Combining genomewide association study and lung eQTL analysis provides evidence for novel genes associated with asthma.

BACKGROUND: Genomewide association studies (GWASs) of asthma have identified single-nucleotide polymorphisms (SNPs) that modestly increase the risk for asthma. This could be due to phenotypic heterogeneity of asthma. Bronchial hyperresponsiveness (BHR) is a phenotypic hallmark of asthma. We aim to identify susceptibility genes for asthma combined with BHR and analyse the presence of cis-eQTLs among replicated SNPs. Secondly, we compare the genetic association of SNPs previously associated with (doctor's diagnosed) asthma to our GWAS of asthma with BHR. METHODS: A GWAS was performed in 920 asthmatics with BHR and 980 controls. Top SNPs of our GWAS were analysed in four replication cohorts, and lung cis-eQTL analysis was performed on replicated SNPs. We investigated association of SNPs previously associated with asthma in our data. RESULTS: A total of 368 SNPs were followed up for replication. Six SNPs in genes encoding ABI3BP, NAF1, MICA and the 17q21 locus replicated in one or more cohorts, with one locus (17q21) achieving genomewide significance after meta-analysis. Five of 6 replicated SNPs regulated 35 gene transcripts in whole lung. Eight of 20 asthma-associated SNPs from previous GWAS were significantly associated with asthma and BHR. Three SNPs, in IL-33 and GSDMB, showed larger effect sizes in our data compared to published literature. CONCLUSIONS: Combining GWAS with subsequent lung eQTL analysis revealed disease-associated SNPs regulating lung mRNA expression levels of potential new asthma genes. Adding BHR to the asthma definition does not lead to an overall larger genetic effect size than analysing (doctor's diagnosed) asthma.

[Asthma/COPD service in general practice. Study into feasibility and effectiveness]. / Een astma/COPD-dienst voor de huisartsenpraktijk.

OBJECTIVE: A study of the effectiveness and functioning of an asthma/COPD service (AC service). DESIGN: Observational study. METHOD: General practitioners (GPs) in the northern part of the Netherlands can refer patients with airway symptoms to the AC service, which was set up in 2007 by local pulmonologists, GPs and the primary care laboratory CERTE. Before the assessment, patients fill in three questionnaires at home: the Clinical COPD Questionnaire (CCQ), the Asthma Control Questionnaire (ACQ) and a medical history list. The laboratory assesses lung function and a physical examination is carried out. All data is sent via the Internet to a pulmonologist, who advises the GP on diagnosis and treatment via an information system. The pulmonologist can offer a follow-up service if required. For this publication we had access to data from 14,748 registered patients and 3721 follow-up consultations. RESULTS: The pulmonologist diagnosed 6201 (42%) patients with asthma, 2728 (19%) with COPD and 1039 (7%) with 'asthma/COPD overlap syndrome'. The pulmonologist advised that 940 patients (6%) should have a change in medication and reassessment after 3 months. In this group, the number of unstable COPD patients (CCQ ≥ 1) dropped from 134 (67%) to 99 (50%). The number of patients with unstable asthma (ACQ ≥ 1.5) dropped from 245 (3%) to 137 (24%). For 1642 (11%) patients the pulmonologist advised no change in medication and the GP referred the patient for reassessment after 12 months. These patients were generally stable, with a slight improvement in smoking status, exacerbations and inhalation technique. CONCLUSION: Approximately 60% of all patients with asthma or COPD in this region were assessed by the AC service at least once in the period 2007-2014. Advice on diagnosis and treatment given to the GP resulted in better patient-related outcomes in both asthma and COPD patients.

Metabolic modulation of cardiac neurosympathetic activity in vivo: effects of potassium and adenosine.

