Gender-specific correlation between plasma myeloperoxidase levels and serum high-density lipoprotein-associated paraoxonase-1 levels in patients with stable and unstable coronary artery disease.

OBJECTIVE: Low high-density lipoprotein (HDL) cholesterol is well-established as a negative risk factor for coronary artery disease (CAD) and its anti-oxidant property has been attributed mainly to the HDL-bound enzyme paraoxonase-1 (PON-1). Recently, myeloperoxidase (MPO), a pro-oxidant enzyme released from activated neutrophils, has been shown to alter the atheroprotective function of HDL to a dysfunctional form. This study investigated the relationship between plasma MPO and serum PON-1 levels in patients with stable (SAP) and unstable angina pectoris (UAP). METHODS: Plasma MPO levels and serum PON-1 concentration/activity were measured in patients with SAP (n = 226), UAP (n = 151) and in control subjects (n = 99). RESULTS: Plasma MPO levels in UAP patients were significantly higher than those in SAP patients or in control subjects (UAP, 21.6[16.7-44.6]; SAP, 19.3[15.7-29.1]; control, 15.9[14.7-18.7] ng/mL; P < 0.0001). Serum PON-1 concentrations in UAP and SAP patients were significantly lower than those in control subjects (UAP, 55.6[45.9-69.7]; SAP, 55.0[46.9-64.9]; control, 62.5[51.1-78.8] µg/mL; P = 0.0002). Plasma MPO levels showed a weak inverse correlation with serum PON-1 concentrations in all subjects (R = -0.163, P < 0.0005). Moreover, in women, plasma MPO levels showed a significant inverse correlation with serum PON-1 concentrations and PON-arylesterase activity in SAP (concentration: R = -0.537, P < 0.0001; arylesterase-activity: R = -0.469, P < 0.001) and UAP (concentration: R = -0.340, P < 0.05; arylesterase-activity: R = -0.350, P < 0.05) patients, but not in men. CONCLUSION: This study demonstrates that plasma MPO levels have a significant inverse correlation with PON-1 levels, especially in women, in SAP and UAP patients, and suggests that an imbalance between pro-oxidants and anti-oxidants may contribute to the progression of coronary plaque instability.

Association between hemoglobin scavenger receptor and heme oxygenase-1-related anti-inflammatory mediators in human coronary stable and unstable plaques.

Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that is induced by intraplaque hemorrhage and degrades free heme and releases ferrous iron, which is rapidly sequestered by ferritin. In vitro studies have shown that binding of hemoglobin to hemoglobin scavenger receptor (CD163) induces HO-1 and the anti-inflammatory mediator interleukin (IL)-10. We immunohistochemically examined the relationship between CD163 expression in macrophages and intraplaque hemorrhage, HO-1, IL-10, and ferritin using coronary atherectomy specimens from patients with stable (SAP) or unstable angina pectoris (UAP). A total of 67 patients underwent atherectomy for SAP (n = 33) or UAP (n = 34). Samples were stained with antibodies against smooth muscle cells, macrophages, glycophorin-A (a protein specific to erythrocyte membranes), CD163, HO-1, IL-10, and ferritin. To identify cell types of HO-1-positive cells, double immunostaining was also performed. Double immunostaining for HO-1 and macrophages revealed that the vast majority of HO-1-positive cells were macrophages. Morphometric analysis demonstrated that CD163-positive macrophage score and the percentage of glycophorin-A-, HO-1-, IL-10-, and ferritin-positive areas were significantly higher in UAP than in SAP patients (CD163, P < .005; glycophorin-A, P < .0001; HO-1, P < .0001; IL-10, P < .005; ferritin, P = .0001). Moreover, CD163-positive macrophage score was positively associated with the percentage of glycophorin-A-, HO-1-, IL-10-, and ferritin-positive areas (glycophorin-A, r = 0.60, P < .0001; HO-1, r = 0.67, P < .0001; IL-10, r = 0.45, P < .0005; ferritin, r = 0.61, P < .0001). These findings suggest that enhanced expression of HO-1 and HO-1-related atheroprotective molecules plays an important role in exerting anti-inflammatory, antioxidant, and scavenging functions, which could contribute to plaque stabilization.

