Genetic variants of glutamate receptor gene family in Taiwanese Kawasaki disease children with coronary artery aneurysms

Background

Patients with Kawasaki disease (KD), a pediatric systemic vasculitis, may develop coronary artery aneurysm (CAA) as a complication. To investigate the role of glutamate receptors in KD and its CAA development, we performed genetic association studies.

Methods and results

We examined the whole family of glutamate receptors by genetic association studies in a Taiwanese cohort of 262 KD patients. We identified glutamate receptor ionotropic, kainate 1 (GRIK1) as a novel susceptibility locus associated with CAA formation in KD. Statistically significant differences were noted for factors like fever duration, 1st Intravenous immunoglobulin (IVIG) used time (number of days after the first day of fever) and the GRIK1 (rs466013, rs425507, and rs38700) genetic variants. This significant association persisted even after using multivariate regression analysis (Full model: for rs466013: odds ratio =2.12; 95% CI =1.22-3.65; for rs425507: odds ratio =2.16; 95% CI =1.26-3.76; for rs388700: odds ratio =2.16; 95% CI =1.26-3.76).

Conclusions

We demonstrated that GRIK1 polymorphisms are associated CAA formation in KD, even when adjusted for fever duration and IVIG used time, and may also serve as a genetic marker for the CAA formation in KD.

     

<Emphasis Type="Italic">Sorting nexin 24</Emphasis> genetic variation associates with coronary artery aneurysm severity in Kawasaki disease patients

Background

The sorting nexin (SNX) family is involved in endocytosis and protein trafficking and plays multiple roles in various diseases. The role of SNX proteins in Kawasaki disease (KD) is not known. We attempted to test whether genetic SNX variation associates with the risk of coronary artery aneurysm (CAA) formation in KD.

Methods and results

Chi-square tests were used to identify SNX24 genetic variants associated with KD susceptibility and CAA formation in KD; models were adjusted for fever duration and time of first administration of intravenous immunoglobulin. We obtained clinical characteristics and genotypes from KD patients (76 with CAA and 186 without CAA) in a population-based retrospective KD cohort study (n?=?262). Clinical and genetic factors were associated with CAA formation in KD. In addition, endothelial cell inflammation was evaluated. Significant correlation was observed between KD with CAA complications and the rs28891 single-nucleotide polymorphism in SNX24. Patients with CC?+?CT genotypes had lesser CAA complications. In lipopolysaccharide-treated human umbilical vein endothelial cells, siRNA knockdown of SNX24 significantly decreased gene expression of the proinflammatory cytokines IL-1 beta, IL-6, and IL-8.

Conclusions

Polymorphisms in SNX24 may be used as genetic markers for the diagnosis and prognosis of CAA formation in KD.

     

Computation of hemodynamics in the left coronary artery with variable angulations

The purpose of this study was to investigate the hemodynamic effect of variations in the angulations of the left coronary artery, based on simulated and realistic coronary artery models. Twelve models consisting of four realistic and eight simulated coronary artery geometries were generated with the inclusion of left main stem, left anterior descending and left circumflex branches. The simulated models included various coronary artery angulations, namely, 15°, 30°, 45°, 60°, 75°, 90°, 105° and 120°. The realistic coronary angulations were based on selected patient's data with angles ranging from narrow angles of 58° and 73° to wide angles of 110° and 120°. Computational fluid dynamics analysis was performed to simulate realistic physiological conditions that reflect the in vivo cardiac hemodynamics. The wall shear stress, wall shear stress gradient, velocity flow patterns and wall pressure were measured in simulated and realistic models during the cardiac cycle. Our results showed that a disturbed flow pattern was observed in models with wider angulations, and wall pressure was found to reduce when the flow changed from the left main stem to the bifurcated regions, based on simulated and realistic models. A low wall shear stress gradient was demonstrated at left bifurcations with wide angles. There is a direct correlation between coronary angulations and subsequent hemodynamic changes, based on realistic and simulated models. Further studies based on patients with different severities of coronary artery disease are required to verify our results.     

