Mark H. Kadowaki

Hemodynamic stress and experimental aortoiliac atherosclerosis

PURPOSE Human aortic atherosclerosis is predominantly localized to the infrarenal aorta where flow is bidirectional and wall shear stress oscillates. Similar flow patterns have been related to carotid atherosclerosis. The thoracic aorta is usually spared, where flow and shear stress are unidirectional. We hypothesized that because heart rate and systemic blood pressure modulate flow velocity and shear stress oscillation, both these hemodynamic forces may enhance aortoiliac atherogenesis. METHODS Eighteen male cynomolgus monkeys were fed an atherogenic diet for 6 months (mean serum cholesterol = 535 +/- 35 mg/dl). Heart rate was determined with 24-hour electrocardiographic telemetry at monthly intervals and blood pressure was measured by direct arterial cannulation. The product of mean heart rate and mean blood pressure was used to define hemodynamic stress for each animal. Atherosclerotic lesion formation at three standard thoracic aortic sites was quantitatively compared with lesion formation at five standard infrarenal aortoiliac locations with computer-assisted morphometry. RESULTS There was significantly more plaque in the aortoiliac segment than in the thoracic aorta (12.4% +/- 9.0% vs. 6.4% +/- 4.5% area stenosis, p = 0.02). No correlation was found between the degree of serum lipid elevations and lesion formation in either aortic location. Mean heart rate was 113 +/- 18 beats/min (87 to 163 beats/min) and mean blood pressure was 85 +/- 19 mm/Hg (62 to 130 mm Hg). Heart rate and blood pressure alone were not significantly related to lesion formation. A significant correlation was, however, found between hemodynamic stress and maximum lesion thickness (r = 0.47, p < 0.05) in the aortoiliac region but not in the thoracic aorta (r = 0.19, p > 0.10). CONCLUSIONS This study demonstrates that heart rate and blood pressure exert a mutually potentiating effect on aortoiliac atherosclerosis but not on thoracic aortic atherosclerosis. Regional differences in aortic atherosclerosis may therefore be attributable to the interaction between these hemodynamic forces and the local flow patterns specific to each aortic location. Additional investigation of these hemodynamic factors in relation to human aortic atherosclerosis is warranted.

Pleuro-peritoneal shunting: alternative therapy for pleural effusions

Pleural effusions are resistant to standard therapy, which causes discomfort and can require prolonged hospitalization. As an alternative, pleuroperitoneal shunting for pleural effusions of various etiologies was evaluated. We implanted 36 shunts in 29 patients. Two patients had bilateral shunts and five had shunt revisions. The effusion was related to a malignancy in 22 patients, postoperative chylothorax in two patients, and other causes in five patients. Therapeutic thoracentesis had been attempted in 28 patients, and eight had had chest tube placement previously with attempted sclerosis. Seven patients had a trapped lung syndrome. There was no operative mortality. All patients were deemed ready for discharge from the hospital if they had recovered from the operation within 48 hours. Five patients had poor results, either because of a moribund status or their refusal or inability to pump the shunt. Of the remaining 24 patients, four had good results with temporary improvement, and excellent results were achieved in 20 patients (83.3%), who experienced symptomatic relief and stabilization or regression of pleural effusion until the time of their death. Patients with chylothorax experienced complete resolution. The 14 patients with malignant effusions had a median survival of 4 months, and there were no instances of peritoneal tumor seeding. In conclusion, pleuroperitoneal shunting is an alternative therapy for pleural effusions that requires a limited hospitalization only, is associated with minimal and short-term discomfort, achieves excellent results in properly selected patients, and is the only viable therapy when lung expansion cannot be achieved.

The effect of microbial contamination on musculocutaneous and random flaps

Although musculocutaneous flaps have been shown to have the ability to withstand a greater inoculum of bacteria than random flaps, it has not been shown that the musculocutaneous flap has any greater ability to decrease the bacterial population in a contaminated wound. In this series of experiments, granulating wounds were developed containing 10(4), 10(5), or 10(6) bacteria per gram of tissue. These contaminated wounds were then covered either with musculocutaneous flaps, random flaps, or left uncovered as a control. In the heavily contaminated wounds containing 10(6) bacteria per gram of tissue, neither type of flap was able to prevent bacterial proliferation and all flaps dehisced. In the minimally contaminated wounds containing 10(4) bacteria per gram of tissue, both the musculocutaneous and random flaps achieved wound healing and decreased the bacterial level in the wound. However, in the intermediate group containing 10(5) bacteria per gram of tissue, musculocutaneous flaps lowered the bacterial count and allowed wound closure, whereas the random flaps did not control the bacterial growth and failed. Therefore, in the moderately contaminated wound, musculocutaneous flaps are advantageous and can decrease bacterial counts and obtain successful closure when random flaps cannot.

