TRPM2, PDLIM5, BCL3, CD14, GBA Genes as Feasible Markers for Premature Coronary Heart Disease Risk.

Background: Beyond non-genetic risk factors, familial hypercholesterolemia (FH) plays a major role in the development of CHD. FH is a genetic disorder characterized by heritable and severely elevated levels of low-density lipoprotein (LDL) cholesterol, which can lead to premature cardiovascular disease, particularly familial coronary heart disease (FH-CHD). Method: To explore genes indicating a risk of familial (premature) coronary heart disease (FH-CHD) development in FH, 30 Thai male volunteers were enrolled: 7 healthy controls (N), 6 patients with hypercholesterolemia (H), 4 with FH, 10 with CHD, and 3 with FH-CHD. Transcriptome data were investigated using next-generation sequencing analysis in whole blood (n = 3). Genes that were significantly expressed in both FH and FH-CHD, but not in N, H, and CHD groups, were selected and functionally analyzed. Results: The findings revealed that 55 intersecting genes were differentially expressed between FH and FH-CHD groups. Ten of the 55 genes (MAPK14, TRPM2, STARD8, PDLIM5, BCL3, BLOC1S5, GBA, RBMS1, CD14, and CD36 were selected for validation. These 10 genes play potential roles in chronic inflammation and are involved in pathways related to pathogenesis of CHD. Using quantitative real-time PCR, we evaluated the mRNA expression of the selected genes in all 30 volunteers. TRPM2, PDLIM5, BCL3 were significantly upregulated and GBA was significantly downregulated in both FH and FH-CHD compared with the N, H, and CHD groups. Conclusion: our preliminary investigation reveals that the TRPM2, PDLIM5, BCL3, and GBA genes may have potential for further development as predictive markers for FH-CHD.

Interleukin-8 in Hyperlipidemia and Coronary Heart Disease in Thai Patients Taking Statin Cholesterol-Lowering Medication While Undergoing Coronary Artery Bypass Grafting Treatment.

The role of interleukin-8 (IL-8), a pivotal chemokine in atherogenesis and coronary heart disease (CHD) development, is diverse and remains unclear. This cross-sectional study investigates the association of the IL-8 expression in hyperlipidemia (H) and CHD patients who have been treated with statin cholesterol-lowering drugs while undergoing coronary artery bypass grafting treatment. Fifty-five Thai volunteers including 13 normal (N), 24 H, and 18 CHD patients were enrolled for the investigation. All the CHD patients had been treated continuously with statin cholesterol-lowering medications since the disease was diagnosed and were undergoing coronary bypass grafting approximately one month later. Therefore, the CHD group was representative of a pathogenesis improvement in CHD. The IL8 mRNA expression was determined by real-time quantitative PCR in the peripheral blood mononuclear cells from heparinized blood. The plasma IL-8 levels were assessed by enzyme-linked immunosorbent assay. The result shows that the IL8 mRNA expression in the H group tended to increase; however, in the CHD group, there was a significant decrease (p=0.0111) compared to the N group. The IL8 mRNA expression and the plasma levels in the CHD group were significantly lower than those in the H group (p < 0.05). A significant negative correlation between the IL8 mRNA (r = -0.499) or plasma IL-8 (r = -0.3875) expression and CHD progression was observed (p < 0.05). In conclusion, the transcriptomic and the phenotypic IL-8 expression decreased significantly in the Thai CHD patients who had continuously received statin-group medications compared to the H and N group participants. Therefore, IL-8 should serve as a feasible marker and could be used to evaluate the therapeutic effects of statins and illustrate the pathology of CHD treatment.

PPBP and DEFA1/DEFA3 genes in hyperlipidaemia as feasible synergistic inflammatory biomarkers for coronary heart disease.

BACKGROUND: Coronary heart disease (CHD) is an important complication of atherosclerosis. Biomarkers, which associate with CHD development, are potential to predict CHD risk. To determine whether genes showing altered expression in hyperlipidaemia (H) and coronary heart disease (CHD) patients compared with controls could be CHD risk biomarkers. METHODS: Control, H, and CHD groups represented atherosclerosis to CHD development. Gene profiling was investigated in peripheral blood mononuclear cells using DNA microarrays. Eight selected genes expressed only in H and CHD groups were validated by real-time quantitative reverse transcription PCR and plasma protein determination. RESULTS: α-defensin (DEFA1/DEFA3), pro-platelet basic protein (PPBP), and beta and alpha2 hemoglobin mRNA expression was significantly increased in H and CHD groups compared with controls, but only plasma PPBP and α-defensin proteins were correspondingly increased. CONCLUSION: PPBP and DEFA1/DEFA3 could be potential CHD biomarkers in Thai hyperlipidaemia patients.

