J Am Geriatr Soc 1968 Jul; 16(7):779-785
TREATMENT OF CORONARY ARTERIOSCLEROTIC HEART
DISEASE WITH CHONDROITIN SULFATE-A: PRELIMINARY REPORT
Lester M. Morrison, M. D.
Los Angeles, California
ABSTRACT: The acid mucopolysaccharide, chondroitin sulfate-A (CSA), which is active in preventing experimentally-induced atherosclerosis in monkeys, rats and rabbits, also has anticoagulant properties in rabbits and in patients with angina pectoris from coronary arteriosclerotic heart disease.
For an average period of one and a half years (range, one to two years), CSA was administered orally (tablet or powder) to 60 patients with clinically manifest coronary arteriosclerotic ban disease, in dosages ranging from 1.5 to 10.0 gm daily. No toxic effects were noted and the medication was well tolerated. These patients were matched with a comparable group of 60 control patients for age, sex, and clinical and laboratory findings.
In the 60 control patients, 13 acute coronary incidents occurred; 7 were myocardial infarctions, of which 2 were fatal and 6 required hospital treatment in coronary-care units for "acute coronary insufficiency" or "acute myocardial ischemia" or impending myocardial infarction.
In the 60 CSA-treated patients there was only 1 coronary incident – a fatal case of myocardial infarction.
This preliminary report suggests that "feasibility" studies are warranted to determine the therapeutic effects of CSA for the prevention of coronary arteriosclerotic heart disease in statistically designed, triple-blind investigations on a larger series of patients over longer periods of time.
Arch Intern Med 1970 Oct; 126(4): 569
Administration of chondroitin sulfate appears to be effective in preventing heart attacks, according to Lester Morrison, MD, professor and director of the Institute for Arteriosclerosis Research at Loma Linda University School of Medicine.
Dr. Morrison reported to the recent American College of Angiology meeting in New York on the results of a double-blind study of 120 patients with a history of myocardial infarction and/or coronary artery disease verified by electrocardiography
Half the patients received chondroitin sulfate A (CSA) in addition to conventional therapy. CSA is a mucopolysaccharide compound.
His results were quite dramatic: six "coronary incidents" and five related deaths in the experimental group compared to 36 "coronary incidents" and nine related deaths the 60 matched control patients.
Dr. Morrison added that experimental studies have shown CSA can prevent as well as accelerate regression and healing of coronary aortic atherosclerosis.
The patients had been treated for ischemic coronary artery heart disease for six months to 20 years before the start of the study. All had received various drugs that were continued and in some cases expanded during the study. The experimental group patients were slightly younger (average of 65.5 than the controls (65.9 years) at the start of the study. The control group included 35 women and the experimental group, 44 women.
Patients received 10 gm/day CSA at the start of the study, but dosage was later reduced to 1.5 gm/day. None of the patients have suffered any toxic effects.
Four of the patients in the experimental group died following myocardial infarction. The fifth patient suffered a fatal massive cerebrovascular hemorrhage complicated by terminal coronary insufficiency and congestive heart failure. The sixth "coronary incident" was a case of acute coronary insufficiency, but that patient recovered.
Sixteen control patients suffered a total of 19 myocardial infarctions. Nine of these patients died. Ten patients also underwent 11 episodes of coronary insufficiency, and there were six cases of myocardial ischemia.
Three other patients among the 120 died. One patient in the CSA group suffered a skull injury that induced ventricular fibrillation leading to death. Another died from a malignant cerebral astrocytoma. One of the control patients died of mesenteric thrombosis.
Atherosclerosis, 1972, 16: 105-118
Elsevier Publishing Company, Amsterdam - Printed in The Netherlands
PREVENTION OF VASCULAR LESIONS BY CHONDROITIN SULFATE A IN THE CORONARY ARTERY AND AORTA OF RATS INDUCED BY A HYPERVITAMINOSIS D AND A CHOLESTEROL-CONTAINING DIET
L. M Morrison, G. S. Bajwa, R. B. Alfin-Slater and B. H. Ershoff
Institute for Arteriosclerosis Research, Loma Linda University School of Medicine, Culver City, Calif. 90230 and the University of California School of Public Health, Los Angeles, Calif. 90024 (U.S.A.)
Severe lesions in the coronary arteries and aortas occurring primarily in the media and consisting of degeneration, calcification, plaque formation, metachromasia and the prD" Cce of intracellular and extracellular stainable lipid material present mainly in the areas of the damaged media were induced within 6 weeks in young adult rats fed a purified diet supplemented with 1.5% cholesterol, 0.5% cholic acid and 1.25 million U.S. P. units of vitamin D2 per kg of ration. Such lesions were noted in the aortas of 17 of 18 male rats as well as 16 of 16 female rats and the coronary arteries of all rats fed the above diet.
