Probucol, blood lipids and the ECG QTc interval.
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Biomedical subjects
Publications and source records attributed to I Graham.
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The effects of calcium on the mixing of synthetic diacylphosphatidylcholines (PC's) and diacylphosphatidylethanolamines (PE's) with the corresponding phosphatidic acids (PA's) have been examined by high-sensitivity differential scanning calorimetry and by measurements of the fluorescence of labeled PA or PC species in PA-PC bilayers. Calorimetrically derived phase diagrams for dimyristoyl- and dielaidoyl-substituted PA-PC and PA-PE mixtures indicate that these species are readily miscible in the absence of calcium but phase-separate very extensively in the presence of high levels of calcium (30 mM). The limiting solubilities of PA (Ca2+) in liquid-crystalline PC or PE bilayers are less than or equal to 10 and approximately 5 mol %, respectively, while approximately 20 mol % of PC or PE can be introduced into the "cochleate" phase of PA (Ca2+) before a distinct PC-rich (or PE-rich) phase appears. The kinetics of calcium-induced lateral phase separations were examined for dioleoyl- and dielaidoyl-substituted PA-PC unilamellar vesicles labeled with fluorescent (C12-NBD-acyl) PA or PC, whose fluorescence becomes partially quenched upon phase separation. Our results indicate that, for the PA-PC system, lateral phase separation is very rapid (approximately less than 1 s) after calcium addition and develops partially (possibly in only one face of the bilayer) when calcium is present only on one side of the bilayer. Moreover, phase separations can develop at a rate faster than that of vesicle diffusion when calcium is added to dilute suspensions of vesicles, suggesting that interbilayer contacts are not essential to promote phase separations.
The effects of calcium ions on mixed membranes of dimyristoylphosphatidic acid (DMPA) and dimyristoylphosphatidylcholine (DMPC) with either the PA or the PC component deuterated have been studied by Raman spectroscopy. The spectra of the pure components show that the acyl chains of hydrated DMPA bilayers are less tightly packed and have more trans bonds than those of DMPC. This behavior appears to be due to the particular arrangement of the polar head groups of DMPA for which the glycerol chain is oriented parallel to the bilayer surface. In agreement with the calorimetrically determined phase diagram [Graham, I., Gagné, J., & Silvius, J. R. (1985) Biochemistry (preceding paper in this issue)], the Raman results show that, in the absence of calcium, DMPA and DMPC are completely miscible at an equimolar ratio but undergo extensive phase separation in the presence of excess calcium. DMPC in phase-separated DMPC-DMPA (Ca2+) mixtures has a conformation that is very similar to that of pure DMPC bilayers, but it is packed more tightly since, depending on the temperature, it is at least partly incorporated into either a solid solution in DMPA or a DMPA-Ca2+-rich "cochleate" phase. This latter shows the same characteristics as the cochleate phase of pure DMPA-Ca2+ which is highly ordered and does not give rise to a thermotropic transition between 5 and 100 degrees C. However, the cochleate phase in DMPA (Ca2+)-DMPC mixtures contains some 20 mol % of DMPC trapped in small domains. These clusters do not melt cooperatively but become as fluid as pure DMPC at 50 degrees C.
In a prospective epidemiologic study of 1001 middle-aged men, we examined the relation between dietary information collected approximately 20 years ago and subsequent mortality from coronary heart disease. The men were initially enrolled in three cohorts: one of men born and living in Ireland, another of those born in Ireland who had emigrated to Boston, and the third of those born in the Boston area of Irish immigrants. There were no differences in mortality from coronary heart disease among the three cohorts. In within-population analyses, those who died of coronary heart disease had higher Keys (P = 0.06) and modified Hegsted (P = 0.02) dietary scores than did those who did not (a high score indicates a high intake of saturated fatty acids and cholesterol and a relatively low intake of polyunsaturated fatty acids). These associations were significant (P = 0.03 for the Keys and P = 0.04 for the modified Hegsted scores) after adjustment for other risk factors for coronary heart disease. Fiber intake (P = 0.04) and a vegetable-foods score, which rose with increased intake of fiber, vegetable protein, and starch (P = 0.02), were lower among those who died from coronary heart disease, though not significantly so after adjustment for other risk factors. A higher Keys score carried an increased risk of coronary heart disease (relative risk, 1.60), and a higher fiber intake carried a decreased risk (relative risk, 0.57). Overall, these results tend to support the hypothesis that diet is related, albeit weakly, to the development of coronary heart disease.
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A study of certified mortality between 1968 and 1981 indicates that mortality from all causes commenced to decline from the mid 1970s in the Republic of Ireland. This trend was apparent for both sexes and for all ages except for men aged 55-64 years. A similar trend of lesser magnitude is suggested for coronary heart disease mortality in males, but not in females. The decrease in the percentage of male cigarette smokers in the population which is also reflected in a marked decline of smoking among male coronary patients, may be related to the trends in mortality.