Exaggerated responsiveness to thyrotrophin releasing hormone: a risk factor in women with coronary artery disease.

Thyroid function tests were performed and thyroid antibodies and serum cholesterol concentrations measured in 12 women aged 60 years or under with severe coronary artery disease proved by coronary angiography. This group was compared with 11 women with normal coronary angiography. Ten out of the 12 women with coronary artery disease had an exaggerated response of thyroid stimulating hormone to thyrotrophin releasing hormone compared with two out of 11 controls (p less than 0.008). The mean serum cholesterol concentration was significantly higher in those with coronary artery disease than in the controls. Thyroid antibodies were present in four of those with coronary artery disease and one of the controls. There was no difference in the risk factors for coronary artery disease between the two groups except for cigarette smoking. Eleven out of 12 in the coronary artery disease group smoked cigarettes compared with four out of 11 in the control group (p less than 0.01). Minimal impairment of thyroid function is an important risk factor for coronary artery disease in women.     

Neurological complications of coronary artery bypass graft surgery: six month follow-up study.

As part of a major prospective study of the neurological complications of coronary artery bypass graft surgery patients were reviewed over six months to determine the clinical course and functional impact of early postoperative complications. One hundred and ninety one out of 312 (61%) patients had developed early postoperative disorders. At six months 165 of the 191 patients with early neurological complications were reviewed. Of the 165, 85 still had detectable neurological signs, but these were often minor and of little functional importance. Only 10 patients had neurological disability at six months, and this was major in only four patients, all of whom had suffered major perioperative stroke. No patient with non-disabling neurological complications in hospital became functionally impaired on returning home. Neurological disorders are not a major cause of failure to return to work by six months after coronary artery bypass surgery. Of 139 patients who were of working age and had not returned to work by six months, only four were prevented by neurological injury related to surgery. The long term prognosis for early neurological disorders after coronary artery bypass surgery is usually favourable, except in those patients who have sustained major perioperative stroke.     

Relation between regional function and coronary blood flow reserve in multivessel coronary artery stenosis

In the setting of chronic coronary stenoses, percent wall thickening (%WT) both at rest and during catecholamine stimulation can be abnormal despite normal resting myocardial blood flow (MBF). We hypothesized that this phenomenon is related to abnormal MBF reserve. Accordingly, 15 dogs were studied between 7 and 10 days after placement of Ameroid constrictors around the proximal coronary arteries and their major branches, at a time when collateral development had not yet occurred. %WT and MBF were measured at rest, after 0.56 mg/kg of dipyridamole, and at incremental doses of dobutamine (5-40 microgram. kg(-1). min(-1)). Resting %WT and MBF were normal in all four sham dogs. Resting transmural MBF was normal in all segments in the 11 study dogs, despite reduced (-2 SD of normal) %WT (<30%) in 40 of 82 segments. MBF reserve was reduced (<3) in segments with reduced %WT, and a close coupling was noted between resting %WT and MBF reserve. All segments showed an increase in %WT with dobutamine up to a dose of 20 microgram. kg(-1). min(-1), above which those with abnormal endocardial MBF reserve showed a "biphasic" response. It is concluded that, in the presence of chronic coronary stenoses, abnormalities in resting %WT as well as inducible reduction in %WT during pharmacological stress are related to the degree of abnormal MBF reserve.     

Helicobacter pylori infection and coronary artery disease

The aim of this investigation was to determine the seroprevalence of H. pylori in patients with coronary artery disease (CAD). Patients with coronary artery disease (n = 90) and control group (n = 90) were enrolled into this randomized, multi-centre study. CAD risk factors analyzed included age, male gender, diabetes mellitus, systemic hypertension, cigarette smoking, hypercholesterolemia and socioeconomic status. The results of this study showed a higher seroprevalence of Helicobacter pylori infection in patients with CAD compared to controls (78.8% versus 58.3%, p < 0.05). However, Helicobacter pylori seropositivity was not associated with coronary artery risk factors (smoking, body mass index, diabetes mellitus, hypertension, total cholesterol and socioeconomic status) either in the whole study population or in the patients and control subjects analyzed separately (P > 0.05). Further study are needed to clarify the precise role of Helicobacter pylori infection on the development of coronary artery disease.     

