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.

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.

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.

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.

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.

Spotty calcification typifies the culprit plaque in patients with acute myocardial infarction: an intravascular ultrasound study.

BACKGROUND: Calcification is a common finding in human coronary arteries; however, the relationship between calcification patterns, plaque morphology, and patterns of remodeling of culprit lesions in a comparison of patients with acute coronary syndromes (ACS) and those with stable conditions has not been documented. METHODS AND RESULTS: Preinterventional intravascular ultrasound (IVUS) images of 178 patients were studied, 61 with acute myocardial infarction (AMI), 70 with unstable angina pectoris (UAP), and 47 with stable angina pectoris (SAP). The frequency of calcium deposits within an arc of less than 90 degrees for all calcium deposits was significantly different in culprit lesions of patients with AMI, UAP, and SAP (P<0.0001). Moreover, the average number of calcium deposits within an arc of <90 degrees per patient was significantly higher in AMI than in SAP (P<0.0005; mean+/-SD, AMI 1.4+/-1.3, SAP 0.5+/-0.8). Conversely, calcium deposits were significantly longer in SAP patients (P<0.0001; mean+/-SD, AMI 2.2+/-1.6, UAP 1.9+/-1.8, and SAP 4.3+/-3.2 mm). In AMI patients, the typical pattern was spotty calcification, associated with a fibrofatty plaque and positive remodeling. In ACS patients showing negative remodeling, no calcification was the most frequent observation. Conversely, SAP patients had the highest frequency of extensive calcification. CONCLUSIONS: Our observations show that IVUS allows the identification of vulnerable plaques in coronary arteries, not only by identifying a fibrofatty plaque and positive remodeling, but also by identifying a spotty pattern of calcification.

Neutrophil infiltration of culprit lesions in acute coronary syndromes.

BACKGROUND: Neutrophils in unstable atherosclerotic lesions have not received much consideration, despite accumulating evidence suggesting a link between systemic inflammation and acute coronary syndromes. METHODS AND RESULTS: Coronary artery segments were obtained at autopsy from 13 patients with acute myocardial infarction (AMI); 8 had a ruptured and 5 an eroded plaque. Patients (n=45) who had died of noncardiovascular diseases served as reference. Atherectomy specimens were obtained from 35 patients with stable angina pectoris (SAP) and from 32 patients with unstable angina pectoris (UAP). Antibodies against CD66b, elastase, myeloperoxidase, and CD11b identified neutrophils; CD10 identified neutral endopeptidase (NEP). CD66b-positive and NEP-positive neutrophils were counted and expressed as a number per square millimeter of tissue. All specimens with plaque rupture or erosion showed distinct neutrophil infiltration; the number did not differ between ruptured and eroded plaques. However, the number of NEP-positive neutrophils was significantly higher (P<0.0001) in ruptured plaques than in eroded plaques. UAP patients showed neutrophils in 14 of 32 culprit lesions; in SAP only 2 of 35 lesions contained neutrophils. The number of neutrophils and NEP-positive cells in patients with UAP was significantly higher (neutrophils, P<0.0005; NEP-positive cells, P<0.005) than in patients with SAP. CONCLUSIONS: The observations suggest that neutrophil infiltration is actively associated with acute coronary events. The high number of NEP-positive neutrophils in ruptured plaques, compared with eroded plaques, may reflect differences in the underlying pathophysiological mechanisms.

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.

Differential localisation of the renin-angiotensin system in de-novo lesions and in-stent restenotic lesions in in-vivo human coronary arteries.

OBJECTIVE: Different components of the renin-angiotensin system (RAS) have been demonstrated in atherosclerotic plaques. However, the involvement of the RAS in in-stent restenosis is not clear. We studied the differential immunolocalisation of angiotensin converting enzyme (ACE) and the angiotensin II type 1 (AT1) receptor in de-novo stenotic lesions and in-stent restenotic lesions in human coronary arteries. METHODS: Using a pullback atherectomy catheter, biopsies from de-novo coronary lesions (n=19) and in-stent restenotic lesions (n=19) were obtained. The biopsies were immunostained for vascular smooth muscle cells (VSMCs), macrophages, ACE and the AT1 receptor. RESULTS: In biopsies from de-novo stenotic lesions ACE-positive macrophages were more numerous than in in-stent restenotic lesions (P=0.002). Moreover, in the latter lesions, ACE-positive macrophages decreased when the time interval of stent implantation was longer. On the other hand, in-stent restenotic lesions contained predominantly young VSMCs, which abundantly expressed AT1 receptors. CONCLUSIONS: Lesional ACE expression is not a prominent feature of in-stent restenotic lesions. In contrast, AT1 receptors are abundantly expressed on young VSMCs. In de-novo lesions ACE and AT1 receptors were found on macrophages and VSMCs, which were present in all specimens.