Lesions of the aorta were completely prevented in 18 of 18 male rats and were present in only 5 of 18 female rats fed a similar ration supplemented with chondroitin sulfate A at a I% level in the diet. Lipid-containing coronary lesions were present in only 3 of 18 male rats and 3 of 18 female rats fed the latter diet. The protective effects of chondroitin sulfate A administration indicated above were not accompanied by a reduction in plasma and liver cholesterol or liver total lipids compared to that of rats fed a similar diet without the chondroitin sulfate A supplement.
Comparative study of the effects of chondroitin sulfate isomers on atherosclerotic subjects
Nakazawa K, Murata K
Effects of isomers of chondroitin sulfate on atherosclerosis were clinically compared, based on sulfate linkage and the amount of sulfate, by using chondroitin 4-sulfate, chondroitin 6-sulfate and chondroitin polysulfate. Fourty eight age-matched atherosclerotic subjects were selected from a home for the elderly in order to the treatment with the agents. The isomers of chondroitin sulfate were given a daily dose of 4.5 g perorally. During the experimental period for 64 months, mortality, serum cholesterol, thrombus-formation time and thrombus weight were examined. The result obtained was as follows: mortality in the groups treated with the isomers of chondroitin sulfate was less than the age-matched untreated control group. Serum cholesterol value in the group treated by the isomers of chondroitin sulfate, chondroitin polysulfate group in particular, fell lower than the pre-treatment value. Thrombus formation time prolonged 150% in the group treated with chondroitin polysulfate over the untreated control group and the resultant thrombus weight was reduced in the treated group. Thus, these data indicated that the isomers of chondroitin sulfate are clinically effective on the treatment of atherosclerosis in the order of chondroitin polysulfate, chondroitin 4-sulfate and/or chondroitin 6-sulfate.
Suppression of atherogenesis in hypercholesterolemic rabbits by chondroitin-6-sulfate
Matsushima T, Nakashima Y, Sugano M, Tasaki H, Kuroiwa A, Koide O
2nd Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan.
The effect of chondroitin-6-sulfate, obtained from shark cartilage, on atherogenesis in rabbits fed a high cholesterol diet was studied. Male Japanese white rabbits were housed for 10 weeks in three groups, one group was fed ordinary pellets and was injected intraperitoneally with saline (standard-diet group), one was fed pellets containing 1% cholesterol and was injected intraperitoneally with saline (cholesterol-diet group), and the third group was fed pellets containing 1% cholesterol, and was injected intraperitoneally with 10 mg of chondroitin-6-sulfate (C-6-S group). Injections were done daily. The plasma total cholesterol, and cholesterol from very low-density lipoprotein in the C-6-S group after 5 weeks in the test period, and low-density lipoprotein cholesterol in the C-6-S group at the end of the test period were lower than those of the cholesterol-diet group. Significantly fewer atherosclerotic lesions of the aortic surface were found macroscopically in the C-6-S group than in the cholesterol-diet group. The cholesterol, esterified cholesterol and calcium concentrations of the aortic intima-media in the C-6-S group were significantly lower than in the cholesterol-diet group. Hydroxyproline levels in these three groups were not different. The uronic acid concentration of the intima-media in the cholesterol-diet group was significantly higher than in the C-6-S group (P less than 0.02). Though the percentage of heparan sulfate on total glycosaminoglycans (GAGs) of the C-6-S group was lower than in the cholesterol-diet group, there were no significant differences in the percentages of dermatan sulfate and chondroitin-4/6-sulfate in total GAGs between the cholesterol-diet and C-6-S groups. These results suggest that chondroitin-6-sulfate suppresses cholesterol deposition in the aorta of rabbits fed a 1% cholesterol diet, probably partly due to a decrease in the plasma low-density lipoprotein cholesterol, and partly due to a change in arterial metabolism.
Exp Med Surg. 25, 61-71, 1967
Treatment of Atherosclerosis with Acid Mucopolysaccharides
By LESTER M. MORRISON, J. JOSEPH QUILLIGAN, Jr.,
KATSUMI MURATA, 0. ARNE SCHJEIDE, LEON FREEMAN,
and BENJAMIN H. ERSHOFF
From the Institute for Arteriosclerosis Research, Loma Linda University School of Medicine, Los Angeles, California; and the Laboratory of Nuclear Medicine' and Radiation Biology, and Department of Biophysics and Nuclear Medicine,
University of California School of Medicine, Los Angeles.
