An Association between MicroRNA-21 Expression and Vitamin D Deficiency in Coronary Artery Disease.

BACKGROUND: Atherosclerosis-related cardiovascular disease and osteoporosis (OP) occur concurrently and may share a common pathogenesis. Aberrant expression of miR-21 and vitamin D deficiency have been independently linked to the pathogenesis of atherosclerosis and OP. OBJECTIVES: To examine the relationship between miR-21 expression and vitamin D in aorta and bone in atherosclerotic disease. METHODS: Aorta, internal mammary artery (IMA) and sternal bone samples were collected from patients undergoing coronary artery bypass graft (CABG) surgery. Bone density was measured by dual x-ray absorbtiometry (DXA). MiR-21 was quantified using a two-step reverse transcription-polymerase chain reaction. RESULTS: Ten patients were included for analysis; 5 were vitamin D deficient (<25nmol/L). MiR-21 was expressed at a greater level in aorta compared with the IMA (p = 0.003), and sternal bone (p = 0.002). Expression of miR-21 between the IMA and bone was similar (p = 0.7). A positive correlation between the magnitude of difference (fold-difference) of miR-21 expression between aorta and IMA and CRP (correlation coefficient 0.9, p = 0.009) was found. Vitamin D deficient patients had greater expression of miR-21 in aorta compared with non-deficient patients (p = 0.03). Increasing CRP and vitamin D deficiency were independent predictors of miR-21 expression in aorta. The lower the difference in miR-21 expression between aorta and bone, the lower the bone density. CONCLUSION: In atherosclerosis, miR-21 is increased in the aorta and associated with vitamin D deficiency. Vitamin D deficiency may influence aberrant miR-21 expression in vasculature and bone contributing to the concurrent development of atherosclerosis and osteoporosis.

Prognostic impact of vascular and lymphovascular invasion in early lung cancer.

BACKGROUND: The prognostic significance of vascular and lymphatic invasion in non-small-cell lung cancer is under continuous debate. We analyzed the effect of tumor aggressiveness (lymphatic and/or vessel invasion) on survival and relapse in stage I and II non-small-cell lung cancer. METHODS: We retrospectively analyzed prospectively collected data of 457 patients with stage I and II non-small-cell lung cancer from 1998 to 2008. Specimens were analyzed for intratumoral vascular invasion and lymphovascular space invasion. Overall survival and disease-free survival were estimated using the Kaplan-Meier method, and differences were determined by the logrank test. Cox regression analysis was performed to identify independent risk factors. RESULTS: The incidence of intratumoral vascular invasion was 23.4%, and this correlated significantly with grade of differentiation, visceral pleural involvement, lymphovascular space invasion, and N status. The incidence of lymphovascular space invasion was 5.5%, and this correlated significantly with grade of differentiation, lymph nodes involved, and intratumoral vascular invasion. On multivariate analyses, intratumoral vascular invasion proved to be an significant independent risk factor for overall survival but not for disease-free survival. Lymphovascular space invasion was associated significantly with early tumor recurrence but not with overall survival. CONCLUSIONS: Vascular and lymphatic invasion can serve as independent prognostic factors in completely resected non-small-cell lung cancer. Intratumoral vascular invasion and lymphovascular space invasion in early stage non-small-cell lung cancer are important factors in overall survival and early tumor recurrence. Further large scale studies with more recent patient cohorts and refined histological techniques are warranted.

Gender influence in isolated coronary artery bypass graft surgery: a propensity match score analysis of early outcomes.

INTRODUCTION: The female gender has been shown as high-risk factor for mortality and morbidity. We sought to assess the influence of female gender on coronary artery bypass graft (CABG) surgery from our own experience. METHODS: This is a retrospective analysis of prospectively collected database from a single centre. Patients were grouped according to gender and potential differences in pre-operative, intra-operative and post-operative factors were explored. Significant high-risk factors were then fitted in a multivariate model to account for differences in predicting gender influence on surgical outcomes. RESULTS: Two thousand eight hundred and four consecutive patients underwent isolated first-time CABG between February 2000 and December 2008; 562 (20%) patients were females. Pre-operatively, females were more likely to have significant comorbidities (age, congestive cardiac failure, hypercholesterolemia, hypertension, ischemic heart disease, peripheral vascular disease, pre-op arrhythmias, small body surface area and poor ejection fraction (p < 0.001)) consistent with higher Euroscore (p > 0.0001) and more urgent surgery (p < 0.002). Intra-operatively, they showed less extent pattern of disease requiring less bypass and cross-clamp time (p < 0.001). Observed surgical mortality was significantly higher in females (3.6 vs. 2.1%, p < 0.042); however, after adjusting for propensity score and significant factors identified in multivariate models, females only independently predicted a higher wound infection, lower neurological complications, lower rate of re-sternotomy, longer hospital stay and post-surgery stay (p < 0.01). CONCLUSIONS: Despite higher risk profile and higher observed surgical mortality, early outcomes in females were similar to their matched males' counterpart in isolated CABG surgery. Females were associated with higher incidence of wound infections but lower rate of neurological complications.