The effects of intracoronary (LAD) infusion of potassium and adenosine on changes in coronary vascular resistance and regional cardiac noradrenaline overflow during graded cardiac sympathetic stimulation were assessed in non-ischaemic myocardium in the open chest anaesthetised dog. Intracoronary potassium at three concentration (10, 25, 75 mmol.litre-1) progressively increased the potassium content of local venous effluent from 3.6 to 9.4 mmol.litre-1 and produced biphasic effects on nerve stimulated regional noradrenaline overflow. At low dose it was inhibitory (peak overflow at 20 Hz stimulation being reduced from (mean(SEM)) 10.2(2.6) to 2.9(1.8) pmol.ml-1 with 10 mmol.litre-1 potassium chloride; p less than 0.01). At high dose, overflow was potentiated to 13.3(2.7) pmol.ml-1 with 75 mmol.litre-1 potassium chloride (p less than 0.05). Noradrenaline overflow from and the potassium content of circumflex territory venous effluent was unchanged. Intracoronary adenosine at high concentration (10(-3) and 10(-2) mol.litre-1) potentiated basal noradrenaline overflow from the heart producing a small negative arteriovenous concentration difference of 0.6(0.7) and 1.0(0.6) pmol.ml-1 respectively. However, noradrenaline overflow during maximal sympathetic stimulation was inhibited from 3.8(1.4) to 0.4(0.7) pmol.ml-1 with 10(-3) mol.litre-1 adenosine and to 0.7(0.6) pmol.ml-1 with 10(-2) mol.litre-1 adenosine (p less than 0.05). The changes in blood flow and coronary vascular resistance seen with sympathetic stimulation were not modified by adenosine, despite major alteration in basal coronary vascular tone. Thus both metabolites may potentially alter local neurosympathetic activity in ischaemic myocardium and act diversely to determine noradrenaline release at the nerve terminal.

Lysolecithin and acute coronary ligation in the anaesthetised dog.

The metabolism of lysolecithin by the normal and by the ischaemic heart was examined in eight anaesthetised dogs. Relative lysolecithin concentrations (%lysolecithin) were measured in arterial, local (ischaemic) venous and coronary sinus (nonischaemic) blood samples, withdrawn before and at 2, 6, 10, 15 and 20 min after ligation of the left anterior descending coronary artery. Before ligation, 9.0 +/- 0.8% of the arterial lecithin was in the form of the lyso-derivative. The heart extracted lysolecithin, as reflected by the positive arterio-venous difference of lysolecithin. Arterio-venous differences of %lysolecithin across both the ischaemic and nonischaemic myocardium tended to diminish after coronary ligation, whether or not the dogs developed ventricular fibrillation. These results do not support the view that the formation of lysolecithin during ischaemia precipitates arrhythmias, since lysolecithin levels do not reach those necessary to induce electrophysiological abnormalities in vitro. Nor will the uniform response of the ischaemic and nonischaemic tissue result in metabolic heterogeneity leading to electrophysiological heterogeneity, which is thought to be an important factor in the development of re-entry arrhythmias.

Cardiovascular protection by oestrogen is partly mediated through modulation of autonomic nervous function.

Experimental studies have provided evidence that the autonomic nervous activity is modulated by oestrogen. Such modulation at central and peripheral levels tends to suppress sympathetic but elevate parasympathetic tone to the cardiovascular system. Thus, available data support the view that cardiovascular protection by oestrogen may, at least in part, be mediated by its influence on autonomic nervous function.

Patterns of flow and conduction during early ventricular arrhythmias following coronary arterial occlusion in the dog.

The early ventricular arrhythmias of acute myocardial ischaemia arise against a background of rapid alterations in regional myocardial blood flow and electrophysiological properties. The relation between patterns of flow and epicardial activation has been examined in eight open chest anaesthetised dogs at time of onset of these arrhythmias following a proximal occlusion of the left anterior descending coronary artery. Data were derived from 80 epicardial and endocardial sites within a 4 X 5 cm area of left ventricular free wall and processed utilising a three-dimensional computer plotting program. Mean flow within the ischaemic zone was reduced to 0.27 and 0.24 cm3 x g-1 x min-1 in epicardium and endocardium respectively. Marked epicardial activation delays and fragmentation of conduction were observed confined to areas of flow less than 0.3 cm3 x g-1 x min-1. 74% of endocardial and 71% of epicardial tissue samples within the ischaemic zone derived from this area and analysis of flow distribution between adjacent samples demonstrated spatial heterogeneity of flow. It is suggested that local spatial variability in flow within the central ischaemic region may be a prerequisite for abnormal fractionation of conduction leading to re-entrant excitation at the time of onset of early ventricular arrhythmias.