Extensive right coronary artery thrombosis

A 65-year-old man presented with a non-ST-elevation acute coronary syndrome. His medical history was unremarkable. Apart from a brother, who sustained a myocardial infarction at the age of 40, no cardiovascular risk factors were present. Coronary angiography revealed normal left anterior descending and circumflex arteries. The right coronary artery was subtotally occluded with an extensive thrombus running into the posterolateral branch (figures 1A and B). Despite appropriate medical treatment, intermittent chest pain persisted. The patient underwent a percutaneous coronary intervention with mechanical removal of the thrombus by aspiration followed by balloon dilatation.     

Treatment of coronary artery aneurysms by percutaneous sealing with bovine-pericardium-covered stents

The clinical significance of coronary artery aneurysms is briefly discussed. Until recently, surgical excision was the only treatment available. Single-case reports have documented aneurysm exclusion with vein-covered stents using 10 or 11 F. guiding catheters. This paper reports four patients with coronary artery aneurysms which were successfully excluded with the use of a novel pericardium-covered stent which is less invasive and shortens procedure time compared with the use of an autologous vein-grated stent and can be deployed using 8 F. or 9 F. guiding catheters. Short-term (five- to eight-month) clinical follow-up has been event-free in all patients, and in three patients six-month follow-up angiography has shown insignificant luminal loss.     

Arterial end-to-side grafting in coronary artery bypass grafting: the Tector procedure

Background. The current treatment of choice in patients with three-vessel coronary disease is coronary artery bypass grafting. The use of the left internal mammary artery in bypass grafting has shown superior long-term outcomes compared with venous grafting. In our study we assess the safety and feasibility of all-arterial coronary artery bypass graft surgery using the procedure as described by Tector et al. in 2001.Methods. Between June 2001 and February 2007, we studied 133 patients eligible for non-emergency surgical revascularisation. Primary endpoints were death or re-infarction within a 30-day period. Secondary endpoints were the need for emergency coronary surgery, angioplasty and mediastinitis. Long-term follow-up had a mean duration of 33 months postoperatively.Results. All 133 patients were successfully revascularised, 98% with the off-pump technique. In 93% of the patients (n=124) full arterial grafting was achieved using both internal mammary arteries. Thirty-day mortality was 1.5% (n=2), ten re-thoracotomies were performed, one myocardial infarction and one case of mediastinitis were reported. In the next four years six additional patients died. Most of these deaths were due to non-cardiovascular causes. Two patients required angioplasty because of distal bypass graft failure and one for new native coronary artery disease. Conclusion. All-arterial bypass grafting using both internal mammary arteries with the technique as described by Tector is safe and feasible without excess deep sternal wound infections. Late major adverse cardiac events are rare and due to distal graft dysfunction, which can be treated by percutaneous coronary intervention. (Neth Heart J 2010;18:7-11.)     

Economics of coronary artery bypass grafting.

To decide whether the number of operations for coronary artery bypass grafting should be increased, maintained at the present levels, or decreased we need to know how cost effective they are relative to other claimants on the resources of the National Health Service. For this purpose effectiveness is taken to be the effect on life expectancy adjusted for the quality of life. In an assessment of the cost per quality adjusted life year gained coronary artery bypass grafting rates well for cases of severe angina and extensive coronary artery disease. The cost, however, rises sharply for less severe cases. Bypass grafting seems to compare favourably with valve replacement for aortic stenosis and implantation of pacemakers for heart block; it is distinctly better than heart transplantation and the treatment of end stage renal failure but is probably less cost effective than hip replacement. If the number of operations for coronary artery bypass grafting were to increase it would be a fairly strong claimant only if restricted to the most severe cases. The data on which these judgments are based are crude and in need of refinement. The methodology is powerful, far reaching, and open to comment.     

