Biomedical subjects
Publications and source records attributed to L Wallentin.
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Coronary blood flow might be reduced by platelet aggregates or by vasospasm induced by platelet-produced thromboxane A2. Therefore the effects of the platelet inhibitor ticlopidine (500 mg daily) on platelet function and on exercise tolerance were investigated in a double-blind placebo-controlled study in 38 middle-aged men with stable incapacitating angina pectoris. Before and after 4 and 8 weeks of treatment, exercise tests were performed in warm and cold environments. The in vitro platelet reactivity to ADP was determined at rest and the plasma levels of beta-thromboglobulin (BTG) and platelet factor 4 (PF4) were measured before and immediately after exercise. There were no signs of increased platelet activity at rest or after exercise as judged by the levels of BTG and PF4. Despite a potent inhibition of platelet reactivity to ADP in vitro during ticlopidine treatment, the exercise tolerance was reduced in exercise tests in both warm and cold environments and in daily life. Therefore platelet activity does not seem to play any significant role in exercise tolerance in the stable phase of angina pectoris.
In 276 men with suspected unstable coronary artery disease i.e. recurring chest pain of new onset, increasing symptoms of anginal chest pain in formerly stable angina pectoris or suspected non-Q-wave infarction, an exercise test was performed 2-7 days after admission. Coronary events i.e. cardiac death (N = 4), Q-wave infarction (N = 11) and coronary artery bypass grafting (N = 34), were registered during one year follow-up. The indication for bypass grafting was incapacitating angina pectoris despite medication, and suitable coronary anatomy. Stepwise multiple regression analysis showed that S-T segment depression and limiting chest pain were the most important prognostic parameters regarding coronary events. In patients with S-T segment depression greater than 0.1 mV or limiting chest pain (N = 94) the occurrence of Q-wave myocardial infarction or cardiac death was 10.6% (N = 10) compared to 2.8% (N = 5) in patients without these criteria (N = 182) (P less than 0.01). Coronary artery bypass graft surgery was performed in 33% (N = 31) of the group with S-T segment depression greater than 0.1 mV or limiting chest pain but in only 1.7% (N = 3) of the other patients (P less than 0.001). Thus, in patients with suspected unstable coronary artery disease, whose symptoms and signs of ischaemia are stabilized by medication, an exercise test can safely be performed after a few days ambulation in the ward. The early exercise test provides important prognostic information regarding the risk for severe coronary events within the next year.
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The concentrations of cholesterol (C) and phospholipid (PL) levels in the high density lipoprotein (HDL) fraction and the HDL2 and HDL3 subfractions were determined in 74 men with incapacitating angina pectoris and coronary artery disease (CAD) verified by angiography. An equal number of randomly sampled healthy men matched for age, occupation and place of living constituted the control group. The HDL2 and HDL3 fractions were separated by a combination of ultracentrifugation and precipitation. The levels of HDL-C and HDL-PL were reduced in the CAD patients. The reduction of HDL lipids was attributed to both the HDL2 and HDL3 fractions. Proportionally there was a greater reduction of C and PL in HDL2 than in HDL3. The decrease of HDL2-C and HDL3-PL were significant also after allowance for the influences of obesity and triglyceride level. The reductions of HDL2 and HDL3 were significant as well in smoking as in nonsmoking CAD patients and both in patients with and without beta-adrenoceptor blocking drugs.
The influence of the platelet inhibitory drug Ticlopidine (T) (500 mg daily) on lipoprotein metabolism was investigated in a double-blind placebo-controlled study of 38 middle-aged men with incapacitating stable angina pectoris. The concentrations of cholesterol (C), phospholipid (PL) and triglyceride (TG) in plasma, and very low density (VLDL), low density (LDL) and high density lipoprotein (HDL) fractions were measured before and after 4 and 8 weeks of treatment. After 8 weeks of T treatment the levels of C, PL and TG were increased by 14%, 15% and 30%, respectively. These elevations were confined to the atherogenic VLDL and LDL fractions. The LDL level showed a continuous increase during the study. There were no changes in the HDL fraction. The present findings emphasize the necessity to investigate several risk factors in all attempts of prevention of atherosclerotic disease. Before and during long-term treatment with T monitoring of plasma lipoprotein levels are recommended.