Nutrient intake was altered favourably in the diets of 38 cardiac patients who were followed up for 1 year as part of a rehabilitation programme. Total energy intake was reduced from 3540 kcal (14.9 MJ) to 2484 kcal (10.4 MJ). Fat intake was reduced from 41 to 37 per cent of energy intake with an accompanying increase in P : S ratio from 0.18 to 0.60. Cholesterol intake was reduced from 564 to 332 mg. Carbohydrate was increased from 38 to 41 per cent of energy intake with an increase in fibre intake from 18 to 24 g. The energy contributed by alcohol was reduced from 6 to 5 per cent. Patients varied in their compliance but all patients made some changes in their dietary intake. Changes in body weight, serum cholesterol levels, cigarette-smoking status and levels of physical activity tended to correspond with the recorded changes in nutrient intake. A low level of education, low socio-economic group, lack of understanding of the illness by the patient and inadequate communication were associated with reduced compliance. Initial motivation and anxiety levels in hospital had less effect on compliance.
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A total of 586 men who survived an initial attack of unstable angina or myocardial infarction have been followed for up to 15 years. A policy of early mobilization and sustained risk factor advice was employed. A conservative approach to treatment was adopted during the acute and follow-up stages. Drugs were employed only for symptomatic reasons, and only two patients proceeded to coronary artery bypass surgery. Survival at 5, 10, and 15 years was 80%, 61%, and 43%. Older patients and those with more severe initial attacks had a higher mortality, but these factors did not relate to combined fatal and nonfatal recurrence of myocardial infarction. Of 22 studies reviewed, 18 report a higher mortality than does our study. Four studies, none strictly comparable, report a similar 5-year mortality. A conservative approach to management does not appear to be harmful and may be beneficial.
Six hundred and thirty-four male patients under 60 years who survived a first attack of unstable angina or myocardial infarction were followed for a period of four years. Details of initial and follow-up smoking habits were examined. Patients who continued to smoke cigarettes or cigars had an excess mortality compared with non-smokers, with those who stopped smoking, and with cigarette smokers who changed to pipe smoking. Pipe smokers who continued smoking the pipe had an observed mortality which was greater than that of the non-smokers, but the numbers were small and the results were not statistically significant. The effect of smoking habit on mortality was not influenced by two other determinants of prognosis: age and severity of initial attack. These results confirm that the long-term prognosis of patients after unstable angina or myocardial infarction may be significantly influenced by smoking habits. They are consistent with the hypothesis that cigar and pipe smoking may have an adverse effect after myocardial infarction but further studies are needed to corroborate the association between cigar and pipe smoking and prognosis of coronary heart disease.
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One hundred one patients with unstable angina were treated conservatively without the routine use of beta receptor blocking agents, calcium antagonist drugs, anticoagulant agents or nitrates. Only two patients underwent arteriography and coronary arterial bypass surgery during hospitalization and one patient during the 1st year of follow-up study. The 28 day mortality rate was 4 percent and the total 1 year cardiac mortality rate 10 percent. Two patients died from carcinoma. The incidence rate of nonfatal myocardial infarction was 9 percent during the first 28 days and a further 3 percent for the 1st year. These results compare favorably with the immediate and 1 year prognosis reported from other studies using different treatment procedures, including modern intensive drug treatment and coronary arterial bypass surgery. Various factors studied during the acute stage of unstable angina were assessed in an effort to predict the immediate and long-term outcome. Only persistence of pain after admission to the hospital was found a significant indicator of an adverse prognosis. Modern medical treatment of unstable angina with beta receptor blocking agents, calcium antagonist drugs, anticoagulant agents, nitrates and antiarrhythmic agents is critically examined. The paucity of proper randomized controlled studies confirming the value of medication is underlined. There is little evidence to show that aggressive or intensive medical or surgical treatment is superior to a conservative approach to management in the coronary care unit. This approach includes bed rest until the pain has resolved, symptomatic drug treatment only, the minimal use of invasive investigations and careful risk factor intervention.
Between 1961 and 1975 the proportion of cigarette smokers among male patients with acute coronary heart disease showed a progressive decline from 87.1 to 66.1%. There was a corresponding increase in the proportion of ex-smokers and non-smokers. Factors which might have accounted for this trend were examined. Changing diagnosis, altered prevalence of other risk factors and social class changes in patient referral would not appear to have accounted for the observed smoking trends. It is suggested that the observed trends in cigarette-smoking habits may be real and that they may represent a change in the epidemiological pattern of coronary heart disease in Ireland.