Propensity analysis of outcome in coronary artery bypass graft surgery patients >75 years old.

PURPOSE: We looked at the complications and hospital resources of an elderly population undergoing first-time isolated coronary artery bypass graft surgery (CABG) in comparison to a younger counterpart for a propensity matched cohort. METHODS: A retrospective analysis of prospectively collected data was conducted on 2804 CABG patients. Two age groups, >75 years and ≤75 years, were generated. Potential differences in demographic, baseline, preoperative, and intraoperative characteristics were investigated. A propensity score based on these differences was calculated and used to create a matched set of patients. Major postoperative complications were recorded, and data on indicators of resource utilization were collected. RESULTS: In all, 311 (11.1%) patients were identified as >75 years of age. The observed complication rate was significantly higher in overall, pulmonary, cardiac, renal, gastrointestinal (GI), neurological, infective, and mortality categories (P < 0.0001). Observed hospital resource utilization was significant in the elderly group in terms of initial stay in the intensive care unit (ICU) and ICU readmission (P < 0.05) and in all preoperative, postoperative, cardiac surgery, and total hospital stays (P < 0.001). However, after propensity matching to 311 patients ≤75 years, the overall postoperative complication rate maintained its significance (P < 0.0001), in addition to atrial fibrillation and neurological, renal, and GI complications (P < 0.05). Elderly patients required longer duration of ventilation postoperatively and longer postoperative stay, cardiac surgery stay, and total hospital stay; and they maintained a higher surgical mortality rate (6.1% vs. 2.6%) (P < 0.05). CONCLUSION: Elderly patients undergoing CABG had significantly higher rates of postoperative complications. Their prolonged hospital stay and consequently higher resources utilization need to be adequately highlighted to heath care officials and appropriately addressed.

Coagulopathy after cardiac surgery may be influenced by a functional plasminogen activator inhibitor polymorphism.

BACKGROUND: Cytokine-mediated inflammation and coagulopathy may occur after cardiac surgery. In this study we investigated the temporal pattern of plasminogen activator inhibitor-1 (PAI-1) gene expression after cardiac surgery and its relation with PAI genotype, and obtained preliminary data regarding its relation to perioperative morbidity. METHODS: The relative change in PAI-1 mRNA 1, 6, and 24 h after cardiopulmonary bypass (CPB) was measured from mononuclear cells in 82 patients undergoing elective cardiac surgery. DNA was analyzed for carriage of the 4G/5G PAI-1 polymorphism. RESULTS: PAI-1 gene expression decreased after CPB in all patients. A larger reduction in PAI-1 gene expression was observed in homozygous carriers of the 5G allele. Homozygous carriers of the 5G allele were also more likely to receive transfusion of coagulation blood products. There was no relation between change in PAI-1 gene expression and duration of CPB. CONCLUSIONS: PAI-1 gene expression decreased over time after CPB. We found a link between PAI-1 genotype, PAI gene expression, and transfusion of coagulation products after cardiac surgery.

Troponin T elevation after coronary bypass surgery: clinical relevance and correlation with perioperative variables.

OBJECTIVE: Elevation in markers of myocardial necrosis is a common feature following coronary artery bypass surgery, but its relevance is unclear. The objective of this study was to evaluate the association between postoperative troponin T elevation, perioperative variables and clinical outcomes. METHODS: We evaluated 100 low-risk patients undergoing first-time elective on-pump coronary artery bypass surgery. The mean age was 62 +/- 9.8 years and 83% were male; patients with diabetes mellitus, renal failure and impaired left ventricular function (ejection fraction < 40%) were excluded. Troponin levels were measured at baseline and 12 and 24 h following the onset of cardiopulmonary bypass. Predefined clinical endpoints included death, new Q waves on 12-lead electrocardiogram and inotropic requirement. RESULTS: Postoperative troponin elevation occurred in 95%. Troponin T elevation was related to the duration of cardiopulmonary bypass (P = 0.0001) and aortic cross-clamp time (P = 0.0003). There was also an inverse relationship with perioperative core temperature (P = 0.0001). There was no association between postoperative troponin elevation and clinical outcomes. CONCLUSIONS: Postoperative troponin T elevation occurs in the majority of patients undergoing elective on-pump coronary artery bypass surgery. In this low-risk cohort, troponin T elevation was associated with procedural duration but not with clinical outcome.

