Anton E. Becker

Left ventricular fibre architecture in man.

In order to investigate the possibility of regional variation of ventricular structure, 25 normal postmortem human hearts were studied by inspection of cavity shape and subepicardial fibre orientation, by dissection, and by the histology of sections in two orthogonal planes. Ventricular architecture was complex. Inlet and outlet long axes were separated by 30 degrees in the left ventricle. In the right the corresponding figure was 90 degrees. The thickest part of the left ventricular wall was at the base. At the apex there was potential endo- and epicardial continuity. Left ventricular cavity shape departed significantly from any simple geometric figure, there being, consistently, regions of both positive and negative curvature on the diaphragmatic aspect. The presence of trabeculae caused considerable variation in wall thickness. Striking variation was found in the arrangement of subepicardial muscle fibres. Most pronounced was the contrast between the longitudinal arrangement of fibres observed on the oblique margin and the circumferential arrangement of those on the acute. On the diaphragmatic surface of the left ventricle, fibres near the crux and apex ran circumferentially while those between ran obliquely; those on the diaphragmatic surface of the right ventricle also ran circumferentially. Deeper in the myocardium the arrangement was simpler. In the mid-wall of the left ventricle fibres were circumferential, best developed towards the base and in the upper part of the septum. Near the apex of the left ventricle and in the mid-wall of the right ventricle such fibres were sparse. The subendocardial region consisted of longitudinally directed fibres forming the trabeculae and papillary muscles, while fibres deep to and between the trabeculae coursed more obliquely. These findings were confirmed by histology. Models based on uniform myocardial fibre structure cannot explain wall movement in normal subjects, and are likely to have significant limitations if used to investigated left ventricular function in disease.

Elevated Levels of Oxidized Low Density Lipoprotein Show a Positive Relationship With the Severity of Acute Coronary Syndromes

BackgroundThere is accumulating data that acute coronary syndromes relate to recent onset activation of inflammation affecting atherosclerotic plaques. Increased blood levels of oxidized low density lipoprotein (ox-LDL) could play a role in these circumstances. Methods and ResultsOx-LDL levels were measured in 135 patients with acute myocardial infarction (AMI; n=45), unstable angina pectoris (UAP; n=45), and stable angina pectoris (SAP; n=45) and in 46 control subjects using a sandwich ELISA method. In addition, 33 atherectomy specimens obtained from a different cohort of patients with SAP (n=10) and UAP (n=23) were studied immunohistochemically for ox-LDL. In AMI patients, ox-LDL levels were significantly higher than in patients with UAP (P <0.0005) or SAP (P <0.0001) or in controls (P <0.0001) (AMI, 1.95±1.42 ng/5 &mgr;g LDL protein; UAP, 1.19±0.74 ng/5 &mgr;g LDL protein; SAP, 0.89±0.48 ng/5 &mgr;g LDL protein; control, 0.58±0.23 ng/5 &mgr;g LDL protein). Serum levels of total, HDL, and LDL cholesterol did not differ among these patient groups. In the atherectomy specimens, the surface area containing ox-LDL–positive macrophages was significantly higher in patients with UAP than in those with SAP (P <0.0001). ConclusionsThis study demonstrates that ox-LDL levels show a significant positive correlation with the severity of acute coronary syndromes and that the more severe lesions also contain a significantly higher percentage of ox-LDL–positive macrophages. These observations suggest that increased levels of ox-LDL relate to plaque instability in human coronary atherosclerotic lesions.

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.

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° 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° 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.

Vascular Endothelial Growth Factor (VEGF) Expression in Human Coronary Atherosclerotic Lesions Possible Pathophysiological Significance of VEGF in Progression of Atherosclerosis

BACKGROUND Vascular endothelial growth factor (VEGF) is an important angiogenic factor reported to induce migration and proliferation of endothelial cells, enhance vascular permeability, and modulate thrombogenicity. VEGF expression in cultured cells (smooth muscle cells, macrophages, endothelial cells) is controlled by growth factors and cytokines. Hence, the question arises of whether VEGF could play a role in atherogenesis. METHODS AND RESULTS Frozen sections from 38 coronary artery segments were studied. The specimens were characterized as normal with diffuse intimal thickening, early atherosclerosis with hypercellularity, and advanced atherosclerosis (atheromatous plaques, fibrous plaques, and totally occlusive lesions). VEGF expression as well as the expression of 2 VEGF receptors, flt-1 and Flk-1, were studied with immunohistochemical techniques in these samples at the different stages of human coronary atherosclerosis progression. The expression of VEGF mRNA was also studied with reverse transcription-polymerase chain reaction. Normal arterial segments showed no substantial VEGF expression. Hypercellular and atheromatous lesions showed distinct VEGF positivity of activated endothelial cells, macrophages, and partially differentiated smooth muscle cells. VEGF positivity was also detected in endothelial cells of intraplaque microvessels within advanced lesions. In totally occlusive lesions with extensive neovascularization, intense immunostaining for VEGF was observed in accumulated macrophages and endothelial cells of the microvessels. Furthermore, VEGF mRNA expression was detected in atherosclerotic coronary segments but not in normal coronary segments. The immunostainings for flt-1 and Flk-1 were detected in aggregating macrophages in atherosclerotic lesions and also in endothelial cells of the microvessels in totally occlusive lesions. CONCLUSIONS These results demonstrate distinct expression of VEGF and its receptors (flt-1 and Flk-1) in atherosclerotic lesions in human coronary arteries. Considering the multipotent actions of VEGF documented experimentally in vivo and in vitro, our findings suggest that VEGF may have some role in the progression of human coronary atherosclerosis, as well as in recanalization processes in obstructive coronary diseases.