Increased expression of T cell activation markers (CD25, CD26, CD40L and CD69) in atherectomy specimens of patients with unstable angina and acute myocardial infarction.

Atherosclerotic plaques contain a chronic immune mediated inflammation in which T cells play an important role. A previous study revealed that the numbers of interleukin-2 receptor-positive T cells is increased in culprit lesions of patients with acute coronary syndromes; a finding of considerable interest since it indicates a recent change in the intraplaque T cell mediated immune response. Confirmation of this observation is important, because it could provide insight into the onset of the acute event. We have, therefore, expanded our earlier work by using a panel of different T cell activation markers (CD25, CD26, CD40L, CD69). The study is based on 58 culprit lesions from patients who underwent coronary atherectomy. There were four groups of patients: chronic stable angina (n=13), stabilized unstable angina (n=16), refractory unstable angina (n=15), and acute myocardial infarction (AMI; n=14). Activated T cells were expressed as a percentage of the total of CD3-positive cells. CD25, CD26, CD40L, and CD69/CD3 percentages increased with the severity of the coronary syndrome. In patients with AMI all percentages were significantly higher than in patients with chronic stable angina. CD25, CD26, CD40L, and CD69/CD3 percentages in patients with an unstable condition (refractory unstable angina and AMI) were significantly higher than those in patients with a stable condition (chronic stable or stabilized unstable angina) The finding that the percentage of T cells with recent onset activation is significantly increased in the culprit lesions of patients with acute coronary syndromes suggests strongly that a recent change in pathogenic stimulation has occurred leading to local T cell activation.

Association between complex coronary artery stenosis and unstable angina and the extent of plaque inflammation.

PURPOSE: Patients with unstable coronary syndromes often have complex morphology of coronary stenoses at angiography. We evaluated the association between qualitative assessment of coronary stenoses and plaque inflammation determined by immunohistochemistry. METHODS: A total of 79 patients with unstable (n = 46) or stable angina (n = 33) underwent directional coronary atherectomy for culprit lesions. Qualitative analysis of coronary angiograms was performed using a modified Ambrose classification. Coronary lesions were categorized as either simple (concentric and eccentric type I, n = 29) or complex (eccentric type II and multiple irregularities, n = 50). Cryostat sections of retrieved atherosclerotic specimens were stained immunohistochemically with monoclonal antibodies, alpha-actin (smooth muscle cells), CD68 (macrophages), and CD3 (T lymphocytes). The extent of atherosclerotic inflammation within each coronary lesion was determined by the percentage of immunopositive macrophages per total tissue area (including smooth muscle cells) and the number of T lymphocytes per mm(2). RESULTS: The mean (+/- SD) percentage of macrophages in atherectomy specimens from patients with unstable angina was greater than in specimens from patients with stable angina (21% +/- 14% vs. 13% +/- 10%, P = 0.01); similar results were seen when complex coronary lesions were compared with simple lesions (23% +/- 13% vs. 9% +/- 8%, P <0.001). In multivariate linear regression models, the combination of unstable angina and lesion complexity was strongly associated with the percentage of plaque macrophages. CONCLUSION: The extent of atherosclerotic plaque inflammation is associated with angiographic grading of coronary lesion complexity and unstable angina.

How structurally normal are human atria in patients with atrial fibrillation?

Atrial myocardium in humans shows structural changes that increase with aging. The most conspicuous are fibro-fatty replacement and patchy replacement fibrosis. The present study reveals that these structural changes are more extensive in hearts of patients with paroxysmal atrial fibrillation (AF) than in "no AF" hearts. The changes involve the myocardial sleeves on pulmonary veins and sites of rapid conduction, such as the terminal crest and Bachmann's bundle. These structural changes should be taken into consideration as potential substrates for initiation and maintenance of atrial arrhythmias.

A review of the coronary venous system: a road less travelled.

Compared with the coronary arterial system, less attention has been paid to the coronary venous system. In the current era, there are therapeutic options for arrhythmias and for heart failure that use the coronary venous system to access target areas. We review the arrangement of the main cardiac veins to provide a morphologic background to interventionists. In general, the venous system is a useful conduit for delivery of percutaneous transcatheter treatment. But, variability in terms of valves, diameter, angulation, extent of muscular sleeves, proximity to other cardiac structures, and cross-over spatial relationship with branches of coronary arteries have implications for practitioners seeking to make use of the system.