Positive association between plasma levels of oxidized low-density lipoprotein and myeloperoxidase after hemodialysis in patients with diabetic end-stage renal disease.

End-stage renal disease (ESRD) patients undergoing hemodialysis (HD) have a high prevalence of cardiovascular events. Low-density lipoprotein (LDL) in dialysis patients has been shown to be susceptible to in vitro peroxidation; therefore, oxidized-LDL (ox-LDL) could be generated in these patients. Moreover, myeloperoxidase (MPO) released from activated neutrophils may play a role in the induction of LDL oxidation. The purpose of this study was to investigate the relationship between plasma ox-LDL levels, plasma MPO levels, and serum high-sensitivity C-reactive protein (hs-CRP) levels during initial HD in patients with diabetic ESRD. Patients (n=28) had serial venous blood samples drawn before and after HD at the initial, second, and third sessions. Plasma ox-LDL levels were measured using a specific monoclonal antibody (DLH3), and plasma MPO levels were measured using an enzyme-linked immunosorbent assay kit. Plasma ox-LDL levels and MPO levels after a single HD session increased significantly (ox-LDL, P<0.005; MPO, P<0.0001) compared with levels before that HD session. However, the increase was transient since the levels returned to pre-HD session levels. Additionally, plasma MPO levels showed a positive correlation with plasma ox-LDL levels during HD (R=0.62, P=0.0029). No significant change was observed in serum hs-CRP levels before and after each HD session. This study demonstrates that plasma MPO levels are directly associated with plasma ox-LDL levels in diabetic ESRD patients during initial HD. These findings suggest a pivotal role for MPO and ox-LDL in the progression and acceleration of atherosclerosis in patients undergoing HD.

Relationship of thrombus characteristics to the incidence of angiographically visible distal embolization in patients with ST-segment elevation myocardial infarction treated with thrombus aspiration.

OBJECTIVES: This study sought to investigate the association between pathological characteristics of aspirated intracoronary thrombi and the incidence of angiographically visible distal embolization (AVDE) during primary percutaneous coronary intervention (p-PCI) in patients with ST-segment elevation myocardial infarction (STEMI) treated with thrombus aspiration. BACKGROUND: AVDE of atherosclerotic and thrombotic material has been shown to impair myocardial perfusion and contribute to poor clinical outcome in patients with STEMI. Recent studies have shown that thrombus composition and size are associated with the incidence of AVDE. METHODS: Aspirated thrombi from 164 STEMI patients within 12 h of symptom onset were investigated immunohistochemically using antibodies against platelets, erythrocytes, and inflammatory cells. RESULTS: The angiographic results showed that AVDE during p-PCI occurred in 22 (13.4%) patients. Pathological analysis revealed that thrombi from patients with AVDE had a greater erythrocyte-positive area (60 ± 15% vs. 43 ± 21%, p < 0.0005) and more myeloperoxidase-positive cells (943 ± 324 cells/mm(2) vs. 592 ± 419 cells/mm(2), p < 0.0005) than those from patients without AVDE. Thrombus size, quantified as the thrombus surface area, was positively correlated with the erythrocyte component (r = 0.362, p < 0.0001). Moreover, multivariate logistic analysis demonstrated that erythrocyte-positive area in the thrombi, glucose levels on admission, larger vessel diameter (≥ 3.5 mm), and pre-balloon dilation were independent predictors of the incidence of AVDE. CONCLUSIONS: This study demonstrated that the erythrocyte-rich component of aspirated thrombi may be associated with the incidence of AVDE during p-PCI in patients with STEMI.

Erythrocyte-rich thrombus aspirated from patients with ST-elevation myocardial infarction: association with oxidative stress and its impact on myocardial reperfusion.