Although atherosclerosis and its complications now account for the majority of deaths in the United States, no satisfactory measure or specific treatment for this "endemic" disease has as yet been found. Atherosclerosis is now believed to be not only a preventable disease, but actually a reversible process as shown by Katz, Pick and their coworkers, Page et al, Anitschkou, Bevans, Davidson, and Kendall , Wilens and others and not necessarily the inevitable end result of "wear and tear", aging or stress, as pointed out earlier by Morrison et al. The following report deals with the treatment of atherosclerosis of the coronary arteries and the aorta by acid mucopolysaccharides (AMPS) and in particular with chondroitin sulfate A (CSA). Studies were conducted with three species of animals: squirrel monkeys (Salmiri sclurea) which develop naturally occurring atherosclerotic lesions similar in a number of respects to those observed in man, rats and rabbits.
In view of the physiologic effects of CSA which we have noted upon RNA and DNA metabolism at the cellular level, we have considered the possibility that CSA may act therapeutically upon the connective tissue of the artery wall, to account for its anti- atherogenic properties in experimental atherosclerosis. It has been repeatedly observed that the atherosclerotic process in the intima and media of the artery wall is associated with or related to local AMPS accumulation. Many investigators believe that AMPS deposition in the atherosclerotic lesions of the arterial wall are part of the complications of the atherosclerotic process, becoming the basis for calcification and leading to irreversability of the lesions. However, other investigators regard this phenomenon as possibly a defense or reactive mobilization in the connective tissue of the arterial wall. Various investigators have also noted a decrease in CSA and/or CSC with concomitant increase in CSB content of the arterial wall with the advancing atherosclerotic and aging process. If this latter is true, it is suggested that CSA may possibly act as "replacement" therapy in experimental atherosclerosis. Further studies could clarify the mechanism of action.
The effect of CSA on serum cholesterol and total lipids was found to be variable in our experience. In monkeys we found that parenteral CSA gave a significant reduction in total serum lipids after nine months of treatment. The effects of CSA on serum cholesterol were variable.
In rats and rabbits we have found no significant changes of serum cholesterol or total lipids in cholesterol-fed animals treated with CSA compared to cholesterol-fed animals not administered CSA. These findings are not unusual since it its common knowledge that the atheroscerotic process is not necessarily related to serum hype rchole sterolemia or hyperlipernia as pointed out by Morrison ,DeBakey et al. and many others. On the other hand, the case for an etiologic role of serum lipids in experimental atherosclerosis is very good and it appears to be reasonably well established in man.
Oshima et al and Kurita have also tested the effect of chondroitin sulfates (presumably combinations of CSA and CSC with other AMPS obtained from shark or whale cartilage) on blood cholesterol levels in human subjects with hypercholesterolemia and in hype rc holesterolemic rabbits. The CSA used in our studies was extracted from nasal and tracheal bovine cartilage obtained from commercial sources.
CSA in therapeutic dosages has proved to be systemically non-toxic, without discernible side-effects or abnormal vital organ tissue abnormalities in animals and man to date (local nodules, however, were often noted in both rats and rabbits at the higher dosage levels at the site of injection).
Atherosclerosis is no longer the unique accompaniment of the "human predicament", since it has been recognized as a naturally occurring disease of sub-human, mammals, birds, and fishes. A direct approach to events occurring in cells in the artery wall is the most critical one necessary for therapeutic studies and should not be precluded by concentrating on indirect or secondary concerns over associated factors such as those found in the circulating blood plasma (e.g. cholesterol or triglycerides).
Further studies are now in progress to explore the potential of the acid mucopolysaccharides as agents which may be effective in the prevention and possibly treatment of atherosclerosis.
The acid mucopolysaccharide chondroitin sulfate A (CSA) was found to have anti-atherogenic properties in sub-human primates, rats and rabbits. Squirrel monkeys, a species which develops spontaneous atherosclerosis similar to that observed in man, were fed cholesterol to accelerate the growth of naturally occurring atherosclerotic lesions. Subcutaneous administration of CSA markedly reduced the incidence and severity of aortic atherosclerosis in these animals. CSA was also active when administered orally in inhibiting the incidence and severity of coronary atherosclerosis in x-irradiated, cholesterol-fed rats. Subcutaneous injections of CSA, however, in contrast to orally administered CSA were without protective effect in the rat. Subcutaneous administration of chondroitin sulfate C, an isomer of CSA, as well as CSA was active in inhibiting aortic atherosclerosis in cholesterol-fed rabbits.
The above findings suggest that certain chondroitin sulfates may have value in the treatment and/or prevention of atherosclerosis in man.