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Gene therapy for dyslipoproteinemia and atherosclerosis
Tuesday 11 October: Workshop Abstracts WI4 Treatment advances: atherosclerosis
turn set the stage for vasoconstrictive response to vasoactive substances. Hypertension causes vascular hypertrophy, which is another structuraladaptation of the vessel. Epidemiological studies have shown that uncontrolled hypertension leads to an increase in the incidence of cardiovascular diseases caused by atherosclerosis and that appropriate treatment of hypertension reduces this risk. Calcium antagonists inhibit transmembrane calcium ion flux, thus producing arterial vasodilation and a decline in blood pressure. These drugs, especially those in the dihydropyridine class such as isradipine and nifedipine are powerful antihypertensive agents, and in animal models (e.g. cholesterol-fed rabbits) these drugs have shown antiatherogenic properties too. One hypothesis for the mechanism is that calcium antagonists suppress myoproliferation in response to injury. Some clinical trials of calcium antagonists as antiatherosclerotic drugs have started; foremost among them am the Montreal Heart Institute Study, the INTACT and the MIDAS A brief description of these trials will be given and their results will be discussed. Radical therapy of atherosclerosis by apheresis or liver transplantation mn Gp, MRC Lipoprotein Team, Hammersmith Hosp., Ducane Road, London W12 OHS, UK
The commonest indication for radical anti-atherosclerotic therapy is severe familial hypercholesterolemia (FH), i.e. homozygotes or drug-resistant heterozygotes. The latter am characterized by low rates of cholesterol synthesis and poor response to statin therapy, as judged by plasma mevalonate levels. Liver transplantation is currently the most effective therapy for homozygous FH and can completely normalize plasma lipoproteins including Lp(a), but necessitates life-long immunosuppression with its accompanying risks. Extracorporeal cholesterol removal by plasma exchange or LDL apheresis is less effective than liver transplantation in reducing LDL and Lp(a) levels in homozygotes but has been shown to regress xanthomatous and atheromatous lesions and increase life expectancy. Such procedures may also be useful in drug-resistant heterozygotes with coronary disease but appear to offer no advantage over combination drug therapy in statin-responsive heterozygotes, even those with high Lp(a) levels, judging from the results of the FH Regression Study (FHRS). The frequency and direction of angiographic change did not differ significantly in the FHRS in heterozygotes treated by biweekly LDL apheresis and simvastatin compared with those treated with colestipol and simvastatin, despite higher Lp(a) levels in the latter group during the f-year trial. Currently a pilot study of Lp(a) apheresis is being undertaken in heterozygotes with markedly raised Lp(a) and persistent coronary disease, despite normalized LDL levels. The results may help resolve the issue of whether therapeutic reduction of Lp(a) is advantageous or not. Gene therapy for dyslipoproteinemia and atherosclerosis Smith, Sparrow JT, Woo SLC, Dept. of Med. and Cell Biol., Baylor Colt of Med., One Baylor Plaza, Houston, TX 77030, USA
Current treatment of dyslipoproteinemia relies primarily on reduction of plasma cholesterol and/or triglycerides by administering pharmaceuticals that require life-long medication and frequently produce undesirable side effects. With the advent of technologies for successful gene transfer in animals that result in their constitutive expression in vivo, the therapeutic genes for atherosclerosis can be introduced somatically into the proper organs for expression that may provide a long-term cure for these diseases. The initial experimental animal model has been Watanabe hereditary hypercholesterolemic rabbits, whose high plasma cholesterol levels am due to a mutation in the LDL recep-
181
tor gene. A 75% reduction in plasma cholesterol from 800 to 200 mg/dl has been observed in these rabbits after adenoviralmediated delivery of the rabbit LDL receptor gene directly into the portal vasculature. Them is also a subsequent 4-fold elevation of plasma HDL-cholesterol level, from 5 to 20 mg/dl, in the treated animals. Current experiments are directed toward improvements of replication-defective adenoviruses that will provide long-term expression of the exogenous genes, as well as the development of novel non-viral DNA delivery systems primarily utilizing synthetic peptides. Efticient delivery and enhanced expression of genes that control the metabolism and clearance of plasma lipoproteins will form the scientific basis for future applications of gene therapy for dyslipoproteinemia and atherosclerosis in man. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study, a controlled trial with antioxidant vitamins: results for cancer and ischemic heart disease mJK, Albanes D, Heinonen OP. Taylor PR, Virtamo J, Edwards BK, Rautalahti M, Haapakoski J, Pietinen P, Palmgmn J, Greenwald P, Public Health Inst., Nannerheimintie 166, 00300 Helsinki, Finland and National Cancer Inst., USA
