Diffusion of gamma globulin into the arterial wall identifies localized entry of lipid and cells in atherosclerosis.

BACKGROUND: The localization of atheromatous lesions in vulnerable arteries and their relatively rare occurrence in other arteries of the same subject cannot be explained by current theories of the aetiology of atherosclerosis. OBJECTIVE: To determine whether abnormal diffusion of gamma globulin into the arterial wall from the lumen will identify defects of barrier function allowing localized entry of lipid and cells in atherosclerosis. METHODS: Paraffin sections of left anterior descending coronary arteries and corresponding internal thoracic arteries from 80 human subjects aged 1-65 years were stained for gamma globulin by the immunoperoxidase technique. Duplicate sections were stained with orcein to demonstrate the elastin structure. RESULTS: The barrier function of the luminal surface of the thickened intima was associated with the presence of an elastin lamina beneath the endothelial cells. With advancing age, the coronary arteries exhibited breakdown of this barrier function in localized areas with entry into the arterial wall of gamma globulin, lipid and cells. This was rare in the internal thoracic artery. CONCLUSION: Lack of continuity or incomplete formation of this sub-endothelial lamina, which was seen particularly in the coronary artery, was associated with localized entry into the arterial wall of gamma globulin, lipid and cells from the circulating blood and with the development of atheromatous lesions.

The initiation of intimal thickening in human arteries.

To obtain more detailed information about the relationship of intimal thickening to defects in the elastin structure of the arterial wall, the internal elastic lamina and subsequent elastin formation in the intima was studied by very oblique sectioning of paraffin sections of the arterial wall, and by scanning electron microscopy of formic acid digested preparations. Comparison was made in the same subject between the internal thoracic artery (a vessel showing only slight intimal thickening) and the anterior descending coronary (which usually develops advanced intimal thickening). There was no evidence of penetration of the normal fenestrations of the internal elastic lamina by medial smooth muscle cells. This took place through major defects of this lamina and resulted in a change from transverse to longitudinal orientation of these cells and the accompanying elastin fibers of the intima. A further condensation of elastin (greater for the internal thoracic) occurred in the intima subjacent to the endothelial cells.

A comparison of coronary arteries from Japanese and NZ subjects.

This paper describes a comparison of the anterior descending branch of the left coronary artery from 198 Japanese subjects of ages less than 60 yrs, with 301 New Zealand individuals of similar ages. The object of the study was to determine whether there were structural differences present which could be partially responsible for the low incidence of atherosclerosis in Japanese as well as the known low blood lipid levels. It was found that the internal elastic lamina of Japanese coronary arteries was less well formed at birth than that of NZ subjects. Intimal thickening was greater in Japanese coronary arteries from birth to the end of the first decade, but increased less rapidly with age, and was only about half as great as that of NZ vessels in the older age groups. The thickened intima of Japanese arteries was more uniform round the circumference of the vessel, the luminal surface was better formed with more stainable elastin present subjacent to the endothelial cells, and there was less evidence of mural thrombosis. NZ arteries showed pronounced eccentricity of the intima, more extensive lipid deposits, a poorly defined luminal surface, and frequent evidence of mural thrombosis.

Primary plexogenic pulmonary hypertension shows imperfect formation of the internal elastic lamina of the pulmonary arteries.

Lung tissue from subjects dying from primary plexogenic pulmonary hypertension (PPH) has shown defects of elastin formation of the lung arteries. Lung vessels from 5 cases of PPH were compared with those of 9 age-matched normal subjects, and 24 individuals having secondary pulmonary hypertension (2 degrees PH). PPH cases and those with 2 degrees PH due to congenital heart disease with left-to-right shunts (2 degrees PH, LRS), showed active proliferation of medial smooth muscle cells (SMC) through defects of the internal elastic lamina (IEL) into the arterial lumen to form typical plexiform lesions. Larger arteries showed accelerated intimal thickening similar to normal aging. Plexiform lesions were not seen in normal subjects or in those developing high pulmonary pressures later in life. The observations showed that the development of discontinuities of the IEL of the pulmonary arteries and intimal thickening is accelerated in normal subjects by high pulmonary artery pressure, especially when this is established at a very young age. They suggest that such discontinuities occur in PPH due to inherent abnormality of the elastin of the arterial walls, with advanced early proliferation of medial SMC and obstruction of the pulmonary arterial circulation.

