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.

Extracorporeal membrane oxygenation support in a situation of diagnostic dilemma.

Severe acute respiratory distress syndrome (ARDS) in children carries a high morbidity and mortality. High frequency ventilation and extracorporeal membrane oxygenation (ECMO) are used as rescue modes of support in difficult situations. Malignancy may be considered to be a relative contraindication to ECMO support. We report a case where the decision was made to support the patient with ECMO for fulminant Epstein-Barr (EBV) infection while investigations were being done to exclude an underlying malignancy.

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.

Long-term maternal high-fat feeding from weaning through pregnancy and lactation predisposes offspring to hypertension, raised plasma lipids and fatty liver in mice.

In rodents, adverse prenatal nutrition, such as a maternal diet rich in fat during pregnancy, enhances susceptibility of the offspring to hypertension, type 2 diabetes and other features of the human metabolic syndrome in adulthood. However, previous experimental studies were confined to short-term modifications of the maternal diet during pregnancy and/or lactation periods, a situation uncommon in humans. Moreover in humans, the offspring may also consume a high-fat diet, which may take them beyond the range to which their development has adapted them to respond healthily. We examined in C57 mice the effects on offspring of feeding their mothers a high-fat (HF) or standard chow (C) diet from weaning through pregnancy and lactation, and whether there are additive phenotypic effects of feeding the offspring an HF diet from weaning to adulthood (dam-offspring dietary group HF-HF). This group was compared with offspring from HF-fed dams fed a C diet from weaning to adulthood (HF-C) and offspring from C-fed mothers fed the C or HF diet (C-C and HF-C, respectively). HF-HF, HF-C and C-HF adult female offspring were heavier, fatter, and had raised serum cholesterol and blood pressure compared with C-C female offspring. We observed a similar trend in male offspring except for the HF-C group which was not heavier or fatter than male C-C offspring. Histology showed lipid vacuoles within hepatocytes in the HF-HF, HF-C and C-HF but not the CC offspring. Serum C-reactive protein was elevated in female (C-HF and HF-HF) but not in male offspring. Elevated blood pressure in the HF-C and C-HF groups was attenuated in the HF-HF group in males but not in females. These findings indicate that long-term consumption of an HF diet by the mother predisposes her offspring to developing a metabolic syndrome-like phenotype in adult life, although cardiovascular effects of an HF diet are related to sex specificity in the HF-HF group.

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.

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.

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.

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.

Revascularization with off-pump coronary artery surgery: what appears new is actually the old rediscovered.

The enormous progress in interventional cardiology during the last 10 years has resulted in a major change in the spectrum of patients referred for coronary artery bypass grafting. Several large retrospective analyses, meta-analyses, and the randomized trials that addressed different aspects of ONCAB and OPCAB to date have compared the two surgical strategies. It is suggested that patients may achieve an excellent outcome with either type of procedure, and individuals' outcomes more likely depend on factors other than whether they underwent ONCAB or OPCAB. Nevertheless, there appear to be trends in most studies. These trends include less blood loss and need for transfusion, less myocardial enzyme release up to 24 h, less early neurocognitive dysfunction, and less renal insufficiency after OPCAB and propensity to lower costs, thereafter proving OPCAB to be safe and clinically effective. Here, we review the physiological advantages and clinical outcomes of OPCAB for myocardial revascularization and examine whether either strategy is superior and in which patients.

Effects of maternal high-fat diet and statin treatment on bone marrow endothelial progenitor cells and cardiovascular risk factors in female mice offspring fed a similar diet.

OBJECTIVES: The aim of this study was to prove that one possible statin-related protective mechanism in dams and offspring fed a high-fat diet (HFD) is the reduction in cardiovascular risk and impairment of the vasculogenic element of endothelial regeneration. METHODS: To explore this, virgin C57 BL/6 mice (n = 8/group) were fed an HFD (fat: 45% kcal) or standard chow (C; fat: 21% kcal) from weaning and throughout their pregnancy and lactation. Half of the HFD group also was given the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pravastatin (S) through their drinking water (5 mg/kg body weight per day) to create HF+S dam group (n = 8/group). Offspring from each group were fed HFD or C diet from weaning to adulthood, generating respective dam/offspring dietary groups (C/C, HF/HF, HF+S/HF; n = 8/group). Body weight, blood pressure, and serum lipid profile were measured in female offspring at age 24 wk, and bone marrow endothelial progenitor cells (EPCs) were cultured. RESULTS: The results indicated that in the female offspring, the statin-fed (HF+S/HF) cohort had lower total and low-density lipoprotein cholesterol concentrations, were less obese and hypertensive, and had reduced C-reactive proteins (CRPs) compared with the HF/HF phenotype. The results also showed an increased bone marrow EPCs expressing colony numbers (P < 0.001) compared with the HF/HF phenotype. CONCLUSIONS: Results from the present study demonstrated that statin administration in early life to dams fed on a HFD had a significant effect on their female offspring in terms of reduction in cardiovascular risk factors. Additionally, statin administration to female offspring on an HFD during early life was associated with reduction in circulating CRPs and an increased bone marrow EPC numbers and colony-forming characteristics.