Right and left inferior extensions of the atrioventricular node may represent the anatomic substrate of the slow pathway in humans.

OBJECTIVES: The purpose of this study was to investigate the electrophysiologic characteristics of the inferior extensions of the human atrioventricular (AV) node and their possible relationship to slow pathway conduction. BACKGROUND: The human heart contains right and left inferior extensions of the AV node that relate to right and left atrial inputs. METHODS: Fourteen patients admitted for catheter ablation of left-sided accessory pathways were studied. Atrial pacing was performed from multiple sites in both atria, and simultaneous His-bundle recordings from right and left sides of the septum were made. RESULTS: Significant differences of A-H and stimulus to His (St-H) intervals with pacing at various sites were found. St-H intervals were similar during constant pacing from the low right atrium or the left inferoparaseptal area (112 +/- 28 ms vs 112 +/- 26 ms, P = .8, for right His recordings and 114 +/- 23 ms vs 111 +/- 25 ms, P = .9, for left His recordings). At maximum decrement, there were significantly shorter St-H intervals during left inferoparaseptal pacing compared to low right atrial pacing (201 +/- 24 ms vs 218 +/- 44 ms, P = .02, for right His recordings, and 200 +/- 24 ms vs 219 +/- 41 ms, P = .009, for left His recordings). Differences on right His recordings between St-H intervals at maximum decrement and at constant pacing from the low right atrium were significantly higher than corresponding differences on left His recordings during pacing from the left inferoparaseptal area (P = .035). CONCLUSIONS: Our findings support the concept that the right and left inferior extensions of the human AV node may represent the anatomic substrate of the slow pathway as defined electrophysiologically.

S-wave predominance of epicardial electrograms during atrial fibrillation in humans: indirect evidence for a role of the thin subepicardial layer.

OBJECTIVES: The purpose of this study was to characterize the morphology of fibrillation electrograms in patients in order to provide insight into the underlying electropathologic substrate of atrial fibrillation (AF). BACKGROUND: Electrograms recorded during AF show a high degree of spatiotemporal variation. METHODS: AF was induced by rapid atrial pacing in 25 patients undergoing cardiac surgery. A unipolar mapping array of 244 electrodes was positioned on the free wall of the right atrium to record multiple epicardial fibrillation electrograms. Local anisotropy in conduction and epicardial wavefront curvature during AF were determined by fitting the best quadratic surface on the activation times of rectangular areas of 3 x 3 electrodes. RESULTS: During AF, unipolar epicardial electrograms revealed a clear predominance of S waves. The average RS difference during type I and II AF was -0.15 +/- 0.08 and -0.22 +/- 0.08. During type III AF, the predominance of S waves was less prominent (-0.07 +/- 0.05; P < .005). In all types of AF, the degree of anisotropy in conduction was remarkably low (anisotropy ratio: 1.24 +/- 0.09), and no clear directional effect on the relative amplitude of R and S waves was found. There was a weak relationship between local curvature of wavefronts and RS difference (r = 0.23; P < .01). Computer simulations showed that the negative RS difference could result from transmural activation in an epicardial to endocardial direction. CONCLUSIONS: The clear predominance of S waves in epicardial fibrillation electrograms is not due to anisotropy and can only be partly explained by a high curvature of fibrillation waves. Predominant epicardial to endocardial activation seems to be important in producing rS electrograms on the epicardium. This finding provides indirect evidence that the thin epicardial layer of atrial myocardium plays an important role in propagation of fibrillation waves.

Small aortic root as a cause of sudden death in a young adult: a controversial topic revisited.

BACKGROUND: Sudden cardiac death over the age of 35 years is mostly due to coronary atherosclerosis, whereas under the age of 35 years, a variety of mainly congenital malformations prevail. However, hypoplasia of the aortic root in adults, first introduced by Laurie in 1968 as a cause of sudden cardiac death in adults, is never included. CASE REPORT: We present a case of a 29-year-old female who suddenly and unexpectedly collapsed during recreational bicycling. Ventricular fibrillation was recorded, but resuscitation attempts failed, and the patient was declared dead about 1 h after the event. Autopsy revealed cardiac hypertrophy with extensive scarring and a small aortic root (calculated inlet/outlet diameters=14.9/14.3 mm), without obstructive coronary artery disease or any other plausible cause for sudden cardiac death. CONCLUSIONS: The observations strongly suggest that small aortic root (less than 2 cm in diameter) provided the background for cardiac hypertrophy and, eventually, myocardial ischemia and ventricular fibrillation. Pathologists should be aware of this possibility while evaluating cases of sudden cardiac death without an obvious pathologic substrate.

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.