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 aortia with respect to the coronary arteries, mitral valve, and the conduction system and may circumvent complications that can arise during its implantation. In this review, therefore, we describe the anatomy of the trifoliate aortic valvar complex and its implications for percutaneous valvar replacement.

Neointimal Tissue Response at Sites of Coronary Stenting in Humans Macroscopic, Histological, and Immunohistochemical Analyses

BACKGROUND Experimental animal studies have shown that coronary stenting induces neointimal proliferation. However, the histopathological events after coronary stenting in humans have not been studied systematically. METHODS AND RESULTS We investigated 11 stented coronary arteries (9 Palmaz-Schatz stents, 1 Wiktor stent, and 1 ACS Multi-Link stent) obtained from 11 patients who had died 2 days to 21 months after stenting. We focused on gross, histological, and immunohistochemical aspects of the repair processes. Two patients developed symptoms of restenosis. Serial sections were stained with antibodies against smooth muscle cells (SMCs), macrophages, and endothelial cells. At 9 and 12 days after stenting, the stent sites showed thrombus formation with early formation of neointima composed of abundant macrophages and alpha-actin-negative spindle cells. From 64 days on, all sites with stenting showed a distinct layer of neointima, albeit to varying degrees. In nonrestenotic lesions, neointimal thickening was markedly less than in restenotic lesions but without qualitative differences; the neointima contained macrophages but was composed predominantly of alpha-actin-positive SMCs. CONCLUSIONS These observations strongly support the concept that neointimal proliferation in humans is a process of staged redifferentiation of SMCs, which may cause in-stent stenosis. Moreover, the exuberant neointimal proliferation with accumulation of macrophages and extensive neovascularization at sites of stent restenosis suggests a role for organization of mural thrombus.

Histologic changes in the normal aging aorta: implications for dissecting aortic aneurysm.

The histologic changes that occur in the media of the normal aorta at various ages were studied in 100 normal aortas. These changes encompassed (1) cystic medial necrosis, defined as pooling of mucoid material; (2) elastin fragmentation, characterized by disruption of elastin lamellae; (3) fibrosis, defined as an increase in collagen at the expense of smooth muscle cells; and (4) medionecrosis, defined as areas with apparent loss of nuclei. The changes showed a striking correlation with age and may represent the normal aging process for the aorta as determined histologically. The alterations showed a close relation in onset and location within the media, suggesting a phenomenon if injury and repair caused by hemodynamic events. These findings in the normal aging aorta reveal that none of the histologic changes observed can be regarded as the specific structural alteration responsible for the development of dissecting aneurysm.

Relation of arterial geometry to luminal narrowing and histologic markers for plaque vulnerability: the remodeling paradox ☆

OBJECTIVE To relate local arterial geometry with markers that are thought to be related to plaque rupture. BACKGROUND Plaque rupture often occurs at sites with minor luminal stenosis and has retrospectively been characterized by colocalization of inflammatory cells. Recent studies have demonstrated that luminal narrowing is related with the mode of atherosclerotic arterial remodeling. METHODS We obtained 1,521 cross section slices at regular intervals from 50 atherosclerotic femoral arteries. Per artery, the slices with the largest and smallest lumen area, vessel area and plaque area were selected for staining on the presence of macrophages (CD68), T-lymphocytes (CD45RO), smooth muscle cells (alpha-actin) and collagen. RESULTS Inflammation of the cap or shoulder of the plaque was observed in 33% of all cross sections. Significantly more CD68 and CD45RO positive cells, more atheroma, less collagen and less alpha-actin positive staining was observed in cross sections with the largest plaque area and largest vessel area vs. cross sections with the smallest plaque area and smallest vessel area, respectively. No difference in the number of inflammatory cells was observed between cross sections with the largest and smallest lumen area. CONCLUSION Intraindividually, pathohistologic markers previously reported to be related to plaque vulnerability were associated with a larger plaque area and vessel area. In addition, inflammation of the cap and shoulder of the plaque was a common finding in the atherosclerotic femoral artery.

The Conducting Tissues in Congenitally Corrected Transposition

The histopathological findings are reported in 11 cases of congenitally corrected transposition. For the purposes of this investigation, only hearts with a well-formed septum separating two ventricular sinuses were classed as corrected transposition. We did not, therefore, study any examples of single ventricle with inverted outlet chamber. Five of the cases formed the basis of a preliminary report, in which the distribution of conducting tissues in the anomaly was shown to differ from that reported in previous investigations. The six new cases confirmed this distribution. Thus, in all cases, the connecting atrioventricular node was anteriorly situated in the right atrium at the lateral junction of pulmonary and mitral valves. An anteriorly situated bundle descended into the morphologically left ventricle (right-sided) and encircled the anterolateral quadrant of the pulmonary outflow tract before descending on the anterior septum and bifurcating. The bundle branches were inverted. This distribution was observed in specimens with intact septa (three cases) and in specimens with ventricular septal defects (eight cases). In the latter cases the conducting tissues were related to the anterior quadrants of the defects. One case was of particular interest since the posterior node in the position of the normal atrioventricular node also made contact with the ventricles via a posterior bundle. In all other specimens this node was hypoplastic and did not have ventricular connections. It is considered that this finding provides a link with previous descriptions of posterior conducting tissue in congenitally corrected transposition. The findings are discussed with relation to the development of complete heart block in this anomaly.