血清尿酸水平与冠心病的相关性研究

目的:众多关于血清尿酸水平与冠心病发展预后的相关性研究结果不一。本研究旨在通过对上海市第一人民医院入院患者的临床资料分析,研究血清尿酸水平与冠心病之间关系。方法:选择2008年7月至2009年4月上海地区、汉族就诊于我院的患者(123例),按入选排除标准,将入院患者分为冠心病组和对照组,分析尿酸水平与冠心病的关系。结果:男性(81.4%vs 51.6%)、吸烟(49.2%vs 21.9%)、血清尿酸水平升高(6.10±1.2 mg/dl vs 5.37±1.5 mg/dl)为冠心病的危险因素,统计值分别为0.02,0.02,0.005。血尿酸水平升高与血管病变严重程度成正相关,除单支血管病变外,双支血管病变患者尿酸水平为(6.11±1.07)mg/dl,对照组为(5.37±1.55)mg/dl,P0.05,三支病变患者尿酸水平为(6.84±1.29)mg/dl,P0.05。结论:血清尿酸水平升高与冠心病的发生、及病变严重程度密切相关。对冠心病患者的预防和治疗中,应重视对尿酸水平的监测。尿酸水平能否作为冠心病患者预后、转归的预测因子以及降低尿酸水平的治疗能否给冠心病患者带来收益有待进一步的研究。     

BMPER-induced BMP signaling promotes coronary artery remodeling

The connection of the coronary vasculature to the aorta is one of the last essential steps of cardiac development. However, little is known about the signaling events that promote normal coronary artery formation. The bone morphogenetic protein (BMP) signaling pathway regulates multiple aspects of endothelial cell biology but has not been specifically implicated in coronary vascular development. BMP signaling is tightly regulated by numerous factors, including BMP-binding endothelial cell precursor-derived regulator (BMPER), which can both promote and repress BMP signaling activity. In the embryonic heart, BMPER expression is limited to the endothelial cells and the endothelial-derived cushions, suggesting that BMPER may play a role in coronary vascular development. Histological analysis of BMPER^−/− embryos at early embryonic stages demonstrates that commencement of coronary plexus differentiation is normal and that endothelial apoptosis and cell proliferation are unaffected in BMPER^−/− embryos compared with wild-type embryos. However, analysis between embryonic days 15.5–17.5 reveals that, in BMPER^−/− embryos, coronary arteries are either atretic or connected distal to the semilunar valves. In vitro tubulogenesis assays indicate that isolated BMPER^−/− endothelial cells have impaired tube formation and migratory ability compared with wild-type endothelial cells, suggesting that these defects may lead to the observed coronary artery anomalies seen in BMPER^−/− embryos. Additionally, recombinant BMPER promotes wild-type ventricular endothelial migration in a dose-dependent manner, with a low concentration promoting and high concentrations inhibiting migration. Together, these results indicate that BMPER-regulated BMP signaling is critical for coronary plexus remodeling and normal coronary artery development.     

Peripheral blood mononuclear cell microRNAs in coronary artery disease

The accuracy of risk prediction for coronary artery disease can be improved with the use of novel molecular or genetic biomarkers. In this study, we investigated the difference of five selected microRNAs (miR or miRNA) in patients with coronary artery disease (CAD) and controls, assessed by coronary angiography. The study population consisted of 85 subjects, aged between 18 and 75 years and underwent invasive coronary angiography. Subjects with more than 30% stenosis in at least one coronary artery, patients with a history of prior percutaneous coronary intervention or coronary by-pass surgery were allocated to the patient group; whereas the subjects without at least 30% stenosis consisted the control group. Groups were similar in age, presence of hypertension, and smoking status. However, the proportion of males and subjects taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta blockers, nitrates, and statins were higher in the patient group. miR-221 and miR-155 were downregulated (P = .02 and .001, respectively), while miR-21 levels were significantly increased (P = .003) in the patient group compared to controls. Changes in miR-145 and miR-126 did not reach statistical significance (P > .05). miRNA- 21, miR-155, and miR-221 were differentially expressed between the patients and controls. miRNAs are promising biomarkers for CAD diagnosis, however, this requires further research with larger groups.     

