy in Adults

Whilst the potential risk to underlying vital structures from redo-sternotomy is well recognized, the actual risk is poorly quantified. Our aim was to determine the incidence of complications directly attributable to redo-sternotomy and to ascertain whether the use of femoro-femoral CPB (FF) prior to redo-sternotomy alters operative morbidity and mortality. Case notes of 185 patients undergoing cardiac surgery necessitating redo-sternotomy between May 1998 and November 2002 were reviewed. Of 121 males and 64 females, the median age was 65.5 years (range 60.1–75 years). Elective FF was performed in 71 (38.3%) of cases and 114 (60%) were performed without the aid of prior femoro-femoral CPB (WFF). Three (1.6%) patients initially planned for WFF were converted to emergency FF due to serious complications. Complications directly attributable to redo-sternotomy occurred in 21 (11.3%) cases; 12 (16.9%) in the FF group and 9 (5.3%) in the WFF group. Overall mortality was 1.6%. In summary, our results suggest that morbidity risk for the operation increases significantly with redo-sternotomy alone. Three deaths in our series from direct complications attributable to redo-sternotomy signify an added risk. Hence the necessity for careful surgical technique and judicious use of elective FF-CPB is emphasized.

Deleterious effects of cardiopulmonary bypass in coronary artery surgery and scientific interpretation of off‐pump's logic

Cardiopulmonary bypass (CPB) has been suggested to be a cause of complex systemic inflammatory response that significantly contributes to several adverse postoperative complications. In the last few years, off‐pump coronary artery bypass grafting (OPCAB) has gained widespread attention as an alternative technique to conventional on‐pump coronary artery bypass grafting (ONCAB). However, a degree of uncertainty regarding the relative merits of ONCAB and OPCAB continues to be a significant issue. Surgeons supporting off‐pump surgery, state that the avoidance of the CPB leads to significantly reduced myocardial ischemia‐reperfusion injury, postoperative systemic inflammatory response and other biological derangements, a feature that may improve the clinical outcomes. However, perfection in perioperative care, surgical technique and methods of attenuating the untoward effects of CPB has resulted in better clinical outcome of ONCAB as well. Possible reasons of these controversial opinions are that high‐quality studies have not comprehensively examined relevant patient outcomes and have enrolled a limited range of patients. Some studies may have been too small to detect clinically important differences in patient outcomes between these two modalities. We present a review of the available scientific interpretation of the literature on OPCAB with regard to safety, hemodynamic changes, inflammation, myocardial preservation and oxidative stress. We also sought to determine from different reported retrospective and randomized control studies, the initial and the long‐term benefits of this approach, despite the substantial learning curve associated with OPCAB.

Significance of Oxidants and Inflammatory Mediators in Blood of Patients Undergoing Cardiac Surgery

C L LOOD CONTACT WITH artificial surfaces within extracorporeal circulation (ECC) triggers a chain of ev hat may induce a temporal change in the patient’s own une system. 1 The complex role played by the immune sys n the ECC-mediated pathophysiology is not yet fully un tood, although several interlinked mechanisms could pla ole. ECC-mediated pathophysiology may be triggered b ide range of factors including the exposure of blood to hysiologic surfaces and mechanical shear stresses, surg rauma, anesthesia, changes in body temperature, increa ntestinal permeation by endotoxins, and ischemia-reperfusi njury.2 The combined action of these factors results in a com mmunologic reaction ( Figs 1 and 2) propagated by bloo eukocytes culminating with the release of reactive oxy pecies (ROS) and arachidonic acid metabolites, endothel latelet-activating factors, proinflammatory cytokines, and e othelial and leukocyte adhesion molecules into circulation 3,4

Does the type of prosthesis influence the incidence of permanent pacemaker implantation following isolated aortic valve replacement.