Effects of dichloroacetate on myocardial substrate extraction, epicardial ST-segment elevation, and ventricular blood flow following coronary occlusion in dogs.

Glucose metabolism in the healthy heart is stimulated by dichloroacetate (DCA). The possibility has been examined in dogs that DCA, by increasing glucose utilization, might limit the severity of acute myocardial ischaemic injury. Intravenous administration of DCA reduced the degree of epicardial ST-segment elevation induced by subsequent coronary occlusion, both under basal conditions and during isoprenaline infusion. A similar result was obtained when DCA was given during an established coronary occlusion. This effect could not be explained by changes in mean aortic blood pressure, heart rate, or regional myocardial blood flow as measured by radioactive microspheres. Measurements in arterial and coronary sinus blood demonstrated an increase in the extraction of glucose and a decrease in that of FFA by the heart. Glucose extraction also tended to be increased in the ischaemic zone, as shown by the differences in the concentrations of these substrates between arterial blood and blood obtained from the local vein draining that zone. Lactate release by the ischaemic zone was markedly reduced.

Relationship of neurosympathetic responsiveness to early ventricular arrhythmias in ischaemic myocardium.

Myocardial catecholamine overflow has been measured in open-chest anaesthetised dogs after graded stimulation of the left ansa subclavia before and during left anterior descending coronary artery occlusion and on reperfusion. Sequential 1 min periods of ansa stimulation over 3 h resulted in reproducible, frequency dependent regional myocardial noradrenaline (NA) overflow without tachyphylaxis. In seven dogs, two successive 10 min periods of LAD occlusion did not modify peak myocardial NA overflow from the predominantly ischaemic (I) or non-ischaemic (NI) areas at either low (1 Hz) or high (10 Hz) frequency ansa stimulation. In a second group of nine dogs, myocardial catecholamine overflow was related to changes in ischaemic area epicardial activation delay during repeated ansa stimulation on four occasions during 75 min of ischaemia. Stimulation at the period of peak spontaneous arrhythmias 5 and 17 min after coronary occlusion resulted in NA overflow from I of 2.8 +/- 1.3 and 3.0 +/- 1.6 pmol X ml-1 respectively and a significant increase in mean activation delay in I of 12 +/- 4 ms at 5 min and 9 +/- 4 ms at 17 min (p less than 0.05). In contrast, stimulation 30 and 60 min after coronary occlusion, when spontaneous arrhythmias are rare, was not associated with NA overflow from ischaemic areas (0.3 +/- 0.3 and 0.9 +/- 0.5 pmol X ml-1 respectively) and resulted in a minor reduction in mean activation delay in ischaemic areas of 2 +/- 3 ms at 30 min and 3 +/- 4 ms at 60 min. NA overflow from non-ischaemic areas and increases in blood pressure and myocardial lactate release were similar during each period of ansa stimulation. Coronary reperfusion induced massive overflow of NA (11.4 +/- 2.8 pmol X ml-1) and reduced extraction of adrenaline (A) from ischaemic areas with a time course similar to early reperfusion arrhythmias. Stimulation-evoked release of NA in ischaemic myocardium is thus maintained during the early period of enhanced vulnerability to arrhythmias and during reperfusion but is inhibited after 30 min. This temporal variability may be a factor in the time course of spontaneous arrhythmias in this model.

Vitamin C and the risk of acute myocardial infarction.