Comparison of intimal thickening of Chinese and New Zealand coronary arteries.

Coronary arteries from forensic autopsies on 170 Chinese subjects aged 0 to 60 years were compared with those of 301 New Zealand individuals of corresponding ages to explore the reasons for the lower incidence of coronary artery disease in Chinese people. Intimal thickening progressed more rapidly in Chinese subjects up to the age of 30 years, but more slowly in the older age groups. The most striking difference was the much reduced lipid content of the intima and the better formed luminal surface of Chinese arteries of older subjects. These observations are consistent with the known dietary and plasma lipid differences between the peoples of China and the Western world, and they offer further evidence of the damaging effect of lipid and macrophages on the formation of an elastin membrane at the luminal surface of the intima subjacent to the endothelial cells.

The importance of a substantial elastic lamina subjacent to the endothelium in limiting the progression of atherosclerotic changes.

This study examines the hypothesis that progressive intimal thickening and atherosclerosis in the larger pulsatile arteries arise from failure to maintain, subjacent to the endothelial cells, a substantial elastin membrane, a component which has been shown to be of special structural significance. The internal thoracic arteries of 293 subjects of all ages up to 60 years were compared histologically with the anterior descending coronary arteries of the same individuals by light- and electronmicroscopy and immunoperoxidase staining for macromolecules. The internal thoracic arteries usually developed a new robust reduplicated internal elastic lamina at an early age, no further intimal thickening, and no significant entry of lipid or cells to the intima. The coronary arteries showed areas of rapid intimal thickening with poor and incomplete reduplicated internal elastic laminae, entry of lipid, macrophages, and other cells to the intima. The reduplicated internal elastic laminae appeared to be formed primarily by the endothelial cells themselves. An elastin membrane subjacent to the endothelial cells appears to be essential. It provides a secure attachment for the cells and a barrier to the entry of macromolecules and cells to the intima. Its absence is associated with progressive intimal thickening and atherosclerosis.

Clinical characteristics of patients in the persistent vegetative state.

Little is known concerning the specific clinical characteristics of patients in persistent vegetative states (PVS). Fifty-one patients from four nursing homes, approximately 3% of the total patients, were identified as being in a PVS. The mean age of the patients was 64.8 +/- 3.2 years (range, 19 to 96 years) and the mean duration of the PVS was 3.3 +/- 5.0 years (range, 1 to 16.8 years), with 13 patients' PVS being longer than 5 years. Cerebrovascular accidents and dementia were the most common causes of the PVS, accounting for 32 of the cases (63%). In the younger patients cerebral trauma secondary to motor vehicle accidents was the most common cause. All 51 patients were fed via tube feeding and 35 patients had urinary catheters (75%). All patients were receiving daily medications, with greater than 50% taking daily vitamins. Over 30% were taking digitalis and/or diuretics and over 32% were taking H2 blockers. Transfer of patients to an acute care hospital was not uncommon, with 31 patients (61%) requiring 63 acute care hospitalizations during their stay in the nursing home. As expected, infections were the most common reason for acute care hospitalization, although 15 of the patients were hospitalized for surgical procedures. Another common problem encountered by the patients was pressure sores, with 78% of patients requiring specific therapy for at least one pressure sore. Surprisingly, only 27 (53%) of 51 patients had a specific resuscitation status designation in the medical chart, and neither presence of a chart designation nor specific resuscitation order was related to the patient's age or the cause or duration of PVS. From these data it would appear that clinical characteristics of patients in PVS are variable. Some patients are young, others are old. The cause varies from cerebrovascular accidents to cerebral trauma. Survival may be prolonged; complications are not uncommon, with some patients requiring acute care hospitalization.