BACKGROUND The incidence of conduction disorders requiring permanent pacing (PPM) in patients operated on for aortic valve replacement (AVR) has been reported to be 5.7%. However, perioperative risk predictors for PPM following AVR are not well characterized and debate exists regarding selection of the prosthesis-type most likely to minimize this incidence. The aim of the study was to assess whether the type of the prosthesis used influences the prevalence of PPM following aortic valve replacement. METHODS A total of 782 consecutive patients with predominant aortic stenosis accepted for isolated non-emergent AVR were studied over a 3 year period; of which 305 patients (Group A) received mechanical prostheses, 335 received stented tissue prostheses (Group B), and the remaining 142 received stentless tissue valves (Group C). A stepwise logistic regression analysis was used to identify the independent predictors for PPM and statistical significance was accepted at a level of P < .05. RESULTS Univariate and multivariate analyses showed a significant relationship between the preoperative factors (poor ejection fraction < 35%; P < .001), left atrial enlargement (LAE; P < .001) and left bundle branch block (LBBB; P < .001), the perioperative variables (bypass time > 100 minutes with x-clamp time > 70 minutes; P < .001) and the incidence of PPM. CONCLUSIONS The proposed predictive model correlated highly with actual pacemaker use, suggesting that the requirement for PPM results from either operative trauma or increased ischemic burden and the incidence of PPM is independent of prosthesis-type implanted.

Inspired Nitric Oxide and Modulation of Oxidative Stress During Cardiac Surgery

Evidence in the literature is contradictory regarding the precise role of nitric oxide (NO) in modulating systemic inflammatory response induced by cardiopulmonary bypass (CPB). We studied the impact of inspired NO gas on physiological function and markers of inflammation-oxidative stress for subjects (n=15, age 62+/-4.5 and 12/3 M/F) scheduled for coronary artery bypass graft (CABG) operation. Outcomes from subjects that received 5 ppm and 20 ppm of inspired NO (n=5/group) were compared to those not given NO gas. Breath-to-breath measurement commenced at the start of intubation and continued up to 4h later. Indices of cardiovascular function, alveolar-capillary gas exchange and haematological parameters were not significantly different in outcomes for the inspired NO groups as compared with control. We observed a reduction in mean systemic arterial in all subjects at 30 min and 4h after bypass when compared with pre bypass values. Markers of systemic inflammatory response and oxidative stress increased during CPB particularly at 4h and 24h after the initiation of bypass. In contrast, we observed a reduction in expired NO, at 24h after surgery in the groups given inspired NO. In addition, there was also a significant reduction in oxidative stress markers in blood at 24h after surgery for the groups given inspired NO as compared with the control group. In contrast, cytokines response remained similar in all the three groups at all time points. The results suggested that inspired NO gas has an antioxidant property that reduces the levels of cell death, and is not associated with significantly worse-off physiological outcomes.

Current concepts underlying benefits of exercise training in congestive heart failure patients.

The pathophysiology of several conditions including heart failure is partly attributable to a failure of the cell energy metabolism. Studies have shown that exercise training (ET) improves quality of life (QOL) and is beneficial in terms of reduction of symptoms, mortality and duration of hospitalization. Increasingly, ET is now achieving acceptance as complimentary therapy in addition to routine clinical practice in patients with chronic heart failure (CHF). However, the mechanisms underlying the beneficial effects of ET are far less understood and need further evaluation. Evidence suggests that while CHF induces generalized metabolic energy depletion, ET largely enhances the overall function of the heart muscle. Hence, research efforts are now aiming to uncover why ET is beneficial as a complimentary treatment of CHF in the context of improving endothelial function and coronary perfusion, decreasing peripheral resistance, induction of cardiac and skeletal muscle cells remodeling, increasing oxygen uptake, substrate oxidation, and resistance to fatigue. Here we discuss the current evidence that suggest that there are beneficial effects of ET on cardiac and skeletal muscle cells oxidative metabolism and intracellular energy transfer in patients with CHF.