Increased alpha-defensin expression is associated with risk of coronary heart disease: a feasible predictive inflammatory biomarker of coronary heart disease in hyperlipidemia patients.

BACKGROUND: Atherosclerosis is a multifactorial disorder of the heart vessels that develops over decades, coupling inflammatory mechanisms and elevated total cholesterol levels under the influence of genetic and environmental factors. Without effective intervention, atherosclerosis consequently causes coronary heart disease (CHD), which leads to increased risk of sudden death. Polymorphonuclear neutrophils play a pivotal role in inflammation and atherogenesis. Human neutrophil peptides (HNPs) or alpha (α)-defensins are cysteine-rich cation polypeptides that are produced and released from activated polymorphonuclear neutrophil granules during septic inflammation and acute coronary vascular disorders. HNPs cause endothelial cell dysfunction during early atherogenesis. In this cross-sectional study, control, hyperlipidemia and CHD groups were representative as atherosclerosis development and CHD complications. We aimed to assess the correlation between α-defensin expression and the development of CHD, and whether it was a useful predictive indicator for CHD risk. METHODS: First, DNA microarray analysis was performed on peripheral blood mononuclear cells (PBMCs) from Thai control, hyperlipidemia and CHD male patients (n = 7). Gene expression profiling revealed eight up-regulated genes common between hyperlipidemia and CHD patients, but not controls. We sought to verify and compare α-defensin expression among the groups using: 1) real-time quantitative RT-PCR (qRT-PCR) to determine α-defensin mRNA expression (n = 10), and 2) enzyme-linked immunosorbent assay to determine plasma HNP 1-3 levels (n = 17). Statistically significant differences and correlations between groups were determined by the Mann-Whitney U test or the Kruskal-Wallis test, and the Rho-Spearman correlation, respectively. RESULTS: We found that α-defensin mRNA expression increased (mean 2-fold change) in the hyperlipidemia (p = 0.043) and CHD patients (p = 0.05) compared with the controls. CHD development moderately correlated with α-defensin mRNA expression (r = 0.429, p = 0.023) and with plasma HNP 1-3 levels (r = 0.486, p = 0.000). CONCLUSIONS: Increased α-defensin expression is a potential inflammatory marker that may predict the risk of CHD development in Thai hyperlipidemia patients.

Phenotypic alterations in human saphenous vein culture induced by tumor necrosis factor-alpha and lipoproteins: a preliminary development of an initial atherosclerotic plaque model.

BACKGROUND: Atherosclerosis is a chronic progressive inflammatory disease of blood vessels particularly the arteries. The development of atherosclerotic plaques or atherogenesis is a complex process that is influenced by cardiovascular risk factors such as vascular inflammation and dyslipidemia. This study demonstrates the ability of tumor necrosis factor-alpha (TNF-α) and low density lipoproteins (LDL) to induce atherosclerotic plaque in human saphenous vein (HSV) organ culture. METHODS: Normal HSV segments, from male patients who had coronary bypass graft, were cultured in DMEM containing 5% heat inactivated fetal bovine serum. TNF-α (5 ng/ml) was applied in combination with native LDL (nLDL) or oxidized LDL (oxLDL) at the dose of 50 µg/ml for 14 days. The phenotypic changes of the organ cultures characteristic of initial atherosclerotic plaques were evaluated. The effect of anti-atherogenic agent, 17-ß estradiol (E2), was also determined. RESULTS: Histologic, histomorphometric, and immunohistochemical examinations revealed that HSV rings stimulated with TNF-α + nLDL or TNF-α + oxLDL can exhibit the essential morphological features of atherogenesis, including fibrous cap formation, cholesterol clefts, evident thickening of the intimal layer, increased proliferation of smooth muscle cells (SMC) and migration to the subendothelial layer, significant SMC foam cell formation, and increased expression of adhesion molecules in the vascular wall. Addition of E2 (50 nM) to the culture significantly modulated the critical changes. Consistently, mRNA profiling of the HSV model revealed that 50 of 84 genes of atherosclerosis were up-regulated. CONCLUSIONS: Phenotypic changes characteristic of the initial development of atherosclerotic plaques can be induced in HSV organ culture.

Stentless aortic valve reoperations: a surgical challenge.