The effect (20mg/day) was studied 29 133 male
of a-tocopherol (SOmg/day) and B-carotene on the incidence of lung cancer and other cancers in a controlled, primary prevention trial among smokers 50-69 years of age from Finland (N Engl J Med 1994; 330: 1029-1035). The intervention continued for 58 years (median 6.1 years). No reduction in incidence of lung cancer was seen in subjects receiving a-tocopherol. Unexpectedly, a higher incidence (+18%) of lung cancer was observed among the men who received /lcarotene. Mortality from IHD was slightly lower among subjects who received a-tocopherol than among those who did not (602 vs. 637) while mortality from hemorrhagic stroke was higher (66 vs. 44). Coronary mortality was higher among the men who received B-carotene than among those who did not (653 vs. 586). Total mortality was 8% higher among the participants who received B-carotene than among those who did not, and 2% higher among those who received a-tocopherol than those who did not. These results do not support the hypothesis that these antioxidants afford protection against lung cancer or cardiovascular diseases. It should be noted, however, that the dose of atocopherol used was relatively small. A study with other doses or longer duration might have given different results. The Heidelberg Regression Study Marbue, Hambrecht R, Niebauer J, Hauer K, Schoppenthau M, Schuler G, Schlierf Cl, Medizinische Universitiitsklinik, Bergheimerstr. 58, 69115 Heidelberg, Germany
The aim of this randomized intervention trial was to determine the influence of physical exercise and a cholesterol-lowering diet on the progression of coronary artery disease (CAD) in middle-aged men. 113 patients were recruited after routine angiography for stable angina pectoris (56 intervention, 57 control group). In 92 patients (40 intervention, 52 control) a second coronary angiography was performed after 1 year, and the results were related to changes in metabolic and hemodynamic data. Patients of the intervention group showed better results: 1. concerning lipid values (TC -10% vs. 0% in the control group; LDL-C -8% vs. +2%; TG -24% vs. -17%); 2. concerning physical work capacity (+23% vs. +6%), myocardial oxygen consumption as estimated from maximal rate-pressure product (10% vs. 4%). and stress-induced myocardial &hernia detected by myocardial scintigraphy (reversible perfusion defect -10% vs. -2%); 3. concerning CAD progression (regression in 30% vs. 4% of the patients, no change in 50% vs. 54%. progression in 20% vs. 42%).
Atherosclerosis X, Montreal, October 1994
turn set the stage for vasoconstrictive response to vasoactive substances. Hypertension causes vascular hypertrophy, which is another structuraladaptation of the vessel. Epidemiological studies have shown that uncontrolled hypertension leads to an increase in the incidence of cardiovascular diseases caused by atherosclerosis and that appropriate treatment of hypertension reduces this risk. Calcium antagonists inhibit transmembrane calcium ion flux, thus producing arterial vasodilation and a decline in blood pressure. These drugs, especially those in the dihydropyridine class such as isradipine and nifedipine are powerful antihypertensive agents, and in animal models (e.g. cholesterol-fed rabbits) these drugs have shown antiatherogenic properties too. One hypothesis for the mechanism is that calcium antagonists suppress myoproliferation in response to injury. Some clinical trials of calcium antagonists as antiatherosclerotic drugs have started; foremost among them am the Montreal Heart Institute Study, the INTACT and the MIDAS A brief description of these trials will be given and their results will be discussed. Radical therapy of atherosclerosis by apheresis or liver transplantation mn Gp, MRC Lipoprotein Team, Hammersmith Hosp., Ducane Road, London W12 OHS, UK
The commonest indication for radical anti-atherosclerotic therapy is severe familial hypercholesterolemia (FH), i.e. homozygotes or drug-resistant heterozygotes. The latter am characterized by low rates of cholesterol synthesis and poor response to statin therapy, as judged by plasma mevalonate levels. Liver transplantation is currently the most effective therapy for homozygous FH and can completely normalize plasma lipoproteins including Lp(a), but necessitates life-long immunosuppression with its accompanying risks. Extracorporeal cholesterol removal by plasma exchange or LDL apheresis is less effective than liver transplantation in reducing LDL and Lp(a) levels in homozygotes but has been shown to regress xanthomatous and atheromatous lesions and increase life expectancy. Such procedures may also be useful in drug-resistant heterozygotes with coronary disease but appear to offer no advantage over combination drug therapy in statin-responsive heterozygotes, even those with high Lp(a) levels, judging from the results of the FH Regression Study (FHRS). The frequency and direction of angiographic change did not differ significantly in the FHRS in heterozygotes treated by biweekly LDL apheresis and simvastatin compared with those treated with colestipol and simvastatin, despite higher Lp(a) levels in the latter group during the f-year trial. Currently a pilot study of Lp(a) apheresis is being undertaken in heterozygotes with markedly raised Lp(a) and persistent coronary disease, despite normalized LDL levels. The results may help resolve the issue of whether therapeutic reduction of Lp(a) is advantageous or not. Gene therapy for dyslipoproteinemia and atherosclerosis Smith, Sparrow JT, Woo SLC, Dept. of Med. and Cell Biol., Baylor Colt of Med., One Baylor Plaza, Houston, TX 77030, USA