AIMS: Recent studies have demonstrated that erythrocytes are a potential component in atheromatous lesions and thrombus formation in patients with ST-elevation myocardial infarction (STEMI). The purpose of this study was to determine the associations of red blood cell (RBC) component of coronary thrombi with oxidative stress and myocardial reperfusion. METHODS AND RESULTS: Aspirated thrombi from 178 STEMI patients within 12 h of symptom onset were investigated immunohistochemically using antibodies against platelets, RBCs, fibrin, macrophages, and neutrophils [myeloperoxidase (MPO)]. The thrombi were divided into tertiles according to the percentage of glycophorin-A-positive area: low (glycophorin-A-positive area <33%; n = 60), intermediate (<54 to 33%; n = 59), and high group (≥54%; n = 59). We also measured plasma MPO levels on admission. In the thrombi, the number of MPO-positive cells in the high-RBC group was significantly greater than that in the low-RBC group (high, 927 ± 385; intermediate, 765 ± 406; low, 279 ± 220 cells/mm(2); P< 0.0001). Plasma MPO levels were significantly higher in the high-RBC group than that in the low-RBC group [low 43.1 (25.0-71.6); intermediate 71.0 (32.9-111.2); high 74.3 (31.1-126.4)ng/mL; P< 0.005]. Distal embolization occurred more frequently in the high-RBC group (P= 0.0009). Moreover, the signs of impaired myocardial reperfusion, as indicated by incomplete ST-segment resolution (STR) and lower myocardial blush grades (MBG), and progression of left ventricular remodelling at 6 months were frequently observed in the high-RBC group (high vs. low: STR, P= 0.056; MBG, P< 0.01; remodelling, P< 0.01). CONCLUSION: The present study demonstrated that erythrocyte-rich thrombi contain more inflammatory cells and reflect high thrombus burden, leading to impaired myocardial reperfusion in STEMI patients.

Two cases of cardiac arteriovenous malformation complicated by a local angioproliferative process.

Vascular malformations of the heart are extremely rare with only a few cases of the arteriovenous type of vascular malformation (AVM) reported. We investigated the pathology of two additional cases, which were complicated by the occurrence of a local vasoproliferative response of immature but benign vessels. We suppose that the mass forming effect of this vasoproliferative response, which has also been reported recently as a complication of congenital AVM elsewhere in the body, has significantly contributed to the onset of symptoms and ultimate death of both patients.

Relation of elevated levels of plasma myeloperoxidase to impaired myocardial microcirculation after reperfusion in patients with acute myocardial infarction.

Previous studies have shown that oxidative stress and endothelial dysfunction are related to impaired myocardial microcirculation after reperfusion. Moreover, elevated myeloperoxidase (MPO) levels are associated with endothelial dysfunction. Plasma MPO levels were measured in patients with ST-segment elevation acute myocardial infarction (n = 160) who had undergone percutaneous coronary stenting within 12 hours of symptom onset. We investigated whether the plasma MPO level at admission was associated with impaired myocardial microcirculation, as indicated by ST-segment resolution and myocardial blush grade after reperfusion, and left ventricular ejection fraction and remodeling at 6 months. The patients were divided into 2 groups according to the median MPO value for the entire cohort (low-MPO group < or =50 ng/ml, n = 80; high-MPO group >50 ng/ml, n = 80). ST-segment resolution and the myocardial blush grade were significantly lower in the high-MPO than in the low-MPO group (48 +/- 27% vs 61 +/- 24%, p <0.005; and 2.1 +/- 0.8 vs 2.4 +/- 0.7, p <0.01; respectively). Moreover, the percentage of increase in the left ventricular end-diastolic volume index was significantly greater and the left ventricular ejection fraction at 6 months was significantly lower in the high-MPO group than in the low-MPO group (8.2 +/- 24.7% vs -1.9 +/- 23.5%, p <0.05; and 46 +/- 9% vs 54 +/- 9%, p <0.0001, respectively). Multiple regression analysis showed that the plasma MPO level was an independent predictor of incomplete ST-segment resolution (odds ratio 6.94, 95% confidence interval 2.10 to 22.9, p = 0.0015). In conclusion, elevated plasma MPO levels at admission were associated with impaired myocardial microcirculation after reperfusion in patients with acute myocardial infarction.

Elevated levels of neopterin are associated with carotid plaques with complex morphology in patients with stable angina pectoris.