BACKGROUND: Stentless aortic valve reoperations may become more common as these bioprostheses reach the limits of their durability. Relatively few studies have examined stentless valve reoperation, and we therefore reviewed our results for these procedures. METHODS: All patients with stentless valves undergoing redo aortic valve replacement (AVR) at our institution were examined (n = 57). Ten patients had a prior Freestyle valve (Medtronic, Minneapolis, MN), and 47 patients had a Toronto stentless porcine valve (SPV; St. Jude Medical St Paul, MN). RESULTS: Redo AVR was performed 8.4 +/- 3.7 years (range, 0.1 to 16.5 years) after stentless valve implantation. Reoperations were elective in 27 patients (49%), and 30 (51%) underwent urgent or emergency procedures. The indication for redo AVR was structural valve dysfunction in 48 patients (84%), acute endocarditis in 7 (12%), and other in 2 (4%). Aortic insufficiency was present in 47 patients (82%). A total of 36 aortic root replacement operations (63% of patients) were required, of which 19 were secondary to severe adhesions between the stentless valve and the native aortic root. Operative mortality was 11% (n = 6) for the entire group. Mortality was higher in patients undergoing redo AVR less than 1 year after stentless valve implantation versus more than 1 year (67% versus 7%, p = 0.03). Long-term survival at 5 years postoperatively was 79% +/- 7% in all patients, and 81% of survivors were in New York Heart Association class I or II. CONCLUSIONS: Reoperation after stentless AVR is a challenging procedure that frequently requires aortic root replacement. Stentless valve reoperation is associated with an increased risk of death, particularly in patients operated on within 1 year of implantation.

Aortic and mitral prosthetic valve replacement in age groups 61-65 & 66-70 years.

Prosthesis choice for aortic and mitral valve replacements in patients aged 61-70 years is difficult. We evaluated prostheses in age groups 61-65 and 66-70 years. Freedom from major thromboembolism and hemorrhage was greater for bioprostheses than mechanical prostheses in both age groups after aortic valve replacement, but only in the younger age group after mitral valve replacement. Freedom from valve-related re-operation was greater after mitral valve replacement with mechanical prostheses in both age groups, but no difference after aortic valve replacement. Valve type was predictive of major thromboembolism and hemorrhage, except in older patients undergoing mitral valve replacement. Bioprostheses are favored for aortic valve replacement in both age groups, but the risk of re-operation with a bioprosthesis in the mitral position in patients aged 61-65 years favors a mechanical prosthesis. Prosthesis choice is less definite in those aged 66-70 years.

Cell transplantation improves ventricular function after a myocardial infarction: a preclinical study of human unrestricted somatic stem cells in a porcine model.

BACKGROUND: Cell transplantation offers the promise in the restoration of ventricular function after an extensive myocardial infarction, but the optimal cell type remains controversial. Human unrestricted somatic stem cells (USSCs) isolated from umbilical cord blood have great potential to differentiate into myogenic cells and induce angiogenesis. The present study evaluated the effect of USSCs on myocardial regeneration and improvement of heart function after myocardial infarction in a porcine model. METHOD AND RESULTS: The distal left anterior descending artery of Yorkshire pigs (30 to 35 kg) was occluded by endovascular implantation of a coil. Four weeks after infarction, single-photon emission computed tomography technetium 99m sestamibi scans (MIBI) and echocardiography were performed. USSCs (100 x 10(6)) or culture media were then directly injected into the infarcted region (n=8 per group). Pigs were immunosuppressed by daily administration of cyclosporin A. At 4 weeks after transplantation, MIBI and echocardiography were repeated and heart function was also assessed with a pressure-volume catheter. The infarcted myocardium and implanted cells were studied histologically. MIBI showed improved regional perfusion (P<0.05) and wall motion (P<0.05) of the infarct region in the transplant group compared with the control. Ejection fraction evaluated by both MIBI and echocardiography decreased in the control group but increased in the transplant group (P<0.01). Scar thickness of the transplant group was higher than the control. The grafted cells were detected 4 weeks after transplantation by both immunohistochemistry and in situ hybridization. CONCLUSIONS: Engrafted USSCs were detected in the infarct region 4 weeks after cell transplantation, and the implanted cells improved regional and global function of the porcine heart after a myocardial infarction. This study suggests that the USSC implantation will be efficacious for cellular cardiomyoplasty.

Performance of bioprostheses and mechanical prostheses in age group 61-70 years.