Shear modulus of porcine coronary artery: contributions of media and adventitia

The epicardial coronary arteries experience significant torsion in the axial direction due to changes in the shape of the heart during the cardiac cycle. The objective of this study was to determine the torsional mechanical properties of the coronary arteries under various circumferential and longitudinal loadings. The coronary artery was treated as a two-layer composite vessel consisting of intima-medial and adventitial layers, and the shear modulus of each layer was determined. Eight porcine hearts were obtained at a local abattoir, and their right coronary and left anterior descending arteries were isolated and tested in vitro with a triaxial torsion machine (inflation, longitudinal stretch, and circumferential twist). After the intact vessel was tested, the adventitia was dissected away, leaving an intact media that was then tested under identical triaxial loading conditions. We proposed a biomechanical analysis to compute the shear modulus of the adventitia from the measured shear moduli of the intact vessel and the media. To validate our predictions, we used four additional hearts in which the shear modulus of the adventitia was measured after dissection of media. Our results show that the shear modulus does not depend on the shear stress or strain but varies linearly with circumferential and longitudinal stresses and in a nonlinear way with the corresponding strains. Furthermore, we found that the shear modulus of the adventitia is larger than that of the intact vessel, which is larger than the vessel media. These results may have important implications for baroreceptor sensitivity, circulation of the vasa vasorum, and coronary dissection.     

Are coronary artery spasm and progressive damage to the heart associated with the hyperventilation syndrome?

A case of coronary artery vasospasm was studied in a man with a four year history of angina. He had evidence of symptomatic hyperventilation during a spontaneous episode of chest pain. When asked to hyperventilate the pain in his chest and ST elevation were reproduced in the same leads as occurred during the spontaneous attack. This may be the first reported case of spontaneous hyperventilation producing vasoconstriction, and the patient''s previous admissions to the coronary care unit may have been associated with coronary vasospasm induced by hyperventilation. When patients with variant angina report pains in the chest in association with dizziness and breathlessness hyperventilation should be considered to be a possible cause of the symptoms. As coronary vasospasm is increasingly implicated in angina after myocardial infarction the role of hyperventilation should be considered more often.     

Apolipoprotein E gene polymorphisms and thrombosis and restenosis after coronary artery stenting

Experimental data support a protective function of apolipoprotein E (apoE) against restenosis, the main factor limiting the long-term benefit of percutaneous coronary interventions. We investigated the possibility that the single nucleotide polymorphisms (SNPs)--219G/T, 113G/C, 334T/C, and 472C/T of the gene encoding apoE (APOE) are associated with the incidence of death and myocardial infarction or restenosis after stenting in coronary arteries. In addition, we asked whether the apoE isotype-related epsilon2/epsilon3/epsilon4 polymorphism, defined by specific allele combinations (haplotypes) of the 334T/C and 472C/T polymorphism, and other APOE haplotypes, derived from all four SNPs investigated, are associated with adverse clinical and angiographic outcomes after stenting. Our study included 1,850 consecutive patients with symptomatic coronary artery disease (CAD) who underwent stent implantation. Follow-up angiography was performed in 1,556 patients (84.1%) at 6 months after the intervention. We found that none of the APOE SNPs is associated with death and myocardial infarction or restenosis after stenting. In addition, we observed no relationship between APOE haplotypes and adverse outcomes. In conclusion, the APOE -219G/T, 113G/C, 334T/C, and 472C/T polymorphisms, either alone or in combination, do not represent genetic markers of the risk of thrombotic and restenotic complications in patients with CAD treated with coronary stenting.     