BACKGROUND: Low-fat soluble-antioxidant status is associated with an increased risk of heart disease. OBJECTIVE: The aim of this study was to examine whether low plasma concentrations of vitamin C confer an independent risk of acute myocardial infarction (AMI). DESIGN: Male patients (n = 180) aged <65 y with a first AMI and without an existing diagnosis of angina (>6 mo) who were admitted within 12 h after onset of symptoms were compared with apparently healthy volunteers (n = 177). Plasma concentrations and dietary intakes of vitamin C were determined during hospitalization and 3 mo later. RESULTS: Compared with the control subjects, the patients had higher total cholesterol and lower HDL-cholesterol concentrations and more of them smoked. The relative risk of AMI for the lowest compared with the highest quintile of plasma vitamin C during hospitalization (14.5 and >60.5 micromol/L, respectively) was 8.37 (95% CI: 3.28, 21. 4) after adjustment for classic risk factors. At 3 mo, mean (+/-SEM) plasma vitamin C concentrations in patients had increased significantly, from 19.6 +/- 1.2 to 35.1 +/- 1.9 micromol/L (P < 0. 001) and no longer conferred a risk of AMI [relative risk: 1.02 (95% CI: 0.51, 2.03)]. Habitual dietary vitamin C intake of patients (before AMI) did not differ significantly from that of control subjects. The increase in plasma vitamin C after recovery from the infarction could not be explained by a similarly large increase in dietary vitamin C. CONCLUSIONS: A low plasma concentration of vitamin C was not associated with an increased risk of AMI, irrespective of smoking status. The apparent risk of AMI due to a low plasma vitamin C concentration was distorted by the acute phase response.

Effect of pindolol versus atenolol on lipid profile in hypertensive patients.

The effect of pindolol (a beta-blocker with intrinsic sympathomimetic activity, ISA) on fasting plasma lipid profile in 30 hypertensive patients was compared with atenolol (without ISA) in a crossover single blind study. Both drugs lowered blood pressure. HDL-cholesterol increased significantly with pindolol (from 1.15 +/- 0.05 to 1.34 +/- 0.05 mmol/l at 12 weeks, P less than 0.001), but not with atenolol. VLDL-cholesterol increased with atenolol (from 0.57 +/- 0.09 to 0.86 +/- 0.14 mmol/l at 12 weeks, P less than 0.002), while there was no change with pindolol. These changes in lipoprotein profile suggest a more favourable effect of pindolol than of atenolol on lipid profile.

Effects of Maxepa on serum lipids in hypercholesterolaemic subjects.

The effect of dietary supplementation with 20 capsules/day Maxepa or olive oil on serum lipids has been studied in 21 hypercholesterolaemic patients using a double-blind crossover design. Platelet membrane eicosapentaenoic acid percentage rose by more than 10-fold after 2 months dietary supplementation with Maxepa. Total serum cholesterol was unchanged and there was a rise in LDL-cholesterol and HDL-cholesterol concentration in men, but no change in LDL-cholesterol, and a fall in HDL-cholesterol in women. In men and women there was a marked fall in total serum triglyceride, VLDL-triglyceride and VLDL-cholesterol levels. Thus, Maxepa is not an effective treatment for isolated hypercholesterolaemia.

Plasma vitamin E, apolipoprotein B and HDL-cholesterol in middle-aged men from southern Italy.

Plasma vitamin E, HDL-cholesterol, apolipoprotein B and triglycerides were measured in an apparently healthy, male, random population sample (n = 74) from Southern Italy. Plasma vitamin E concentration was positively correlated to that of serum cholesterol, non-HDL cholesterol, triglycerides and apolipoprotein B (all P less than 0.001). The results of partial correlation analysis showed that apo B, the apolipoprotein constituent of LDL, was related to vitamin E independently of serum triglycerides, a fairly accurate marker of VLDL. On the other hand, triglycerides were related to vitamin E independently of apo B. Both correlations were much weaker if an adjustment was performed for non-HDL-cholesterol. No independent relationship was demonstrated between plasma vitamin E and HDL-cholesterol.