Living with off-pump coronary artery surgery: evolution, development, and clinical potential for coronary heart disease patients.

The enormous progress in interventional cardiology during the last 10 years has resulted in a major change in the spectrum of patients referred for coronary bypass surgery. These patients are older and sicker and frequently have had previous percutaneous coronary interventions. Consequently, cardiac surgery is responding by adding new surgical techniques: off-pump open-chest coronary bypass surgery (OPCAB), minithoracotomy bypass surgery, videothoracoscopic (robotic) procedures, etc. Several registries published to date have proved OPCAB to be safe and clinically effective. Randomized studies and meta-analysis research in this field provide scientific support and suggest that myocardial, renal, and neurological functions, amongst others, are better preserved by OPCAB than by classic techniques that use a cardiopulmonary bypass pump (CPB). Moreover, avoidance of CPB yields significantly reduced oxidative stress and systemic inflammatory response. This results in higher safety for ischemic heart disease patients undergoing revascularization, thus offsetting the propensity to lower costs. The present review examines the physiological advantages and clinical outcomes of this simple mode of myocardial revascularisation and evaluates the wider implications arising from its evolution.

Comparative analysis of the Bonanno catheter and tube thorocostomy in effective aspiration of pleural effusion.

BACKGROUND AND METHODS: In our earlier report, we suggested the Bonanno catheter (a 14-gauge suprapubic catheter) as a less traumatic but equally effective alternative for drainage of a variety of fluid collections, including pleural effusion. This study aims to evaluate the efficacy of the Bonanno catheter compared with closed-tube thoracostomy in draining pleural effusion in 38 patients following routine cardiac surgery between 2003 and 2004. Twenty patients were managed using the Bonanno catheter and 18 were treated with standard tube thoracostomy. Data were collected retrospectively and statistical analysis was performed using the SPSS software. P < .05 was considered significant. RESULTS: There were 20 (53%) male and 18 (47%) female patients with a mean age of 63.5 years (range, 31-83 years). Significant differences were observed with regards to the amount of lignocaine administered locally, intra-procedure pain score, post-procedure pain score after 15 minutes, and amount of analgesia used on a regular basis (P < .05 in each case). Statistically, significant differences were also noted during 2 to 3 weeks follow-up between the 2 groups with regards to pain score. In the the tube thoracostomy group, 22.2% developed infection of the procedure site, requiring antibiotic treatment, whereas no infection was reported in the Bonanno group (P < .001). CONCLUSION: This study provided evidence that smallbore drains such as the Bonanno catheter are safe and better tolerated than standard chest drains. This is consistent with the British Thoracic Society guidelines that strongly recommend small-bore drains for the drainage of pleural effusions as they are more comfortable than larger-bore tubes.

Predictors of permanent pacemaker implantation during the early postoperative period after valve surgery.

The ability to preoperatively identify patients who may require permanent pacemaker implantation is rather poorly understood. The aim of this study is to determine the current incidence of permanent pacing after valve surgery and to determine which factors place the heart valve patient at risk of requiring permanent pacemaker implantation. We audited the records of 2,392 consecutive adult patients who underwent cardiac valve surgical procedures by the same surgical team from 25 April 1998 through 31 March 2003. Of these, 118 patients (group A) required the postoperative implantation of permanent pacemakers during the same hospitalization; they were compared with 1,959 heart valve patients (group B) who did not require pacemaker placement. Multivariate logistic regression analysis showed that reoperations (odds ratio [OR], 8.23; P <0.001), longer cumulative cross-clamp times (OR, 5.9; P <0.001), multiple-valve surgical procedures (OR, 3.46; P <0.05), and absence of preoperative sinus rhythm (OR 2.52; P <0.001) were independent predictors of the need for permanent pacemaker implantation after valve surgery. These results suggest that patients who display these risk factors for arrhythmias that require permanent pacemaker implantation receive closer observation and advance counseling about the likelihood of such implantation.

Quiescent interplay between inducible nitric oxide synthase and tumor necrosis factor-alpha: influence on transplant graft vasculopathy in renal allograft dysfunction.