Gene polymorphism and requirement for vasopressor infusion after cardiac surgery.

BACKGROUND: Genes in the class III region of the MHC, encoding proteins involved in inflammation and vascular regulation, were investigated for association with the occurrence of vasodilation and requirement for vasopressor infusion. METHODS: A cohort of 236 elective cardiac surgical patients was studied. Hemodynamic and metabolic variables and dosage of vasopressor medications were recorded for the first 12 hours of intensive care unit admission after cardiac surgery on an electronic patient record. Demographic factors and operative details were recorded from other institutional databases. The DNA was extracted from peripheral blood mononuclear cells and genotyped for the presence of polymorphic alleles in genes coding for inflammation-related proteins. RESULTS: Carriage of the dimethylarginine dimethylaminohydrolase II (DDAH II) -449 G allele and the lymphotoxin alpha +252 G allele was significantly less frequent in patients who required infusions of vasopressors after cardiac surgery. On multivariate analysis, prior myocardial infarction, prolonged bypass, and the homozygous carriage of the DDAH II C allele were associated with postoperative vasopressor requirement. CONCLUSIONS: Vasopressor requirement after surgery may be related to an interaction of genotype, preoperative morbidity, and prolonged surgery.

Preoperative atrial histological changes are not associated with postoperative atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) remains the most common complication of cardiac surgery. Prophylactic therapies have been studied, but their utility has been limited by the inability to accurately identify patients who will develop this complication. Recent studies have suggested that atrial myolysis and lipofuscin pigmentation are associated with post-coronary artery bypass grafting (CABG) AF. We sought to determine whether there is an association between preoperative atrial histology and subsequent post-CABG AF. METHODS: Samples of right atrial appendage were obtained from 94 patients undergoing CABG. Tissue was formalin fixed and paraffin embedded. Sections 4 mum thick were cut, stained with hematoxylin and eosin, and examined for the following parameters: fibrosis, myolysis, inflammation, nuclear size, pericardial exudates, lipofuscin pigment, arteriolar hypertrophy, contraction banding, mesothelial hyperplasia, and atrial diverticula. Results were graded as absent, mild, moderate, or severe by two independent observers who were blinded to the clinical outcomes. Univariate and multivariate analyses were carried out. RESULTS: Thirty-six (38%) patients developed AF. No correlation was found between the 10 features assessed, including myolysis and lipofuscin pigmentation, and the development of AF. CONCLUSION: Simple morphology of right atrial appendages does not predict the development of postoperative AF.

Tumor necrosis factor-alpha and interleukin-10 gene expression in peripheral blood mononuclear cells after cardiac surgery.

OBJECTIVE: Cytokine response after cardiac surgery may be genetically influenced. A study was carried out to investigate the relation between cytokine gene expression in peripheral blood mononuclear cells, genotype, and clinical events after cardiac surgery. DESIGN: A case-control study was performed. SETTING: Cardiac intensive care unit in a university hospital. SUBJECTS: A total of 82 patients having elective cardiac surgery were divided into those having uncomplicated recovery (n = 48) or recovery complicated by hyperlactatemia or requirement for inotropic support (n = 34). INTERVENTIONS: The relative change in peripheral blood mononuclear cell tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) messenger RNA 1 and 6 hrs after cardiopulmonary bypass was compared with a baseline preoperative level using quantitative reverse transcriptase polymerase chain reaction. DNA was analyzed for carriage of TNF-alpha and IL-10 polymorphic alleles. MEASUREMENTS AND MAIN RESULTS: Cardiopulmonary bypass was longer in duration in the complicated group. TNF-alpha gene expression decreased and IL-10 gene expression increased in peripheral blood mononuclear cells after surgery when compared with preoperative levels. One hour after cardiopulmonary bypass, the complicated group had more TNF-alpha and less IL-10 messenger RNA production than the uncomplicated group. The IL-10/TNF-alpha ratio was greater in uncomplicated than in complicated recovery patients. An IL-10 haplotype was identified that was less frequent in the complicated group. There was no difference between groups in TNF-alpha genotype. On multivariate analysis, cardiopulmonary bypass time and the IL-10/TNF-alpha messenger RNA ratio were independent predictors of outcome. CONCLUSIONS: There is a predominant anti-inflammatory cytokine response after uneventful cardiac surgery. IL-10 may have a protective role after cardiac surgery.

Brain natriuretic peptide elevation and the development of atrial fibrillation following coronary artery bypass surgery.