The safety of and the diagnostic information provided by a predischarge exercise test performed 2-7 days after admission to the coronary care unit (CCU) was evaluated in 400 patients less than 65 years of age with suspected unstable coronary artery disease, i.e. probable or definite non-transmural myocardial infarction, progressive angina pectoris or recurring chest pain of recent onset ('new chest pain'). No serious complications occurred. Signs of ischaemia during exercise tests were more common in older than in younger men and more often found in subjects with than without pathological findings in resting ECGs in the CCU. Above 45 years of age, more than half of the men with progressive angina or non-transmural MI had SI depression greater than or equal to 2 mm and/or limiting chest pain, whereas men less than 45 years of age had a 10-25% incidence of corresponding findings in the test. In women above 55 years with progressive angina or non-transmural MI, 30-35% had ST depression and/or limiting chest pain at the test while 20-30% of women below 55 years of age had similar findings at the test. Beta-adrenoceptor blockade was used by half of the patients but did not seem to conceal signs of severe ischaemia. Thus a predischarge exercise test can be performed safely in patients with suspected unstable coronary artery disease in order to support or reduce the suspicion of severe disease.
The effects on the lipoprotein metabolism of six cycles of treatment with 2 mg of the anti-androgenic progestogen Cyproterone acetate + 50 micrograms of ethinyl estradiol were prospectively studied in 22 healthy premenopausal women. The plasma level of cholesterol (C) was unchanged, while the levels of HDL-C and its subfractions HDL2-C and HDL3-C were significantly elevated after only one cycle. The LDL-C decreased after one month but then returned to pretreatment levels. VLDL-C was unchanged. The phospholipid concentrations within the various lipoprotein fractions generally resembled those of the corresponding cholesterol fraction. The levels of fibrinogen in plasma and of triglycerides in plasma and in the lipoprotein fractions were elevated. It is concluded that the drug had a predominant and rather pronounced estrogenic profile.
Ten women with endometriosis were treated with medroxyprogesterone acetate (MPA), 150 mg intramuscularly every second week. After 2 weeks, there was a significant (8%) decrease in the high-density lipoprotein (HDL) concentration. This reduction became more pronounced after 8 and 24 weeks' medication. The HDL reduction was confined to the HDL2 subfraction, which was decreased by 15%, 33%, and 58% after 2, 8, and 24 weeks, respectively; there was no significant change in the HDL3 concentration. During treatment, there was a continuous increase in the mean MPA plasma level and a strong inverse correlation between this level and the mean HDL and HDL2 cholesterol concentrations. It was concluded that MPA affects HDL metabolism in a dose-dependent way and in the same direction as other progestins.
The lecithin:cholesterol acyl transfer (LCAT) reaction produces cholesteryl esters and lysolecithin in plasma. The rate of LCAT is related to the plasma lipoprotein concentrations. During pregnancy there are pronounced elevations of the lipid and lipoprotein concentrations. Therefore, we studied the LCAT rate and its relation to the lipid levels in plasma lipoproteins in 19 healthy women before conception, every sixth to eighth week during pregnancy, and 8 weeks after delivery. In the first part of gestation the mean molar LCAT rate (the amount of cholesteryl esters produced during a certain time, in micromoles per liter per hour) remained unchanged, whereas pronounced elevations were seen in the very low-density lipoprotein (VLDL), high-density lipoprotein (HDL), and HDL2 levels. The molar LCAT rate did not increase until the last trimester of pregnancy, when it reached a maximal 20% mean increase simultaneous with the maximal increase of the mean triglyceride and VLDL levels and a slight decline of the HDL2 elevation. The mean fractional LCAT rate (the part of unesterified cholesterol that is esterified during a certain time, in percent per hour) showed a continuous decrease from the fourteenth until the twenty-eighth week, simultaneous with a progressive rise of the mean cholesterol and low-density lipoprotein (LDL) concentrations. During pregnancy the molar LCAT rate was positively correlated to the VLDL concentration and negatively to the HDL2 level, and the fractional LCAT rate was negatively correlated to the LDL concentration.
