In Situ Oxidative Stress and Atrial Cell Deaths in Patients with Valve Disease.

BACKGROUND: Left ventricular hypertrophy and myocardial remodeling occur with aortic valve disease and may lead to heart failure. Although increased oxidative stress and inflammatory factors have been implicated in heart failure, their role in the progression of valve disease remains unclear. OBJECTIVES: We investigated the role of oxidative stress and inflammatory factors in valve disease whether this relates to cell death. METHODS: Blood samples were taken from 24 patients with valve disease before surgery and the results were compared with those from blood samples from 30 control healthy subjects. Myocardial biopsies from patients with valve disease were also collected before cannulation of the right atrial appendage. NF-κB activities in atrial and mononuclear cells nuclear extracts were determined by electrophoretic mobility shift assay. RESULTS: Nuclear factor kappaB activities were significantly greater in mononuclear cells from AVD patients compared with healthy controls and the antigens were detectable in atrial tissues valve disease patients. Plasma C-reactive protein, B-natriuretic peptides, plasma tumor necrosis factor alpha and soluble tumor necrosis factor receptor 1 and 3-nitrotyrosine levels were significantly higher in valve disease patients. Inducible nitric oxide and 3-nitrotyrosine antigens and cells expressing CD45 antigens were detected within atrial tissues obtained from valve disease patients suggesting oxidative stress originated from in situ leukocytes. CONCLUSION: The findings suggest that oxidative stress originating from in situ leukocytes within the atrial myocardium may be the potential trigger for excessive transcriptional activities and apoptotic cell death within the atrial myocardium of valve disease patients. This represents a potential therapeutic target.

A Review of Interventions to Improve Enrolment and Adherence to Cardiac Rehabilitation Among Patients Aged 65 Years or Above.

PURPOSE: This review provides an overview and quality assessment of existing interventions, assessing the intervention types that are most effective at increasing enrolment and adherence to cardiac rehabilitation in older patients aged ≥65 years Methods: The review of the literature was performed using electronic databases to search for randomised controlled trials that aimed to increase enrolment and/or adherence to cardiac rehabilitation in older patients aged ≥65 years. The main key words were cardiac rehabilitation, enrolment, adherence and older patients. Studies were included if; (1) the intervention targeted improving enrolment and/or adherence to at least one of the following components of the cardiac rehabilitation programme: exercise, education or maintaining lifestyle changes; (2) assess the effectiveness of an intervention on increasing enrolment and/or adherence to a cardiac rehabilitation programme or any of its components; (3) include measures for assessing enrolment and/or adherence to a cardiac rehabilitation programme or any of its components; (4) the study included patients with a mean age of ≥65 years who were deemed eligible to participate in a cardiac rehabilitation programme. Included studies could be published in any language and there were no date restrictions for included studies. Studies focusing on pharmaceutical adherence were not included for the purpose of this review. RESULTS: Seven studies were included, with four investigating enrolment (1944 participants) and three assessing adherence to intervention programmes (410 participants). Three studies (1919 participants) reported higher enrolment to cardiac rehabilitation in the intervention group. Two studies that reported increases in enrolment to cardiac rehabilitation were deemed to have an unclear or high risk of bias. All three studies (410 participants) reported better adherence to cardiac rehabilitation in the intervention group when compared to the control group. Two studies that reported better completion of cardiac rehabilitation were deemed to have an unclear or high risk of bias. No formal meta-analysis was conducted due to the observed multiple heterogeneity among outcome measures, the low number of included studies and variability in study designs. CONCLUSION: This review found only weak evidence to suggest that interventions can increase enrolment or adherence to cardiac rehabilitation programmes for patients aged ≥65 years, therefore no practice recommendations could be made and further high-quality research is needed in this population group.

The impact of social deprivation on coronary revascularisation treatment outcomes within the National Health Service in England and Wales.