Smoking and coronary artery disease assessed by routine coronary arteriography.

The association between extent and duration of smoking habit and severity of coronary atheroma was examined in 387 patients undergoing routine coronary ateriography before valve replacement surgery. Total number of cigarettes smoked in life correlated significantly with severity of coronary artery disease (p less than 0.001) and number of coronary arteries with stenoses of 50% or more (p less than 0.001). Severity of coronary artery disease in current smokers was similar to that in former smokers. Multiple regression analysis showed diastolic blood pressure, cigarette consumption, age, ratio of total cholesterol to high density lipoprotein cholesterol, and history of angina to be the important predictors of severity of coronary artery disease. An estimate of the number of cigarettes smoked in life can be useful in identifying patients with coronary artery disease if used in conjunction with data on other important risk factors.     

Clinical implication of coronary tortuosity in patients with coronary artery disease

BackgroundCoronary tortuosity (CT) is a common coronary angiography finding. The exact pathogenesis, clinical implication and long-term prognosis of CT are not fully understood. The purpose of this study is to investigate the clinical characteristics of CT in patients with suspected coronary artery disease(CAD) in a Chinese population.MethodsA total of 1010 consecutive patients underwent coronary angiography with complaints of chest pain or related symptoms were included in the present study (544 male, mean age: 64±11 years). CT was defined by the finding of ≥3 bends (defined as ≥45° change in vessel direction) along main trunk of at least one artery in systole and in diastole. Patients with or without CAD were further divided into CT-positive and CT-negative groups, all patients were followed up for the incidence of major adverse cardiovascular events (MACE) for 2 to 4 years.ResultsThe prevalence of CT was 39.1% in this patient cohort and incidence of CT was significantly higher in female patients than that in male patients (OR = 2.603, 95%CI 1.897, 3.607, P<0.001). CT was positively correlated with essential hypertension (OR = 1.533, 95%CI 1.131, 2.076, P = 0.006) and negatively correlated with CAD (OR = 0.755, 95%CI 0.574, 0.994, P = 0.045). MACE during follow up was similar between CAD patients with or without CT.ConclusionsCT is more often seen in females and positively correlated with hypertension and negatively correlated with coronary atherosclerosis.     

Phagocyte activation in coronary artery disease

Abstract Recent studies suggest that granulocytes (PMNs) play a role in the pathogenesis of acute and chronic myocardial ischemia and extension of myocardial injury. Granulocytes can release a variety of molecules mediating tissue injury which act synergistically with other molecules and cells. The aim of our investigation was to evaluate the granulocyte function in patients affected by coronary artery disease (CAD) and during coronary angioplasty (PTCA). We studied 20 patients suffering from CAD. The PMN's aggregating activity was greater in the coronary sinus than in the aorta ( P <0.01). The increase in aggregating activity was evident in patients who were smokers: their cells release significantly lower quantities of leukotriene C₄ ( P <0.025). In the 20 patients who underwent coronary angioplasty we analyzed superoxide release after stimulation with phorbolmyristate-acetate (PMA). The results showed a greater decrease of PMN's superoxide production in the coronary sinus than in the aorta ( P <0.05). In all patients affected by CAD we evaluated the PMN's expression of CD11b/CD18 membrane integrins. In these patients the increase in expression of CD11b/CD18 was statistically significant in comparison with the controls ( P <0.01). This increase in expression correlates with a higher aggregation (r=0.87, P <0.001). The potential role of leukocytes, oxygen radicals, leukotrienes and granulocyte enzymes in the pathophysiology of myocardial injury due to regional ischemia and reperfusion is an area of intense investigation. This paper presents studies carried out in vivo which have been instrumental in demonstrating the role of granulocytes as mediators of myocardial ischemia.