The study was designed to determine whether the development of atrial fibrillation is associated with post-operative left ventricular dysfunction and subsequent left atrial stretch. We recruited 133 patients with well preserved pre-operative left ventricular function undergoing bypass surgery. Brain natriuretic peptide was measured at baseline, 24 and 48 h after the onset of cardiopulmonary bypass, and patients were monitored for 72 h after surgery. Atrial fibrillation occurred in 65 patients. Median 48 h brain natriuretic peptide levels were greater in the atrial fibrillation group (440 pg/ml (AF) and 319 pg/ml (non AF) P=0.001). As atrial fibrillation can cause an elevation in brain natriuretic peptide we divided the subjects into early atrial fibrillation (<48 h) and late (>48 h). In those with early atrial fibrillation there was no difference in the 24 h brain natriuretic peptide levels (381 pg/ml and 365 pg/ml P=0.73). In those with late atrial fibrillation the median 48 h brain natriuretic peptide level was greater than in the control group (405 pg/ml and 319 pg/ml, respectively, P=0.02). Brain natriuretic peptide levels rise significantly following bypass surgery. This increase was more evident in those who develop late atrial fibrillation which may suggest a role for atrial stretch in this arrhythmia.

Aging is associated with increased matrix metalloproteinase-2 activity in the human aorta.

BACKGROUND: Aging is a major risk factor for the development of arterial stiffness and vascular disease, and it is related to the upregulation of matrix metalloproteinase-2 (MMP-2) in the aorta of rats and nonhuman primates. This study aimed to determine whether MMP activity in the human vasculature changes with aging. We also assessed regional differences in MMP activity at two locations in the arterial tree, the aorta and the internal mammary artery (IMA). METHODS: Both MMP-2 and MMP-9 activity in the human aorta and IMA were determined by gelatin zymography and were localized within the tissue using in situ zymography. Tissue inhibitor of metalloproteinase-2 (TIMP-2) levels was determined by Western blot. RESULTS: Active MMP-2 (but not pro-MMP-2, pro-MMP-9, or active MMP-9) was positively correlated with age in the human aorta (r = 0.65; P < .001) but not in the IMA. Active MMP-2 and TIMP-2 (but not pro-MMP-2 or pro- or active MMP-9) levels are higher in the aorta than in the IMA (P < .001; P < .05). In the aorta, MMP activity is highest in the intima and is also detectable in the media and adventitia. To a lesser extent, MMP activity is present in all layers of the IMA. CONCLUSIONS: This study demonstrates that age-related MMP-2 upregulation occurs in the human aorta but not in the IMA.

Saphenous vein graft aneurysms; the true, false and ugly!

The reported incidence of minor dilation of reversed saphenous vein grafts used for coronary artery bypass grafting varies up to 14%, however significant aneurysmal dilation is unusual. We report on the findings and management of a series of four patients with reversed saphenous vein graft aneurysms (rSVG). These cases show some of the salient and very unusual features at presentation. rSVGs are usually asymptomatic (12-47%), however they may present with cough, unstable angina or sudden death. One of our cases presented with haemoptysis, which has only been described once previously in association with a rSVG. Diagnosis is usually done with a combination of chest X-ray, ECHO, coronary angiography and CT or MRA. Management options including coil embolisation, covered stenting and surgery are discussed. The histology of these cases exemplifies the varying pathogenesis for true and false aneurysms. Our recommendation remains that rSVGs should be treated surgically, if they show signs of enlargement, or they become symptomatic.

Lactic acidosis after cardiac surgery is associated with polymorphisms in tumor necrosis factor and interleukin 10 genes.

BACKGROUND: Lactic acidosis after cardiac surgery is a manifestation of excess cytokine production. Cytokine-related genetic polymorphisms account for variability in cytokine response and may predispose to the development of lactic acidosis after cardiac surgery. METHODS: Routine postoperative cardiac surgery patients were studied. Lactic acid levels were greater than 4 mmol/L in study patients and less than 4 mmol/L in controls. Polymerase chain reaction-based techniques were used to examine carriage of tumor necrosis factor beta (TNF-beta), TNF G-308A, and interleukin 10 (IL-10) G-1082A alleles. RESULTS: Demographic characteristics and details of surgery were similar for 30 control and 21 study patients. Lactic acid levels after intensive care admission changed over time and were related to both TNF-beta and IL-10 G-1082A polymorphisms. All 4 study patients homozygous for TNF-beta1 and carrying an IL-10-1082A allele developed lactic acidosis (p = 0.02). There was no relation between the rate of epinephrine infusion or duration of cardiopulmonary bypass and lactic acid levels. CONCLUSIONS: Genetic factors have a role in the development of lactic acidosis after cardiac surgery.