BACKGROUND: There is strong evidence to suggest that social deprivation is linked to health inequalities. In the UK, concerns have been raised regarding disparities in the outcomes of acute cardiac services within the National Health Service (NHS). This study explored whether differences exist in (a) elective hospital presentation time (b) indicators of severity and disease burden and (c) treatment outcomes (hospital stay and mortality) on the basis of the index of multiple deprivation (IMD) status. DESIGN: This study was a retrospective analysis of data from NHS databases for 13,758 patients that had undergone cardiac revascularisation interventions at the Liverpool Heart and Chest Hospital between April 2007-March 2012. METHODS: The data was analysed by descriptive, univariate and multivariate statistics to explore the association between the IMD quintiles (Q1-Q5) and revascularisation type, elective presentation time, hospital length of stay and mortality. RESULTS AND CONCLUSIONS: Univariate analysis indicated that there were significant differences between patients from the most deprived areas (Q5) compared with patients from the least deprived areas (Q1), these included admission volumes, time before presentation to hospital and proportion of non-elective cases. After risk-adjustments, percutaneous coronary intervention patients from Q5 compared with Q1 had significantly greater length of hospital stay and risk of in-hospital major acute cardiovascular events. After multivariate adjustment for baseline risk factors, patients from Q5 were associated with significantly worse five-year survival as compared with Q1 (hazard ratio (HR) 1.52, 95% confidence interval (CI): 1.36-1.71; p < 0.001). In conclusion, there is evidence to suggest that inequalities in cardiac revascularisation choices and outcomes in the UK may be associated with social deprivation.

A Single-Center Randomized Trial of Intraoperative Zero-Balanced Ultrafiltration During Cardiopulmonary Bypass for Patients With Impaired Kidney Function Undergoing Cardiac Surgery.

OBJECTIVES: The authors investigated whether zero-balance ultrafiltration (Z-BUF) during bypass significantly improves clinical and cost outcomes or biomarkers of kidney injury for patients with preoperative kidney impairment (estimated glomerular filtration rate [eGFR]<60 mL/minute) undergoing cardiac surgery. DESIGN: A single-center randomized controlled trial recruited, patients between 2010 and 2013, with a 12-months follow-up. SETTING: Hospital. PARTICIPANTS: One hundred ninety-nine patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). INTERVENTIONS: Patients were assigned randomly to receive zero-balance ultrafiltration (Z-BUF) or not, with stratification for degree of kidney dysfunction and diabetes. MEASUREMENTS AND MAIN RESULTS: The authors assessed clinical efficacy and kidney function biomarkers. Cumulative probability of discharge from the intensive care unit (ICU) was assessed by Kaplan-Meier plots and was found not to be significantly different between the two trial arms (p = 0.61). After adjusting for EuroSCORE, diabetes, eGFR, cardioplegia types and type of surgery in a Cox proportional hazard model, hazard ratios (HR) for ICU length of stay between the Z-BUF and no-Z-BUF groups was not significantly different: HR (95% CI): 0.89 (0.66, 1.20; p = 0.44). In contrast, significant reductions in postoperative chest infections and the composite of clinical endpoints (death, strokes, and myocardial infarctions) in the Z-BUF group were observed. In addition, Z-BUF significantly abrogated the rise in the kidney damage markers urinary NGAL/creatinine ratio, urea, creatinine and eGFR during CPB and adverse events risks. CONCLUSIONS: Z-BUF during bypass surgery is associated with significant reductions in morbidity and biomarkers of CPB-induced acute kidney injury soon after CPB, which are indicative of clearance of inflammatory/immune mediators from the circulation.

One problem two issues! Left ventricular systolic and diastolic dysfunction in aortic stenosis.

Reports suggested that immediate post-aortic valve replacement (AVR); left ventricular (LV) dysfunction may be an important risk for morbidity and mortality in patients requiring positive inotropic support. Several factors have been identified as significant prognostic factors i.e., LV systolic dysfunction, LV diastolic dysfunction (LV-DD), heart failure and myocardial infarction (MI). Specific to pathophysiological changes associated with AS, markers of systolic LV function (e.g., LVEF) have been extensively studied in management, yet only a few studies have analysed the association between LV-DD and immediate post-operative LV dysfunction This review brings together the current body of evidence on this issue.

Gender differences in the expression of genes involved during cardiac development in offspring from dams on high fat diet.