Effects of safflower oil and evening primrose oil in men with a low dihomo-gamma-linolenic level.

Low levels of essential polyunsaturated fatty acids of the n-6 series are associated with coronary heart disease. Linoleic acid, but not gamma-linolenic acid requires the activity of delta 6-desaturase for its conversion to dihomo-gamma-linolenic and arachidonic acid. Evening primrose oil (EPO) and safflower oil (SO) are rich in linoleic acid, but EPO contains also 9% gamma-linolenic acid. The effect of EPO (10, 20 and 30 ml/day) and SO (20 ml/day) for 4 months on the deposition of linoleic acid metabolites in adipose tissue of 4 groups of 6-9 men with low adipose dihomo-gamma-linolenic acid was examined. EPO but not SO increased adipose dihomo-gamma-linolenic acid level from 0.080 +/- 0.005% to 0.101 +/- 0.005% (P less than 0.01; 20 ml/day for 4 months). Adipose dihomo-gamma-linolenic/linoleic acid ratio increased with EPO from 0.99 +/- 0.16 X 10(2) to 1.13 +/- 0.14 X 10(2) and fell on SO from 1.04 +/- 0.10 X 10(2) to 0.90 +/- 0.07 X 10(2) (P less than 0.01). Similar qualitative changes in the relative amount of dihomo-gamma-linolenic acid in serum triglyceride and cholesteryl ester fractions were observed. At the dose of 20 ml/day, SO and EPO did not differ in their effect on serum cholesterol (7.13 +/- 0.43 vs. 7.33 +/- 0.42 mmol/l (NS)), LDL-cholesterol (5.10 +/- 0.32 vs. 4.88 +/- 0.46 mmol/l (NS)) nor did the 2 oils differ in their effect on HDL-cholesterol. These results suggest that linoleic acid is not readily converted to dihomo-gamma-linolenic acid due to a low activity of delta 6-desaturase in these highly selected men. EPO was not an effective hypocholesterolaemic agent in this study.

Glucose tolerance, plasma insulin, HDL cholesterol and obesity: 12-year follow-up and development of coronary heart disease in Edinburgh men.

The insulin response to a standard oral glucose tolerance test (OGTT) and other anthropometric and biochemical risk factors for coronary heart disease (CHD) were measured in a random sample of 107 Edinburgh men, who were initially studied in 1976 when they were 40 and who were reexamined in 1988-89. Fasting glucose and glucose response to OGTT were higher in 1988-89 than in 1976. In contrast, insulin levels did not differ between the initial and follow-up study either before or after the glucose load. Body mass indices increased, except triceps skinfold. Changing patterns in both fasting and OGTT insulin or glucose levels in individuals were related to changes in bodyweight or in subscapular skinfolds. Modifications in serum total and HDL cholesterol were related to changes in fasting insulin and insulin area, respectively, but not to glucose data. Eleven men developed clinical CHD. Neither glucose nor insulin measures obtained in 1976 differed between those with and without CHD. Weight-height index and abdominal skin-folds were higher in those with CHD. HDL cholesterol was significantly lower (P less than 0.05). Abdominal skin-fold but not body mass index remained significant when adjusted for HDL cholesterol. This small study confirms the importance of central obesity and low HDL cholesterol but failed to identify insulin as a risk factor for CHD in this Scottish population.

Relationships of plasma viscosity, coagulation and fibrinolysis to coronary risk factors and angina.

Plasma viscosity, molecular markers of activated coagulation and fibrinolysis (fibrinopeptides A and B beta 15-42), coagulation factors (fibrinogen and factor VII) and antiplasmins were measured in 529 men aged 35-54 years and related to new angina pectoris (n = 117) and to coronary risk factors in controls without angina (n = 412). Five major risk factors (cigarette-smoking, blood pressure, cholesterol, triglyceride and body mass index) were each associated with increases in plasma viscosity, coagulation factors, and imbalance of coagulation over fibrinolysis (increased ratio of fibrinopeptide A/fibrinopeptide B beta 15-42). Increased viscosity and fibrinogen in smokers were partly reversed in ex-smokers, but the imbalance of coagulation and fibrinolysis persisted. Cholesterol and triglyceride were also associated with increased antiplasmin activity. In men with angina, only fibrinogen was elevated compared to controls. We suggest that increased plasma viscosity and an imbalance of coagulation over fibrinolysis may be mechanisms by which known risk factors promote arterial thrombosis, but are not present in stable angina.