OBJECTIVE: Neopterin is an activation marker for monocytes/macrophages, and circulating levels of neopterin are elevated in patients with coronary complex lesions in unstable angina pectoris. We investigated the possible association between neopterin and complex carotid plaques which may be associated with the risk of ischemic stroke in patients with stable angina pectoris (SAP). METHODS: We measured plasma levels of neopterin in 102 patients with SAP and carotid ultrasound was performed for evaluation of the presence of carotid plaques and plaque surface characteristics categorized as complex or noncomplex. In addition, endarterectomy specimens of extracranial high-grade carotid stenosis with complex plaques from five patients with SAP were immunohistochemically examined with antibodies to smooth muscle cells, endothelial cells, platelets, macrophages, and T cells. RESULTS: Plasma neopterin levels were significantly higher in patients with complex carotid plaques than in those with noncomplex plaques (median [interquartile range]: 24.2 [19.2-39.3]nmol/L vs. 19.4 [11.9-25.1]nmol/L; P=0.01) or without any plaques (18.8 [14.9-23.6]nmol/L; P=0.001). On multivariate logistic analyses after adjustment for traditional atherosclerotic risk factors, multi-vessel coronary disease and high sensitivity C-reactive protein, neopterin levels were independently associated with the presence of complex carotid plaques (adjusted OR 2.21 per SD increase, 95%CI 1.13-4.33, P=0.02). Immunohistochemical staining revealed abundant neopterin-positive macrophages in carotid complex lesions. CONCLUSION: These findings demonstrate that carotid plaques with complex morphology have increased circulating neopterin levels and immunohistochemical localization of neopterin in patients with SAP. Neopterin can be considered an important biomarker of plaque destabilization in carotid artery atherosclerotic lesions in this population.

Enhanced expression of haemoglobin scavenger receptor in accumulated macrophages of culprit lesions in acute coronary syndromes.

AIMS: Effective clearance of extracellular haemoglobin (Hb) is thought to limit systemic oxidative heme toxicity, which is presumed to contribute to the pathogenesis of plaque instability. We immunohistochemically examined the relationship between intraplaque haemorrhage, 4-HNE (4-hydroxy-2-nonenal), an index of lipid peroxidation, and the Hb scavenger receptor (CD163), using coronary atherectomy specimens from 74 patients with stable angina pectoris (SAP, n = 39) or unstable angina pectoris (UAP, n = 35). METHODS AND RESULTS: Atherectomy samples were stained with antibodies against glycophorin A (a protein specific to erythrocyte membranes), CD31, 4-HNE, and CD163. Quantitative analysis demonstrated that glycophorin A-positive areas, 4-HNE-positive macrophage score, and CD163-positive macrophage score in UAP patients were significantly higher (glycophorin A, P < 0.0001; 4-HNE-positive macrophage score, P < 0.0001; CD163-positive macrophage score, P < 0.0005) than in SAP patients. The percentage of the glycophorin A-positive area showed a significant positive correlation with the number of CD31-positive microvessels and the 4-HNE-positive macrophage score (microvessels, R = 0.59, P < 0.0001; 4-HNE, R = 0.59, P < 0.0001). Moreover, the CD163-positive macrophage score was positively correlated with glycophorin A-positive area and the 4-HNE-positive macrophage score (glycophorin A, R = 0.58, P < 0.0001; 4-HNE, R = 0.53, P < 0.0001). CONCLUSION: These findings suggest a positive association among intraplaque haemorrhage, enhanced expression of Hb scavenger receptor, and lipid peroxidation in human unstable plaques.

Mild inflammatory activation of mammary arteries in patients with acute coronary syndromes.