Previously we have demonstrated that maternal high fat diet (HF) during pregnancy increase cardiovascular risk in the offspring, and pharmacological intervention using statins in late pregnancy reduced these risk factors. However the effects of maternal HF-feeding and statin treatment during pregnancy on development of heart remain unknown. Hence we measured expression of genes involved in cell cycle progression (cyclin G1), ventricular remodelling brain natriuretic peptide (BNP), and environmental stress response small proline-rich protein 1A (SPRR 1A) in the offspring left ventricle (LV) from dams on HF with or without statin treatment. Female C57 mice were fed a HF diet (45% kcal fat) 4 weeks prior to conception, during pregnancy and lactation. From the second half of the pregnancy and throughout lactation, half of the pregnant females on HF diet were given a water-soluble statin (Pravastatin) in their drinking water (HF + S). At weaning offspring were fed HF diet to adulthood (generating dam/offspring dietary groups HF/HF and HF + S/HF). These groups were compared with offspring from dams fed standard chow (C 21% kcal fat) and fed C diet from weaning (C/C). LV mRNA levels for cyclin G1, BNP and SPRR 1A were measured by RT-PCR. Heart weights and BP in HF/HF offspring were higher versus C/C group. Maternal Pravastatin treatment reduced BP and heart weights in HF + S/HF female offspring to levels found in C/C group. LV cyclin G1 mRNA levels were lower in HF/HF versus both C/C and HF + S/HF offspring. BNP mRNA levels were elevated in HF/HF females but lower in males versus C/C. BNP gene expression in HF + S/HF offspring was similar to HF/HF. SPRR 1A mRNA levels were similar in all treatment groups. Statins given to HF-fed pregnant dams reduced cardiovascular risk in adult offspring, and this is accompanied by changes in expression of genes involved in adaptive remodelling in the offspring LV and that there is a gender difference.

Nitric Oxide-Dependent Regulation of Cytokines Release in Type-II Diabetes Mellitus.

The mechanism of release of proinflammatory cytokines by blood granulocytes in diabetes is unknown. We investigated whether diabetes mellitus affects the production of cytokines by granulocytes (PMN) and mononuclear cells (PBMCs) and whether this is modulated by NO. Isolated PMN and PBMC from with or without type-II diabetes mellitus were incubated at 37°C for 6 h with S-nitroso-N-acetylpenicillamine (SNAP) at 0, 1, and 100 µ M with or without lipopolysaccharides (LPS) stimulation (1 µ g/mL). Supernatants were assayed for tumor necrosis factor- α (TNF- α ) and interleukin-8 (IL-8) by sandwich ELISA. Significant increases in TNF- α and IL-8 were observed only in PMN from diabetic subjects with or without LPS stimulation and that exogenous NO inhibited further production of cytokines in a concentration-dependent manner. However, activity of PBMC when stimulated with LPS was greatly enhanced by diabetes, but not affected by NO production. Hence, suggesting that granulocytes activation and participation in diabetes related complications is modulated by NO bioavailability.

Patients' attitudes and perceptions of two health-related quality-of-life questionnaires used to collect patient-reported outcome measures in the English National Health Service: A qualitative study of patients undergoing cardiac interventions.

OBJECTIVES: To explore patients' views on the EuroQol-5D and Coronary Revascularisation Outcome Questionnaire, tools currently used for collecting patient-reported outcome measures in the English National Health Service. The key questions were as follows: (1) whether patients consider them sensitive enough to detect change in their health after cardiovascular disease interventions and (2) whether they consider the health-related quality-of-life questions as meaningful. METHODS: Data were collected on patients' views using focus groups. We held four focus groups selecting participants on the basis of their baseline and follow-up EuroQol-5D scores. Data were analysed using framework analysis and grounded theory. RESULTS: Focus group participants confirmed that they had derived substantial health benefits from their cardiac interventions despite the lack of measurable effects on the EuroQol-5D scores. Participants felt that the EuroQol-5D questionnaire was limited because of the following reasons: Their health fluctuates from day to day.They had difficulty assessing their general health status on the visual analogue scale.They felt that the Coronary Revascularisation Outcome Questionnaire was limited because of the following reasons: They did not understand the clinical terms used.The impact of tiredness on their quality of life was not captured.They were unable to distinguish between the effects of their heart condition and other health issues.Additionally, neither questionnaire considers the adjustments people have made to their domestic arrangements to improve their health-related quality of life. CONCLUSION: This study provides evidence that the two questionnaires do not capture some aspects of health that patients consider important. Furthermore, the presence of co-morbidities masks the symptoms relating to the heart disease and the effect of their cardiac interventions. Future work on patient-reported outcome measures should consider developing new questionnaires that address these major concerns.

Serum gamma glutamyl transferase: a novel biomarker for screening of premature coronary artery disease.