Sympathectomy in the Treatment of Angina and Arrhythmias

Sympathectomy has been used as treatment for several different cardiac conditions. These include classic angina pectoris, Prinzmetals angina, paroxysmal atrial tachycardia, ventricular tachycardia, and long QT syndrome. To understand the rationale of such treatment, the innervation of the human heart is reviewed with discussion of the cardiac plexus and coronary innervation. Results in published studies are summarized and discussed.

Role of fibrinopeptide B in early atherosclerotic lesion formation

The development of atherosclerotic lesions involves many cell types, including macrophages. Fibrinopeptide B (FPB) has been shown to be a potent chemotactic agent for macrophages, which are abundant as intimal foam cells in atherosclerotic lesions, especially in cholesterol-fed rabbits. We hypothesize that intimal low-density lipoproteins also cause fibrinogen in the intima to release FPB and that FPB attracts macrophages in response to the high lipid levels associated with lesion development. To test our hypothesis, we used an atherosclerotic model. Silk sutures containing either FPB, fibrinopeptide A (FPA), lipopolysaccharide (LPS), or saline control were prepared. One suture of each type was placed in the adventitia of the femoral artery of a rabbit. Animals were killed at 1 or 2 weeks. Only vessels exposed to either FPB or LPS showed significant intimal thickening in the region adjacent to the suture site. Semi-thin electron microscopic sections indicated that the intimal wall was highly cellular and that many cells contained lipid vacuoles after 2 weeks. These sections also showed that the endothelium remained intact and that no injury to the media of the artery had occurred. Electron microscopy of the tissue samples showed the proliferation of smooth muscle cells and deposition of extracellular matrix in the 2-week animals, whereas foam cells were present in the 1-week animals. We conclude that FPB does indeed attract macrophages to the intima and that these macrophages may become foam cells. The model we have developed can be used to study possible mechanisms for the entry of macrophages into the intima during early lesion development and to further understand the complex interactions of FPB, fibrinogen, and lipids in atherosclerotic lesion development.

Comparison of prosthetic graft materials as intracardiac right atrial patches

An experimental animal model was developed to study the fate of prosthetic graft materials within the heart. Autologous pericardium, bovine pericardium, polytetrafluoroethylene, woven Dacron, and autologous right atrium (control) patches were implanted into the wall at three sites on the right atrium in each of 10 dogs (six patches for each graft material). The atria were harvested 90-100 days later and histologic examination and quantitation of calcium were performed. Chronic inflammation and fibrosis were found in 29 of 30 grafts. Cartilage formed in 26 of 30 sites and was found both in the center and around the edges of the grafts. In addition to cartilage, bone including marrow elements formed in the two autologous materials at 4 of the 12 sites and in 1 of the Dacron graft sites. Calcium content was greater in the control and the bovine pericardial grafts than in the other graft materials (P = NS). The incidence and degree of inflammation, fibrosis, calcification and cartilage, and bone formation were similar in all materials. We conclude that the healing process of these intracardiac graft materials is a generalized phenomenon independent of the inherent properties of a specific graft material.

Congenital left atrial aneurysm in an infant

Congenital left atrial aneurysm, without associated cardiac abnormalities, is a rare defect. We report the case of a large left atrial aneurysm filling almost the entire left hemothorax. This is the first report of this anomaly occurring in an infant less than 1 year of age.