Acute coronary syndromes (ACS) are characterized by multiple unstable coronary plaques and elevated circulating levels of inflammatory biomarkers. The endothelium of internal mammary arteries (IMA), which are atherosclerosis resistant, is exposed to proinflammatory stimuli as vessels that develop atherosclerosis. Our study investigated the IMA endothelial expression of inflammatory molecules in patients with ACS or chronic stable angina (CSA). IMA demonstrated normal morphology, intact endothelial lining, and strong immunoreactivity for glucose transporter 1. E-selectin expression was observed more frequently in IMA of ACS patiention than CSA patients (ACS 61% vs. CSA 14%, P = 0.01). High fluorescence for major histocompatibility complex (MHC) was significantly more frequent on the luminal endothelium (ACS 66.7% vs. CSA 17.6%, P = 0.001 for class I; and ACS 66.7% vs. CSA 6.2%, P = 0.0003 for class II-DR) and on the vasa vasorum (ACS 92.9% vs. CSA 33.3% and 7.7%, P = 0.0007 and P < 0.0001 for class I and class II-DR, respectively) of ACS patients than CSA patients. ICAM-1, VCAM-1, Toll-like receptor 4, tissue factor, IL-6, inducible nitric oxide synthase, and TNF-alpha expression were not significantly different in ACS and CSA. Circulating C-reactive protein [ACS 4.8 (2.6-7.3) mg/l vs. CSA 1.8 (0.6-3.5) mg/l, P = 0.01] and IL-6 [ACS 4.0 (2.6-5.5) pg/ml vs. CSA 1.7 (1.4-4.0) pg/ml, P = 0.02] were higher in ACS than CSA, without a correlation with IMA inflammation. The higher E-selectin, MHC class I and MHC class II-DR on the endothelium and vasa vasorum of IMA from ACS patients suggests a mild, endothelial inflammatory activation in ACS, which can be unrelated to the presence of atherosclerotic coronary lesions. These findings indicated IMA as active vessels in coronary syndromes.

Nodoventricular accessory pathways in PRKAG2-dependent familial preexcitation syndrome reveal a disorder in cardiac development.

BACKGROUND: Familial preexcitation syndrome is linked to mutations in PRKAG2. Previous studies on the R302Q mutation have provided evidence for a remarkably high proportion of otherwise rare accessory pathways with atrioventricular (AV) node-like conduction properties (Mahaim fibers). Yet, histopathologic proof is still lacking. We aimed to provide such proof. METHODS AND RESULTS: We retrospectively studied the medical records of 17 members of a 5-generation family. Five subjects died prematurely. The R302Q mutation was found in 8 living subjects and 2 deceased subjects (obligate carriers). Cardiac hypertrophy was found in 7 mutation carriers. ECGs compatible with preexcitation were found in 13 subjects and AV block at varying degrees in 5 subjects. All mutation carriers had electrocardiographic evidence of preexcitation, AV block, or both. Three individuals had high-grade AV block with preexcited conducted beats. Electrophysiological studies in 3 individuals revealed bypasses with AV node-like properties. Histopathologic studies of 1 suddenly deceased mutation carrier revealed concentric hypertrophy of the left ventricle with extensive myocardial disarray associated with slight interstitial fibrosis but no lysosomal-bound glycogen. Moreover, there were 3 small nodoventricular tracts (Mahaim fibers) passing through the central fibrous body and connecting the AV node with the working myocardium of the interventricular septum. CONCLUSIONS: Preexcitation associated with the R302Q mutation in PRKAG2 is associated with Mahaim fibers. These findings support the novel insight that PRKAG2 may be involved in the development of the cardiac conduction system.

Anatomy of the aortic valvar complex and its implications for transcatheter implantation of the aortic valve.

The books and articles devoted to the anatomy of the aortic valvar complex are numerous. Until now, however, little consideration has been given to understanding the anatomy with percutaneous valvar replacement in mind. It is axiomatic that knowledge of the anatomy of the valve is fundamental in understanding key principles involved in valvar replacement.Such an appreciation of the anatomy helps better understand the optimal positioning for the prosthetic valve within the root of the aorta with respect to the coronary arteries, mitral valve, and the conduction system and may circumvent complications that can arise during its implantation [corrected] In this review, therefore, we describe the anatomy of the trifoliate aortic valvar complex and its implications for percutaneous valvar replacement.

Retrograde slow pathway conduction in patients with atrioventricular nodal re-entrant tachycardia.