BACKGROUND AND AIM OF THE STUDY: The performance of bioprostheses (BP) and mechanical prostheses (MP) from valve-related composites of complications and combined major thromboembolism and hemorrhage were considered in order to facilitate decision-making for the patient age group of 61-70 years. METHODS: The aortic valve replacement (AVR) population (BP, n = 619; MP, n = 303) was differentiated by age, concomitant coronary artery bypass, diabetes mellitus, chronic obstructive pulmonary disease (COPD) and preoperative renal failure. The mitral valve replacement (MVR) population (BP, n = 353; MP, n = 312) was differentiated by valve type, age, concomitant coronary artery bypass, ejection fraction, NYHA and preoperative renal failure. RESULTS: Actual freedom from reoperation for AVR was 92.1 +/- 1.5% for BP and 98.7 +/- 6.6% for MP, and for MVR was 74.5 +/- 2.6% for BP and 93.8 +/- 2.2% (12 years) for MP. Actual freedom from major thromboembolism and hemorrhage for AVR was 85.1 +/- 1.7% for BP and 76.9 +/- 3.6% for MP, and for MVR was 82.7 +/- 2.4% for BP and 76.7 +/- 3.8% (12 years) for MP. Linearized rates were undifferentiated for major thromboembolism. The hemorrhage rate for AVR-BP was 0.55%/pt-yr and for AVR-MP was 2.3%/pt-yr (p < 0.0001); for MVR-BP, the rate was 0.69%/pt-yr and for MVR-MP was 1.85%/pt-yr (p = 0.0011). The only predictor of AVR reoperation was age, and predictors for MVR reoperation were prosthesis type and follow up NYHA class. Predictors of AVR major thromboembolism and hemorrhage were prosthesis type, age, diabetes mellitus and COPD. There were no predictors of MVR major thromboembolism and hemorrhage. CONCLUSION: For the age group of 61-70 years, MP are recommended for MVR to protect from BP reoperation, whilst for AVR BP are recommended to protect from anticoagulant hemorrhage. Freedom from reoperation for AVR was undifferentiated for BP and MP at 12-15 years.

The effects of steroids on the occurrence of postoperative atrial fibrillation after coronary artery bypass grafting surgery: a prospective randomized trial.

OBJECTIVE: Atrial fibrillation remains one of the most common postoperative complications of coronary artery bypass grafting. Despite many clinical studies, there is still no consensus regarding the best prevention strategy for atrial arrhythmia. A randomized, double-blind, placebo-controlled trial was conducted to determine the effect of steroids on the occurrence of atrial fibrillation after elective coronary artery bypass grafting. METHODS: Eighty-eight consecutive patients were prospectively entered in this study. No patient had documented or suspected arrhythmias before surgery. Forty-three patients received 1 g of methylprednisolone before surgery and 4 mg of dexamethasone every 6 hours for 1 day after surgery, and 43 patients received only placebo. The primary end point was the overall occurrence of postoperative atrial fibrillation. RESULTS: Postoperative atrial fibrillation occurred in 9 (21%) of the 43 patients in the steroid group, as compared with 22 (51%) of the 43 patients in the placebo group ( P = .003). Minor postoperative complications occurred in 15 steroid patients (35%) and in 6 patients (14%) receiving placebo ( P = .01). Major complications occurred in 4 patients who received steroids (9%) and in 2 patients (5%) who received placebo ( P = .68; for all complications, P = .05). CONCLUSIONS: Prophylactic short-term steroid administration in patients undergoing coronary artery bypass grafting significantly reduced postoperative atrial fibrillation. In this study, there was no significant difference between the steroid group and the placebo group with regard to the length of hospital stay; however, the steroid group had more complications, which may contribute to prolonged hospitalization.

Reducing cerebral emboli during cardiopulmonary bypass.

Neurologic injury is a common complication of cardiac surgery and is associated with significant morbidity, mortality, and resource utilization. The incidence varies widely according to the definition used, patient age, and complexity of surgery. The manifestations of neurologic injury are broad, ranging from subtle neurocognitive dysfunction to frank stroke. An increasing amount of evidence points to cerebral embolization during cardiopulmonary bypass (CPB) as the principal etiologic factor of these neurologic complications. Cerebral emboli may be composed of atherosclerotic debris, calcium, air, fat, platelet thrombi, or CPB tubing. Advancements in perfusion technology, CPB techniques and surgical strategies may lead to a reduction in neurologic injury during cardiac surgery. In the current paper, we discuss the pathophysiology of neurologic injury after cardiac surgery and methods of reducing cerebral embolization. Reducing emboli and neurologic injury during CPB requires a multidisciplinary approach that includes several simple diagnostic and therapeutic strategies. Reducing cerebral emboli should be a major goal for future research in the fields of cardiac anesthesia, surgery and perfusion.