The effect of hypercholesterolemia on early atherosclerotic lesions initiated by fibrinopeptide B

Hypercholesterolemia and thrombosis have been implicated as factors in the development of atherosclerosis. Fibrinopeptide B (FPB) is a short chain peptide cleaved from fibrinogen during the production of fibrin. FPB is a known chemoattractant and has been shown to produce experimental atherosclerotic lesions in association with hypercholesterolemia. The present study was designed to examine the role of hypercholesterolemia in this process and to study the time course of the development of these lesions. Twelve New Zealand White rabbits were placed on an atherogenic diet and had suture carrying either FPB, fibrinopeptide A (FPA), or saline (controls) implanted in the adventitia of the femoral arteries and were sacrificed at 14 days. An equal number of animals were left on a standard diet and underwent similar treatment. Eleven animals were treated as the hypercholesterolemic group but were sacrificed at 2, 4, and 7 days. The thickness of the intima was measured adjacent to the suture in the animals sacrificed at 14 days, and the hypercholesterolemic FPB sites were thicker (12.23 mu +/- 6.60) than either hypercholesterolemic FPA (6.06 mu +/- 3.72), saline (4.94 mu +/- 1.42), or the normocholesterolemic FPB (5.99 mu +/- 4.61), FPA (3.89 mu +/- 2.20), or saline (3.97 mu +/- 1.83) (P less than 0.05 for all groups). Transmission electron microscopy of the hypercholesterolemic FPB group showed evidence of macrophages, actively secreting smooth muscle cells with newly deposited elastin, and foam cells by 7 days. We conclude that FPB attracts or stimulates macrophages and smooth muscle cells and that the resultant cellular and extracellular proliferation favors early atherosclerotic lesion formation in the presence of hypercholesterolemia.

Comparative studies of prosthetic materials in the left atrium of the dog

To assess the healing process of various intracardiac prosthetic graft materials, we inserted autologous left atrium (control), autologous pericardium (AP), bovine pericardium (BP), polytetrafluoroethylene (PTEE) and woven Dacron (WD) patches into excised defects in the left atrial wall of 15 dogs. Two patches were implanted into each heart utilizing six patches for each material. Three months after graft placement, histological examination revealed chronic inflammation and fibrosis for all materials. Dense connective tissue surrounded the grafts in which fibrosis was most prominent. Cartilage formation occurred in 11 grafts 5 BP, 4 PTFE, 1 control and 1 AP site. This change was not evident with WD. The extent of cartilage formation was greatest in BP. Bone formation occurred in 3 BP sites, 2 PTFE and 1 control site. Quantitative calcium concentrations were similar for all of the grafts without bone formation. Calcium concentrations at sites with bone formation averaged 15.13 mg/g±6.39 mg/g compared to 0.939±0.419 for sites without bone formation (p<0.0001). We conclude that while inflammation, fibrosis and connective tissue thickening occur with healing of all graft materials, cartilage and bone formation differ with respect to the material employed.

The role of chromosome 3 deletions in lung cancer

Lung cancer is currently the major cause of cancer death in the United States in both males and females, accounting for approximately 142,000 deaths per year in the United States [14]. This disease remains both highly and rapidly fatal. Despite the advances enjoyed in many other areas of medicine, the response to current therapy of lung cancer remains unchanged over the past 20 years. One exception to this is the small cell variety of lung cancer, for which advances in chemotherapy and radiation therapy have made major improvements in the response rates. Despite these advances, the survival rate for small cell lung cancer is less than that of other forms of lung cancer [4]. Improvements in the treatment of lung cancer can only be expected if new therapeutic modalities or strategies are developed. Such advances in treatment must be based on advances in the knowledge of the biology of the disease. Recent information regarding small cell lung cancer on a cellular and molecular level demonstrates the prognostic and therapeutic capabilities of such approaches. Improvements in treatment can be expected only if these molecular and cellular mechanisms are understood and their significance appreciated. Recent molecular genetic work has shown that lung cancer, both small cell and non-small cell, is associated with loss of genetic material from chromosomes 3, 11, 13 and 17 [16, 191. With the loss of heterozygosity at a genetic locus, several mechanisms can be hypothesized to account for an association with a malignancy. A recessive gene, such as an oncogene or a mutant gene, could be unmasked or, alternatively, the loss of a dominant gene or anti-oncogene, could result in activation of a malignant process. A regulatory gene, such as the c-erb-A gene which will be discussed, may play a role in repressing the transcription of other genes which cause cancer; the loss of such a regulatory gene could permit other genes to cause cancer. This