AIMS: To study retrograde slow pathway conduction by means of right- and left-sided septal mapping. METHODS AND RESULTS: Nineteen patients with slow-fast atrioventricular nodal re-entrant tachycardia (AVNRT) were studied before and after slow pathway ablation. Simultaneous His bundle recordings from right and left sides of the septum, using trans-aortic and trans-septal electrodes, were made during right ventricular pacing. Pre-ablation, decremental retrograde ventriculo-atrial (VA) conduction without jumps or discontinuities was recorded in eight patients (group 1). In six patients, retrograde conduction jumps were demonstrated (group 2) and in the remaining four patients, there was minimal prolongation of stimulus to atrium (St-A) intervals (group 3). The maximal difference (Delta St-A) between St-A intervals obtained with pacing at a constant cycle length of 500 ms and at the cycle length with maximal retrograde VA prolongation was significantly longer measured from the right His compared with the left His (122 +/- 25 vs. 110 +/- 33 ms, P = 0.02, respectively) in group 1 and group 2 (140 +/- 23 vs. 110 +/- 35 ms, P = 0.03), but not in group 3 (10 +/- 4 vs. 13 +/- 8 ms, P = 0.35). Post-ablation, Delta St-A intervals were similar between right and left His recordings (77 +/- 37 vs. 76 +/- 33 ms, P = 0.53, respectively) in group 1, (100 +/- 24 vs. 103 +/- 21 ms, P = 0.35) group 2, and (63 +/- 32 vs. 66 +/- 33 ms, P = 0.35) group 3. CONCLUSION: In patients with typical AVNRT, retrograde conduction through the slow pathway results in earliest retrograde atrial activation on the left side of the septum and catheter ablation in the right inferoparaseptal area abolishes this pattern. These findings are compatible with the concept of slow pathway conduction by means of the inferior AV nodal extensions.

Elevated plasma levels of oxidized low-density lipoprotein relate to the presence of angiographically detected complex and thrombotic coronary artery lesion morphology in patients with unstable angina.

BACKGROUND: Increased levels of oxidized low-density lipoprotein (ox-LDL) are related to plaque instability, so the aim of the present study was to investigate whether there is a relationship between angiographic coronary plaque morphology in patients with unstable angina pectoris (UAP) and the level of ox-LDL. METHODS AND RESULTS: Plasma ox-LDL levels were measured in 149 patients with UAP and in 88 control subjects, using a highly sensitive enzyme-linked immunosorbent assay method. Angiographic morphology of the culprit lesion was classified as either simple or complex based on the Ambrose classification. Plasma ox-LDL levels in patients with Braunwald class III were significantly higher than in patients with class I (p<0.0001) or in control subjects (p<0.0001). In each of the 3 Braunwald classes, plasma ox-LDL levels in patients with a complex lesion were significantly higher than in patients with a simple lesion. Multivariate logistic regression analysis revealed that ox-LDL level and Braunwald class III were independent factors associated with angiographically detected complex lesions. CONCLUSION: In each Braunwald class of UAP, elevated plasma levels of ox-LDL closely relate to the presence of angiographically detected complex and thrombotic lesion morphology.

Atrial activation during atrioventricular nodal reentrant tachycardia: studies on retrograde fast pathway conduction.

BACKGROUND: Detailed right and left septal mapping of retrograde atrial activation during typical atrioventricular nodal reentrant tachycardia (AVNRT) has not been undertaken and may provide insight into the complex physiology of AVNRT, especially the anatomic localization of the fast and slow pathways. OBJECTIVES: The purpose of this study was to investigate the pattern of retrograde atrial activation during typical AVNRT by means of right-sided and left-sided septal mapping and implementation of pacing maneuvers for separating atrial and ventricular electrograms recorded during tachycardia. METHODS: Twenty-two patients with slow-fast AVNRT were studied by means of simultaneous His-bundle recordings from the right and left sides of the septum. Patterns of retrograde atrial activation were recorded during tachycardia following specific pacing maneuvers and during right ventricular apical (RVA) pacing at the tachycardia cycle length. RESULTS: The pattern of retrograde atrial activation could be mapped in 17 of 22 patients during AVNRT. In 9 (53%) patients, the earliest retrograde atrial activation was recorded on the left side of the septum, in 3 (17%) patients on the right side, and in 5 (29%) patients both right and left atrial septal electrograms occurred simultaneously. Stimulus to atrial electrogram times recorded during RVA pacing in 14 patients were 138.5 ms from the right His bundle, 134.5 ms from the left His bundle, and 148.0 ms from the ostium of the coronary sinus (P <.001). The predominant site of earliest retrograde atrial activation during RVA pacing was the left side of the septum (10 patients [71%]). Only 8 (57%) of 14 patients demonstrated concordance in the pattern of retrograde atrial activation during AVNRT and RVA pacing. CONCLUSION: Earliest retrograde atrial activation during AVNRT is most often recorded on the left side of the septum. Breakthrough of atrial activation may be discordant from that observed during RVA pacing.