Patients in a persistent vegetative state attitudes and reactions of family members.

Patients in a persistent vegetative state (PVS) constituted approximately 3% of the population in four Milwaukee nursing homes. In order to understand family members' attitudes and reactions toward such patients, 33 (92%) of 36 family members of patients in PVS contacted were studied. The age of the patients ranged from 19 to 95 with a mean age of 73.4 +/- 17.2 years, and family members' ages ranged from 41 to 89 with a mean age of 61.8 +/- 3.3 years. The etiology of the PVS varied from dementia to cerebral trauma. The mean duration of the PVS was 54 +/- 8.4 months (range 12 to 204). Family members reported that they visited patients 260 times during the first year following the onset of the PVS and were still visiting at a rate of 209 visits yearly at the time of the interview. There was no significant correlation between the frequency of the family members visits and the duration of the PVS, the patient's or family member's age, or the family member's relationship to the patient. Ninety percent of patients were considered by family members to have some awareness of pain, light or darkness, environment, taste, verbal conversation, or the family member's presence. Most family members thought they understood the patient's medical condition, and the majority did not expect the patient to improve. Nevertheless, the majority of family members wanted the patient to undergo therapeutic interventions, including transfer to the acute hospital and surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

The intima of human coronary arteries.

Intimal thickness relative to that of the media (r) was measured in coronary and internal mammary arteries from 300 human subjects. Whereas this ratio remained low (less than 0.17) in the mammary arteries, coronary arteries showed progressive intimal thickening (r = 4.10 by 60 years). The intimal surfaces of 70 pairs of arteries were compared by light, transmission, and scanning electron microscopy. The mammary arteries had a continuous endothelial lining, but the coronary arteries showed incomplete coverage of the thickened intima. In affected vessels the endothelial cells showed loss of attachment to adjacent cells and to the underlying tissue. It was concluded that the progressive intimal thickening of the human coronary artery, which develops early in life and is associated with defects in the internal elastic lamina, is also associated with endothelial cell separation and detachment, with the formation of denuded areas on the intimal surface.

A comparison of structural features of the walls of coronary arteries from 10 different species.

The intimal thickness of the coronary arteries of humans less than 20 years of age was compared with that 9 other species. It was found that humans were unique amongst the species studied in showing substantial intimal thickening at an early age. The intimal thickening was associated with defects of the internal elastic lamina (IEL), which in humans were not repaired, but which in other species were associated with an effective reduplication of the IEL. This reformed IEL appeared in other species to form a significant obstruction to the diffusion of macromolecules from the lumen into the arterial wall, but did not do so in humans. Preliminary observations also indicated that the endothelial cells were closely associated with a well-formed elastin membrane in other species, and formed a continuous inner lining for the arterial wall. In human coronary arteries with substantial intimal thickening, the endothelium was incomplete, with many bare areas.

The internal elastic lamina in normal and abnormal human arteries. A barrier to the diffusion of macromolecules from the lumen.

The distribution of albumin in the walls of normal and abnormal human arteries from surgical and autopsy material was studied to gain insight into the barriers affecting the outward diffusion of plasma macromolecules. In normal arteries there was a steep reduction in albumin concentration at the position of the internal elastic lamina (IEL), suggesting that it acts as a barrier to diffusion. In abnormal arteries such as small vessels present in inflammatory tissue, the IEL was frequently discontinuous and associated with intimal thickening. In these small vessels reduplication of the IEL at the luminal margin of the thickened intima appeared to offer an effective new barrier to the diffusion of albumin from the lumen. In larger vessels such as the coronary arteries of adults, which invariably showed discontinuities of the IEL and intimal thickening, no such effective reduplicated IEL was present, and albumin diffused freely into the thickened intima. These observations suggest that the failure to form and maintain an IEL surrounding the arterial lumen may be associated with continued proliferation of intimal cells and progressive intimal thickening.