The effects of ticlopidine (T) (500 mg daily) on platelet function were investigated in a double-blind placebo-controlled study in 38 middle-aged men with stable incapacitating angina pectoris. The in vitro platelet reactivity to aggregating agents, the platelet sensitivity to prostacyclin and the plasma levels of platelet specific proteins and fibrinogen were determined before and after 4 and 8 weeks of treatment. T exerted a potent inhibitory effect on ADP-and collagen-induced platelet aggregation. The effect of T was proportional to the pretreatment reactivity to ADP and collagen. The inhibitory effect of T on the epinephrine response was less pronounced. The plasma levels of beta-thromboglobulin, platelet factor 4 and fibrinogen were not influenced by T. The platelet inhibition of prostacyclin was potentiated by T, and it was demonstrated that T and prostacyclin had synergistic inhibitory effects on platelet aggregation.
In this study 74 men, 40-60 years old, with incapacitating angina pectoris and angiographically verified coronary artery disease (CAD) were compared to an equal number of randomly sampled healthy men matched for age, occupation and place of living. Obesity and smoking were more common in patients than in controls. The patients had elevated cholesterol (C), triglycerides (TG), and phospholipid (PL) levels dependent on raised concentrations of these lipids in the VLDL and LDL. The C and PL levels in the HDL fraction were decreased. Obesity had a significant influence on the VLDL and HDL levels. Also after taking this influence into account, the CAD patients had higher VLDL and LDL levels and a lower HDL concentration than the controls. Furthermore, regardless of the influence of the TG concentration, the HDL level was reduced in the patients. Smoking habits had no significant influence on the lipoprotein levels. Treatment with beta-adrenoceptor blocking drugs was not associated with any significant alteration of the VLDL or the HDL level. The results strengthen the importance of lipoprotein aberrations as risk factors for coronary heart disease also if observed in association with obesity, smoking and treatment with beta-adrenoceptor blocking drugs.
The effects of glyceryl-trinitrate (GTN) and dipyridamole (DIP) on relaxation of bovine coronary arteries and on inhibition of aggregation of human platelets have been studied in vitro with special reference to the cyclic GMP (cGMP) system. GTN had a dose-dependent relaxant effect on bovine coronary arteries, and at a high concentration (10(-5) M) it had an inhibiting effect on platelet aggregation. The effects were associated with an increase in the cGMP levels of the tissues. DIP (5 X 10(-7) M respectively 5 X 10(-6) M) potentiated the coronary artery relaxation induced by GTN (10(-8) M) and the inhibition of platelet aggregation caused by GTN in the concentrations 10(-7)-10(-4) M. The potentiation was associated with higher levels of cGMP than those produced by GTN alone, at least in bovine coronary arteries. However, at a concentration of 10(-4) M, GTN, in combination with DIP, caused a significant fall in the cGMP level compared to GTN alone. GTN and DIP were not found to significantly increase the cAMP levels in the concentrations tested. DIP was shown to inhibit phosphodiesterase (PDE) from both platelets and bovine coronary arteries. This might be one of the possible mechanisms that can explain the above mentioned potentiation. It is suggested that the combination of DIP + GTN may be of some clinical importance since the potentiating effects were seen at concentrations comparable to the therapeutic plasma concentration for the respective drugs.
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In 19 healthy women the levels of plasma lipoprotein fractions were determined before conception, at exact gestational ages every six to 8 weeks during pregnancy, and eight weeks after delivery. The high density lipoprotein level was elevated in the 14th week and showed a maximum rise by 41% in the 28th week of pregnancy because of a doubling of the high density lipoprotein2 level. The low density lipoprotein level decreased in early pregnancy but then increased continuously. The very low density lipoprotein triglyceride concentration showed a continuous increase from week 14, and in week 36, it was three times higher than before pregnancy. During lactation, eight weeks after delivery, the low density lipoprotein concentration remained elevated, whereas the other lipoproteins had returned to prepregnancy levels.
Twelve women with pelvic endometriosis were treated with 600 mg of danazol daily for 24 weeks. The molar and fractional lecithin:cholesterol acyl transfer (LCAT) rates and the concentrations of cholesterol, phospholipids, and triglycerides were determined in plasma and in the very low-density lipoprotein, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and HDL2 and HDL3 fractions before, during, and after the medication. After 2 weeks the HDL, HDL2, and HDL3 cholesterol concentrations were reduced by 49%, 73%, and 29%, respectively, while the LDL level was increased by 14%. The molar and fractional LCAT rates decreased during treatment, and these reduced LCAT rates are consistent with a reduced fractional LDL removal. Within 8 weeks after cessation of medication, all parameters had returned to the pretreatment levels.