Ultrastructural pathology of aortic dissections in patients with Marfan syndrome: Comparison with dissections in patients without Marfan syndrome.

Despite the discovery in 1990 that mutations in the fibrillin-1 gene cause the Marfan syndrome, the pathogenesis of the life-threatening dissections associated with this disease is far from elucidated. Both the massive number of known fibrillin-1 mutations that result in a heterogeneous patient population and the strongly heterogeneous histology of patients' aortae presumably contribute to this lack of knowledge. We performed a detailed ultrastructural immunoelectron microscopic and histochemical analysis of the dissected media of ascending aortae of 10 patients with Marfan syndrome and compared them with those of 6 patients without Marfan syndrome and 77 individuals without known aortic disease. Relatively similar abnormalities were found in both patient groups, although they were more numerous and more diffusely spread in the patients with Marfan syndrome than in the patients without Marfan syndrome. The most conspicuous ultrastructural defects were the formation of abrupt transverse tears in thick and compact elastic lamellae and the local breaking up of smooth muscle cell-elastic lamella connections (that largely consist of microfibrils and elastic extensions, protruding from the elastic lamellae). This breaking up was characterized by a strongly reduced number of microfibrils and a severe shortening of the elastic extensions. Finally, the elastic extensions detached from the lamellae to ultimately degenerate and disappear. These changes were found mainly in the oldest group of patients with Marfan syndrome, indicating that they represented a loss of previously normally developed structures. We also compared our findings with those from a recently developed murine Marfan model (Pereira L, Lee SY, Gayraud B, Andrilopoulos K, Shapiro SD, Bunton T, Biery NJ, Dietz HC, Sakai LY, Ramirez F. Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1. Proc Natl Acad Sci. U. S. A. 1999: 96: 3819-3823). Next to similarities, several striking differences existed, demonstrating that this model is not fully representative of the human Marfan syndrome.

Effect of slow pathway ablation in atrioventricular nodal reentrant tachycardia on the electrophysiologic characteristics of the inferior atrial inputs to the human atrioventricular node.

The inferior atrial extensions of the atrioventricular (AV) node have been related to the anatomic substrate of the slow pathway, but their role in AV nodal reentrant tachycardia (AVNRT) is unknown. Ten patients with slow-fast AVNRT were studied before and after successful slow pathway ablation. Simultaneous His bundle recordings from the right and left sides of the septum were made during right and left inferoparaseptal pacing. Longer stimulus to His (St-H) intervals were measured during right inferoparaseptal pacing than during left inferoparaseptal pacing (284 +/- 55 vs 246 +/- 46 ms, p = 0.005 for right His recordings and 283 +/- 56 vs 244 +/- 46 ms, p = 0.005 for left His recordings) at similar coupling intervals during AVNRT induction. After ablation, the St-H intervals at the maximum AV nodal conduction decrement were similar during right inferoparaseptal and left inferoparaseptal pacing (217 +/- 32 vs 207 +/- 21 ms, p = 0.10 for right His and 215 +/- 32 vs 206 +/- 20 ms, p = 0.13 for left His) at similar coupling intervals. The difference (DeltaSt-H) between St-H intervals during AVRNT induction or at the maximum conduction decrement and during constant pacing for right His recordings with right inferoparaseptal pacing were significantly greater than DeltaSt-H measured with left His during left inferoparaseptal pacing (173 +/- 64 vs 137 +/- 55 ms, p = 0.005) before ablation, but not after (117 +/- 39 vs 100 +/- 40 ms, p = 0.44). Resetting of AVNRT with delivery of left inferoparaseptal extrastimuli was achieved in 7 of 10 patients. In conclusion, the electrophysiologic characteristics of the right and left inferior atrial inputs to the human AV node in patients with AVNRT and their response to slow pathway ablation provide further evidence that the inferior nodal extensions represent the anatomic substrate of the slow pathway.

Persistent high levels of plasma oxidized low-density lipoprotein after acute myocardial infarction predict stent restenosis.