Discontinuities in the internal elastic lamina: a comparison of coronary and internal mammary arteries.

The internal elastic lamina (iel.) of the anterior descending branch of the left coronary artery, and the internal mammary artery, were studied in 166 unselected subjects of different ages and races. The coronary artery showed substantial defects in the iel. even in the first few years of life, while the iel. of the mammary artery showed only minimal defects in all age groups. The defects in the iel. were associated with the presence of medial cells in the intima, and the thickness of the intima was correlated with the magnitude of the defects in the iel. (Correlation coefficient 0.95 for the coronary artery and 0.80 for the mammary artery). Small arteries involved in chronic inflammatory or neoplastic disease showed a similar relationship if the vessel were present in an edematous area. These vessels which do not usually show intimal thickening, displayed a thickened intima in the vicinity of defects of the iel. It is suggested that the pronounced difference in the incidence of arteriosclerosis between the coronary and internal mammary arteries is related to these defects in the internal elastic lamina.

A comparison of coronary and internal mammary arteries and implications of the results in the etiology of arteriosclerosis.

Comparison was made between the intimal thickening of the anterior descending branch of the left coronary artery and the internal mammary artery in 352 necropsy examinations. The coronary arteries showed severe intimal thickening, progressing in severity throughout life, whereas the internal mammary showed no more than slight changes at any age. These observations, together with the variation in severity of the changes in different portions of the same vessel, and the freedom from this disease of the smaller arteries throughout the body, strongly suggest that a local or anatomic factor is the dominant influence in coronary artery disease.

The arterial wall in malignant disease.

The intimal thickening of arteries present in 95 resected specimens of carcinoma of the colon was studied, using sections from the tumour area and from adjacent normal bowel. Arteries from the tumour area showed a very significant increase in intimal thickening as compared with the controls. It is suggested that the local factor associated with the tumour area is an impaired drainage of macromolecules from the intimal compartment of the arteries due to obstruction of the lymphatic channels of the surrounding interstitial tissue by tumour cells and fibrosis.

The mechanism of intimal thickening in arteriosclerosis.

The limitations of current theories of the mechanism of intimal thickening in arteriosclerosis are briefly reviewed. The suggestion is advanced that this change is due to intimal oedema, arising from failure of the lymphatic system of the surrounding tissue to remove adequately, protein-containing fluid filtering outwards through the vascular endothelium. It is postulated that such local environmental influences account for the variability in the degree of arterial degeneration seen in different arteries, and in different portions of the same artery.

A comparison of the effects of halothane and other anaesthetic agents on hepato-cellular function in patients submitted to elective operations.

In an attempt to gather objective evidence of possible hepato-cellular toxicity of the halogenated anaesthetics halothane and methoxyflurane pre-operative and post-operative enzyme estimations were done on patients admitted for elective operations. The series of approximately 500 cases included 160 patients submitted to cholecystectomy, an operation associated with a high percentage of detectable alteration of hepatocellular function in the post-operative period. There was no significant difference between the groups of patients receiving halothane, methoxyflurane, or nitrous oxide and oxygen with analgesic supplement. The magnitude of the increased post-operative enzyme activity and the post-operative temperature elevation were not significantly different in the three groups studied.

Serum arginino-succinate lyase: observations on the sensitivity and specificity of this test in the detection of minimal hepatocellular damage.

The serum argino-succinate lyase (ASAL) activity was measured in preoperative and post-operative serum samples, from approximately 500 patients submitted to elective surgery. The results were compared with the determinations of 6 other enzyme activities on the same serum specimens. Serum ASAL elevations correlated highly with increases in serum alanine aminotransferase (ALT) activity, and were nearly twice as great. They also correlated well with serum aspartate aminotransferase (AST), but were approximately 2.7 times greater. It is confirmed that the serum ASAL activity is a sensitive and specific test for liver cell damage, suitable use in special conditions where high sensitivity is required.