Mechanisms of phase 1a and 1b early ventricular arrhythmias during acute myocardial ischemia in the dog.

Two phases of ventricular arrhythmia occur within the first 30 minutes of experimental myocardial ischemia. Possible differences in their mechanisms of pathogenesis were investigated in anesthetized dogs by detailed mapping of patterns of epicardial activation and regional myocardial blood flow during phase 1a and phase 1b early ventricular arrhythmias induced by high ligation of the left anterior descending coronary artery. Data were derived from 80 sites in a 4 by 5 cm area of left ventricular anterior free wall and displayed using computer graphics. Regional myocardial blood flow and the relation of regional flow to epicardial delay did not differ significantly during the 2 phases of arrhythmia in central ischemic or nonischemic areas, although epicardial flow in border region segments was increased during phase 1b. Significantly greater mean epicardial delays and spatial heterogeneity of epicardial delay (assessed by intersite variance within the ischemic area) occurred during phase 1a arrhythmias. Serial studies show striking increases in spatial heterogeneity of delays during phase 1a, but not during phase 1b, relating to temporal dispersion of a phenomenon of transient prolongation of activation delay at individual electrode sites. These data are consistent with the concept that phase 1a and 1b arrhythmias arise through different electrophysiologic mechanisms independent of flow-dependent effects.

Adipose fatty acid composition and the risk of serious ventricular arrhythmias in acute myocardial infarction.

The relation between subcutaneous adipose tissue fatty acid composition and serious ventricular arrhythmias during acute myocardial infarction was studied in 2 groups of patients. In group 1 (n = 42), studied retrospectively, patients with ventricular fibrillation or tachycardia had a higher concentration of long-chain saturated fatty acids than those without (32.5 +/- 0.8% vs 29.7 +/- 0.4% [mean +/- standard error of the mean], p less than 0.01). In a prospective study, patients with arrhythmias (n = 106) had higher levels of long-chain saturated fatty acids (32.1 +/- 0.5% vs 30.7 +/- 0.4%, p less than 0.05) and of stearic acid (4.9 +/- 0.2% vs 4.4 +/- 0.1%, p less than 0.02) and a lower concentration of palmitoleic acid (7.3 +/- 0.3% vs 8.1 +/- 0.2%, p less than 0.005). When peak plasma creatine kinase concentrations were included with the individual fatty acid levels in a multiple logistic regression, only creatine kinase correlated significantly with ventricular arrhythmias (p less than 0.01). Thus, saturated fatty acids in cardiac membranes may lead to greater vulnerability to ventricular arrhythmias, although infarct size is the only statistically significant predictor after multiple regression analysis.

Metabolic requirements for release of endogenous noradrenaline during myocardial ischaemia and anoxia.