OBJECTIVE: Recently, elevated levels of plasma oxidized low-density lipoprotein (LDL) have been shown to relate to plaque instability in human atherosclerotic lesions. We investigated prospectively patients admitted with acute myocardial infarction (AMI) who underwent primary coronary stenting to evaluate whether the 6-month outcome could be predicted by measuring plasma oxidized LDL (ox-LDL) levels at the time of hospital discharge. METHODS AND RESULTS: Plasma ox-LDL levels were measured in 102 patients with AMI undergoing primary coronary stenting using a highly sensitive ELISA method. Measurements were taken on admission and at discharge, and the findings related to the clinical outcome. At 6-month follow-up, angiographic stent restenosis occurred in 25 (25%) of the 102 AMI patients. Plasma ox-LDL levels at discharge were significantly (P=0.0074) higher in the restenosis group than those in the no-restenosis group (1.03+/-0.65 versus 0.61+/-0.34 ng/5 microg LDL protein). Multiple regression analysis showed that only plasma ox-LDL levels at discharge were a statistically significant independent predictor for late lumen loss after stenting (beta=0.645; P<0.0001). CONCLUSIONS: This prospective study demonstrates that persistence of an increased level of plasma ox-LDL at discharge is a strong independent predictor of stent restenosis at 6-month follow-up in AMI patients.

Epstein Barr virus specific T-cells generated from unstable human atherosclerotic lesions: Implications for plaque inflammation.

OBJECTIVE: T-cell activation is an essential feature of atherosclerotic plaque inflammation, which eventually may lead to plaque rupture. In this study, we investigated if EBV, a common herpes virus, is capable of stimulating atherosclerotic plaque derived T-cells and thus could contribute to atherosclerotic plaque inflammation. METHODS: Plaque derived T-cell cultures were established from symptomatic carotid atherosclerotic plaques of 19 patients. B-cells from the same patients were transformed with EBV to form lymphoblastoid cell lines (B-LCL) that served as antigen presenting cells. The proliferation of T-cells in the presence of autologous B-LCL was analyzed using 3H-thymidine incorporation. The presence of EBV in atherosclerotic material was analyzed by PCR. RESULTS: Of the 19 cell obtained T-cell cultures, 11 responded to EBV (58%, mean stimulation index: 10.1+/-3.1). PCR analysis showed that EBV DNA was present in 15 of the tissue samples (79%). All the specimens that contained EBV responding T-cells also contained EBV. EBV specific T-cells secreted granzymes, as indication of functional cytotoxic potential. CONCLUSIONS: EBV-specific cytotoxic T-cells and EBV DNA can be frequently observed in human atherosclerotic plaques. This suggests that a T-cell response against EBV could contribute to plaque inflammation, and thus to the onset of acute clinical symptoms.

Toward a cardiovascular pathology training report on the forum held in Vancouver, March 6, 2004, Society for Cardiovascular Pathology.

Cardiovascular pathology is a subspecialty of anatomic pathology that requires both clinical education and expertise in contemporary physiopathology. The Society for Cardiovascular Pathology sponsored a special workshop within the frame of the USCAP Annual Meeting, held in Vancouver, March 6-12, 2004, to address the present and future role of cardiovascular pathology in research, clinical care, and education. Clearly, the recruitment and training of young pathologists are crucial to this aim. The forum tried to answer a series of questions. First, is there room for cardiovascular pathologists and clinicopathologic correlations in the era of extraordinary advances of in vivo human body imaging? What is the evolving role of the autopsy? How can the cardiovascular pathologist simultaneously be an autopsy prosector, a surgical pathologist, a molecular pathologist, and an experimental pathologist? Is there a specific domain content for training in cardiovascular pathology and does it meet the constellation of market needs and demands? What are the experiences in Europe, North America and elsewhere? What is the influence of cardiovascular pathology in departments of pathology? Is the subdiscipline still a Cinderella in the anatomic theatre or a Princess with a double helix coat of arms? The Society for Cardiovascular Pathology is strongly committed to optimizing the academic and professional profile of the future generation of cardiovascular pathologists. This article reports the outcome of the forum and directions that may lead to a vibrant future for well-trained cardiovascular pathologists.