Current treatment of dyslipoproteinemia relies primarily on reduction of plasma cholesterol and/or triglycerides by administering pharmaceuticals that require life-long medication and frequently produce undesirable side effects. With the advent of technologies for successful gene transfer in animals that result in their constitutive expression in vivo, the therapeutic genes for atherosclerosis can be introduced somatically into the proper organs for expression that may provide a long-term cure for these diseases. The initial experimental animal model has been Watanabe hereditary hypercholesterolemic rabbits, whose high plasma cholesterol levels am due to a mutation in the LDL recep-
181
tor gene. A 75% reduction in plasma cholesterol from 800 to 200 mg/dl has been observed in these rabbits after adenoviralmediated delivery of the rabbit LDL receptor gene directly into the portal vasculature. Them is also a subsequent 4-fold elevation of plasma HDL-cholesterol level, from 5 to 20 mg/dl, in the treated animals. Current experiments are directed toward improvements of replication-defective adenoviruses that will provide long-term expression of the exogenous genes, as well as the development of novel non-viral DNA delivery systems primarily utilizing synthetic peptides. Efticient delivery and enhanced expression of genes that control the metabolism and clearance of plasma lipoproteins will form the scientific basis for future applications of gene therapy for dyslipoproteinemia and atherosclerosis in man. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study, a controlled trial with antioxidant vitamins: results for cancer and ischemic heart disease mJK, Albanes D, Heinonen OP. Taylor PR, Virtamo J, Edwards BK, Rautalahti M, Haapakoski J, Pietinen P, Palmgmn J, Greenwald P, Public Health Inst., Nannerheimintie 166, 00300 Helsinki, Finland and National Cancer Inst., USA
The effect (20mg/day) was studied 29 133 male
of a-tocopherol (SOmg/day) and B-carotene on the incidence of lung cancer and other cancers in a controlled, primary prevention trial among smokers 50-69 years of age from Finland (N Engl J Med 1994; 330: 1029-1035). The intervention continued for 58 years (median 6.1 years). No reduction in incidence of lung cancer was seen in subjects receiving a-tocopherol. Unexpectedly, a higher incidence (+18%) of lung cancer was observed among the men who received /lcarotene. Mortality from IHD was slightly lower among subjects who received a-tocopherol than among those who did not (602 vs. 637) while mortality from hemorrhagic stroke was higher (66 vs. 44). Coronary mortality was higher among the men who received B-carotene than among those who did not (653 vs. 586). Total mortality was 8% higher among the participants who received B-carotene than among those who did not, and 2% higher among those who received a-tocopherol than those who did not. These results do not support the hypothesis that these antioxidants afford protection against lung cancer or cardiovascular diseases. It should be noted, however, that the dose of atocopherol used was relatively small. A study with other doses or longer duration might have given different results. The Heidelberg Regression Study Marbue, Hambrecht R, Niebauer J, Hauer K, Schoppenthau M, Schuler G, Schlierf Cl, Medizinische Universitiitsklinik, Bergheimerstr. 58, 69115 Heidelberg, Germany
The aim of this randomized intervention trial was to determine the influence of physical exercise and a cholesterol-lowering diet on the progression of coronary artery disease (CAD) in middle-aged men. 113 patients were recruited after routine angiography for stable angina pectoris (56 intervention, 57 control group). In 92 patients (40 intervention, 52 control) a second coronary angiography was performed after 1 year, and the results were related to changes in metabolic and hemodynamic data. Patients of the intervention group showed better results: 1. concerning lipid values (TC -10% vs. 0% in the control group; LDL-C -8% vs. +2%; TG -24% vs. -17%); 2. concerning physical work capacity (+23% vs. +6%), myocardial oxygen consumption as estimated from maximal rate-pressure product (10% vs. 4%). and stress-induced myocardial &hernia detected by myocardial scintigraphy (reversible perfusion defect -10% vs. -2%); 3. concerning CAD progression (regression in 30% vs. 4% of the patients, no change in 50% vs. 54%. progression in 20% vs. 42%).
Atherosclerosis X, Montreal, October 1994