The metabolic conditions required for noradrenaline (NA) release from ischaemic and anoxic perfused hearts of the rat were studied. Forty minutes of flow reduction to approximately 0.25 ml g-1 min-1 did not elicit enhanced noradrenaline overflow from the isolated heart perfused with normoxic perfusate even in the absence of added substrate. Enhanced overflow did occur when substrate-free ischaemia was induced after a 60 min period of substrate-free perfusion. Noradrenaline overflow was enhanced by perfusion at normal flow rates with an anoxic (Po2 less than or equal to 1 mmHg) perfusate containing no substrate. Such enhanced overflow occurred in the absence of calcium in the perfusate and was almost completely abolished by the addition of 11 mM glucose. Enhanced noradrenaline overflow occurring either during low flow ischaemia after substrate deprivation or during anoxic substrate-free perfusion at normal flow rates was markedly suppressed by desipramine. Exocytotic noradrenaline overflow induced by electrical stimulation of the left cervico-thoracic ganglion continued unchanged during 60 min of anoxia if the perfusate contained 11 mM glucose. In the absence of added substrate there was a decline in the overflow induced by such stimulation which was more rapid with anoxic than normoxic perfusate. Re-introduction of calcium, oxygen and substrate after 10, 20 or 30 min of calcium-free, substrate-free, anoxic perfusion was associated with a massive overflow of the intracellular enzyme lactate dehydrogenase. At 10 min there was an associated transient minor increase in NA overflow but at 20 and 30 min the overflow of NA, elevated as a result of anoxic perfusion, returned to pre-anoxic levels on the re-introduction of substrate and oxygen. 7 These studies demonstrate a central role for the metabolic status of the sympathetic nerve terminal in determining the magnitude ofexocytotic and nerve-impulse independent noradrenaline release from the heart. During the course of myocardial ischaemia in vivo nerve-impulse independent release would be expected to occur only in regions of severe flow reduction. This may produce heterogeneous stimulation of the myocardium.

Low plasma vitamins E and C. Increased risk of angina in Scottish men.

Cross-cultural studies suggest that low plasma antioxidant levels contribute to the high incidence of coronary heart disease (CHD) in Scotland. One hundred twenty-five cases of angina without reported history were identified by a postal WHO chest pain questionnaire from a systemic population sample of 6000 Edinburgh men (35-54 years). Classical CHD risk factors (lipids, blood pressure, smoking, and relative weight), plasma vitamins, and a new independent CHD risk factor, adipose tissue linoleate, were measured in angina (n = 125) and healthy controls (n = 430). Cigarette smoking was common in angina (46% vs. 29%, p less than 0.01), and adipose tissue linoleate was lower (8.77 +/- 0.18% vs. 9.81 +/- 0.14% (p less than 0.01). Classical CHD risk factors were not different. Vitamin E/cholesterol molar ratio (micron/mM) was lower in angina than in controls: 1.58 +/- 0.03 vs. 1.66 +/- 0.02 (p less than 0.01). Plasma vitamin C was also lower in angina than in controls: 23.6 +/- 1.7 vs. 30.5 +/- 1.1 microM (p less than 0.001). The relative risk of angina for those in the lowest versus those in the highest quintile of the vitamin E/cholesterol ratio distribution was 2.2:1, irrespective of other risk factors (p less than 0.009). Adipose tissue linoleate removed the association between vitamin E and angina. The relative risk of angina for those in the lowest versus those in the highest quintile of plasma vitamin C was 2.6:1 (p less than 0.01), and the increased risk was also independent of classical risk factors, but closely related to a smoking habit. Low plasma vitamin E or adipose linoleate predisposes to angina, and smoking may increase the risk of angina by lowering plasma vitamin C levels in Scottish men.

Correlation of cardiovascular and neuroendocrine tests of autonomic function in diabetes.

Six normal subjects and 16 insulin-dependent diabetics with varying degrees of autonomic damage each had blood sampled for norepinephrine and pancreatic polypeptide for fifteen minutes after a mixed meal and intravenous (IV) edrophonium (Tensilon). The normal subjects showed a brisk but short-lived rise in norepinephrine after edrophonium (average maximum increase 70% between 2 and 6 minutes), as did most diabetics. However, diabetics with cardiovascular reflex evidence of sympathetic damage showed no rise in norepinephrine. Pancreatic polypeptide concentrations increased up to 400% above baseline after a mixed meal in both the normal and the diabetic group with normal cardiovascular reflexes. There was no significant rise in pancreatic polypeptide either in the diabetics with parasympathetic damage alone or in those with additional sympathetic damage. These results provide further evidence for the diffuse nature of the damage in diabetic autonomic neuropathy.