BACKGROUND: We aimed to elucidate the association between gamma glutamyl transferase (GGT) activity with prevalence of premature coronary artery disease (CAD) in young Pakistani patients undergoing diagnostic coronary angiography. METHODS: A total of 218 young adults (age ≤ 45 years) underwent diagnostic angiography. Serum samples were taken from all the patients and analyzed for serum GGT activity, cholesterol and triglycerides. RESULTS: Coronary artery disease patients had significantly increased GGT activity (P = .001) and exhibited a significant positive correlation with blood pressure, cholesterol, blood glucose, and smoking and negative correlation with total antioxidant status (P < .01). CONCLUSION: The study revealed good diagnostic accuracy at cutoff of 35 U/L with a sensitivity of 92%, specificity of 81%, and diagnostic odds ratio of 48 in estimation of premature CAD in young Pakistanis.

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.

Tumor necrosis factor alpha -308 gene locus promoter polymorphism: an analysis of association with health and disease.

Tumor necrosis factor-alpha (TNF-alpha) is a potent immunomediator and proinflammatory cytokine that has been implicated in the pathogenesis of a large number of human diseases. The location of its gene within major histocompatibility complex and biological activities has raised the possibility that polymorphisms within this locus may contribute to the pathogenesis of wide range of autoimmune and infectious diseases. For example, a bi-allelic single nucleotide substitution of G (TNFA1 allele) with A (TNFA2 allele) polymorphism at -308 nucleotides upstream from the transcription initiation site in the TNF-alpha promoter is associated with elevated TNF-alpha levels and disease susceptibilities. However, it is still unclear whether TNF-alpha -308 polymorphism plays a part in the disease process, in particular whether it could affect transcription factor binding and in turn influence TNF-alpha transcription and synthesis. Several studies have suggested that TNFA2 allele is significantly linked with the high TNF-alpha-producing autoimmune MHC haplotype HLA-A1, B8, DR3, with elevated serum TNF-alpha levels and a more severe outcome in diseases. This review discusses the genetics of the TNF-alpha -308 polymorphism in selected major diseases and evaluates its common role in health and disease.

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.

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-catalysed 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 signalling pathways including transcription factors activity, a process that is ubiquitous in cardiovascular disease related to ischemia/reperfusion injury have also been presented.

Should the cardiotomy suction blood be cell-saver processed before retransfusion? A clinico-pathologic mystery.

The use of cardiotomy suction (CS) in cardiopulmonary bypass (CPB) surgery is associated with a pronounced systemic inflammatory response and a resulting coagulopathy as well as exacerbating the microembolic load. However, CS is yet been employed to preserve autologous blood during on-pump surgery. Though processing CS blood with a cell saving device is considered paramount in significantly reducing the inflammatory effects, yet this might also have potential harmful effects on the outcome of the patient. Here we discuss the results of the different prospective and randomized studies to address these issue if the cell saver technique in processing CS blood before retransfusion is to establish its identity and role in the CPB surgery.

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 metaanalyses, 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.

Functional adaptation to oxidative stress by memory T cells: an analysis of the role in the cardiovascular disease process.

T cells participate in combating infection and critically determine the outcomes in any given disease process. Impaired immune response occurs in a number disease processes such as in cancer and atherosclerosis although the underlying mechanisms are still not fully understood. This article gives an up-to-date review of T cells development and functional adaptation to pathophysiological stimuli and participation in the cardiovascular disease process. In addition, we have discussed the signaling pathways controlled by the microenvironment that determine T cells function and resultant type of immune response. We have also discussed in detail how oxidative stress is a key component of the micro environmental interaction.

A variant of position -308 of the Tumour necrosis factor alpha gene promoter and the risk of coronary heart disease.

PURPOSE: The aim of this study was to investigate whether the variability between individuals with coronary heart disease (CHD) is related to the prevalence of TNF-alpha gene promoter -308 variant in un-matched British Caucasian population from East Midlands. PROCEDURES: Genotypes and allele frequencies were determined using restriction fragment length polymorphism analysis of polymerase chain reaction (PCR) products. Genomic DNA prepared from peripheral blood leukocytes of patients (n=97) and healthy controls (n=95) demonstrated two alleles TNF*1 (G) and TNF*2 (A). FINDINGS: The genotype distribution in patients was GG, n=59; GA, n=36; and AA, n=2 and in controls was GG, n=41; GA, n=40; and AA, n=14 (P=0.014). The association analysis demonstrated that TNF*1 allele in patients appears to be associated with greater incidences of CHD (OR 2.15; CI, 1.36-3.39; P=0.001). CONCLUSIONS: Our results suggest that TNF*1 allele (TNF-alpha -308 GG or GA) has a high prevalence among British Caucasian population that correlates with an increased CHD risk.

Nitric oxide in blood. The nitrosative-oxidative disequilibrium hypothesis on the pathogenesis of cardiovascular disease.

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.