A healthy endothelium is essential for vascular homeostasis, and preservation of endothelial cell function is critical for maintaining transplant allograft function. Damage to the microvascular endothelial cells is now regarded as a characteristic feature of acute vascular rejection, an important predictor of graft loss. It is also linked with transplant vasculopathy, often associated with chronic allograft nephropathy. Large bursts of nitric oxide in infiltrating monocytes/macrophages modulated by inducible nitric oxide synthase are considered pivotal in driving this mechanism. Indeed, it has been shown recently that increased circulating levels of tumor necrosis factor-alpha in the rejecting kidneys are largely responsible for triggering inducible nitric oxide synthase expression. This in turn suggests that several structural and functional features of graft rejection could be mediated by tumor necrosis factor-alpha. Despite the large body of evidence that supports immunologic involvement, knowledge concerning the cellular and biochemical mechanisms for nephritic cell dysfunction and death is incomplete. The role of tumor necrosis factor-alpha in mediating pathophysiological activity of inducible nitric oxide synthase during transplant vasculopathy remains contentious. Here, we discuss the effect of inducible nitric oxide synthase and tumor necrosis factor-alpha interaction on progressive damage to glomerular and vascular structures during renal allograft rejection. Selective inhibition of inducible nitrous oxide synthase and tumor necrosis factor-alpha as a potential therapy for ameliorating endothelial dysfunction and transplant graft vasculopathy is also discussed.

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.

Acute renal failure in patients with ischemic heart disease: causes and novel approaches in breaking the cycle of self-perpetuating insults abrogated by surgery.

At present, there seems to be diametrically opposing views on the causes of acute renal insufficiency in patients with ischemic heart disease (IHD) elective for cardiac revascularization. In this review, we examined recent advances in the understanding of the pathophysiology of acute renal failure in patients with IHD and surgery-induced acute phase reaction. Emphasis is given to the cellular and molecular mechanisms that contribute to the initiation and progression of inflammation. We evaluated the different pharmacological, technical, and surgical strategies used to improve the outcome of patients with IHD with impaired renal dysfunction and analyzed the influence of renal insufficiency on long-term results after surgery.

Consequence of patient substitution of nattokinase for warfarin after aortic valve replacement with a mechanical prosthesis.

This report describes a patient's self-substitution of nattokinase for the vitamin K antagonist warfarin after aortic valve replacement with a mechanical prosthesis. Nattokinase is an enzyme derived from a popular fermented soybean preparation in Japan (natto), which has fibrinolytic properties and is gaining popularity in nontraditional health journals and nonmedical health websites as an over-the-counter thrombolytic. After nearly a year of use of nattokinase without warfarin, the patient developed thrombus on the mechanical valve and underwent successful repeat valve replacement. We believe this is the first documented case of nattokinase being used as a substitute for warfarin after valve replacement, and we strongly discourage its use for this purpose.

Early hemofiltration improves survival in post-cardiotomy patients with acute renal failure.

OBJECTIVE: The application and timing of hemofiltration (continuous veno-venous hemofiltration, CVVH) in patients with acute renal failure (ARF) post cardiac surgery has been called into question because of uncertain short-term outcome. The aim of the present study was to identify how the timing of introduction of hemofiltration affects the morbidity and mortality in patients with ARF after cardiac surgery. METHODS: 1264 consecutive patients who underwent adult cardiac surgical procedures performed between January 2002 and January 2003 were audited. Out of these, case notes of 64 patients who required renal supportive intervention were reviewed. Statistical significance was accepted at a level of P<0.05. RESULTS: Of the 64 (5%) patients, who developed ARF and required CVVH, there were 48 males and 16 females. Mean age was 70+/-6.8 years. The hospital mortality was 43% (12 patients) in Group-I and 22% (8) in Group-II (P<0.05), giving an overall 1.5% mortality associated with ARF. The mean time between the operation and the initiation of CVVH was 2.55+/-2.2 days in Group-I and 0.78+/-0.2 days in Group-II (P<0.001). The mean duration of CVVH was 4.57+/-11.4 days in Group-I and 4.61+/-2.0 days in Group-II (P=NS). Older age (P=0.013), elevated preoperative creatinine (P=0.002), postoperative pulmonary oedema (P=0.01), sepsis (P=0.001), multiple organ failure (P=0.031), hypotension (P=0.031) and preoperative renal failure (P<0.05) were the independent factors influencing the poor postoperative outcome and cardiac instability. CONCLUSION: Early and aggressive use of CVVH is associated with better than expected survival in severe ARF after cardiac operations.