C-reactive protein in migraine sufferers similar to that of non-migraineurs: the Reykjavik Study.

C-reactive protein (CRP), a marker of inflammation, has been associated with cardiovascular disease. Risk of cardiovascular disease is increased in migraineurs with aura. Results from a clinical report, case-control and a cohort study suggest that CRP is elevated in migraineurs compared with non-migraineurs. We examined the proposed association in a case-control study nested within two large population-based studies. The relationship between migraine and CRP (high-sensitivity CRP) was studied in 5906 men and women aged 55.0 +/- 8.5 years in the Reykjavik Study and 1345 men and women aged 27.7 +/- 5.5 years from the Reykjavik Study for the Young. A modified version of the International Headache Society's criteria was used to categorize people into migraineurs (two or more symptoms) or non-migraineurs. Migraineurs with visual or sensory symptoms were further defined as having migraine with aura (MA) or without aura (MO). Multivariable-adjusted CRP levels were similar in migraineurs and non-migraineurs for men (0.83 vs. 0.79 mg/l, P = 0.44) and for women (0.87 vs. 0.87 mg/l, P = 0.90). When further stratified by migraine aura and age, no differences were found between non-migraineurs, MO and MA among men. In women, CRP levels were borderline higher in those with MO compared with non-migraineurs and those with MA (1.01 mg/l vs. 0.81 and 0.75 mg/l, P = 0.08 and P = 0.08) in age group 19-34 years, but significantly lower in age group 60-81 years (0.52 mg/l vs. 1.07 and 1.01 mg/l, P = 0.007 and P = 0.03). CRP levels were not increased among migraine sufferers compared with non-migraineurs. Older women migraineurs without aura had lower CRP values than non-migraineurs and migraineurs with aura.

Increasing glucose levels and BMI predict future heart failure experience from the Reykjavík Study.

BACKGROUND: Heart failure is common in diabetes and ischaemic heart disease is the most likely link. Still, it has been suggested that the relation extends beyond such disease. METHODS: 7060 subjects with two or more visits in the Reykjavík Study were followed--during 30 years from 1967. All underwent oral glucose tolerance tests. Disease status was defined according to the glycaemic level and presence of heart failure. The incidence and predictive factors for these diseases were determined. FINDINGS: Age and sex standardized incidence of heart failure was 5.3/1000/year, of diabetes 4.6/1000/year and abnormal glucose regulation 12.6/1000/year. Body mass index (BMI) and fasting glucose predicted the development of these conditions (p<0.001). Increasing fasting glucose by 1 mmol/l increased the risk for heart failure by 14% (p=0.04) after adjusting for IHD, BMI and other risk factors for CVD. There was a strong association between diabetes and heart failure, OR 3.0 (2.3-4.0), and abnormal glucose regulation and heart failure, OR 1.8 (1.5-2.3). Diabetes and heart failure were, however, not independent predictors of each other. INTERPRETATION: There was an independent relationship between increases in fasting glucose and development of heart failure. BMI was a strong predictor of heart failure. Although fasting glucose and BMI were significant risk factors for glucose disturbances and heart failure the conditions themselves did not independently predict each other.

Inhibitory effects of meta-iodo-benzylguanidine (MIBG) on endothelial histamine receptor binding.

Meta-iodo-benzylguanidine (MIBG), a selective inhibitor of mono-ADP-ribosylation, has been shown to inhibit histamine induced inositol-trisphosphate and prostacyclin production. The purpose of this study was to evaluate the effect of MIBG on the binding of histamine to the H1-receptor and to study its effects on phospholipid metabolism in human endothelial cells. The effects of MIBG and MIBA (meta-iodo-benzylamine), which does not affect cellular ADP-ribosylation, on agonist induced cGMP production in cultured HUVEC's were measured by RIA and a binding study carried out to evaluate their effects on the binding of [3H]mepyramine to membrane fractions. MIBG (0.3 mM) reduced histamine induced cGMP production by 90.8% but did not inhibit the cGMP production induced by other agonists. MIBA had no effect. MIBG also reduced the binding of [3H]mepyramine (1.0 nM) to membrane fractions with IC50 at 0.094 mM and maximal inhibition (83%) at 0.22mM MIBG. The calculated Ki was 0.076mM. MIBG and MIBA altered phospholipid metabolism in a similar way as the cationic amphiphilic drug propranolol. MIBA caused up to 42% reduction in [3H]mepyramine binding, probably due to its inhibition of nonspecific binding. These results indicate that MIBG reduces histamine induced cGMP production by inhibiting its binding to H1-receptors and alters phospholipid metabolism in cultured endothelial cells in a similar way as known cationic amphiphilic drugs.

Silent ST-T changes in an epidemiologic cohort study--a marker of hypertension or coronary heart disease, or both: the Reykjavik study.

OBJECTIVES: We sought to evaluate the prognostic value and clinical characteristics associated with electrocardiographic (ECG) ST-T changes among men without other manifestations of coronary heart disease. BACKGROUND: Recent achievements in secondary prevention and treatment of coronary heart disease have highlighted the importance of early diagnosis of both symptomatic and silent forms of the disease. The prognostic and clinical importance of ST-T changes in men with no other manifestations of coronary heart disease is still unclear. Do they reflect silent coronary heart disease or hypertension, or both, and what is their independent contribution to prognosis? METHODS: The subjects were 9,139 men born in the years 1907 to 1934 and followed up for 4 to 24 years. On initial visit they were assigned to different categories of coronary heart disease on the basis of Rose chest pain questionnaire, hospital records, 12-lead ECG, history and physical examination. RESULTS: The prevalence of silent ST-T changes among men without overt coronary heart disease was strongly influenced by age, increasing from 2% at age 40 years to 30% at age 80 years. Men with such ST-T changes were older and had higher serum triglyceride levels and worse glucose tolerance than men without such changes or other evidence of coronary heart disease. Their blood pressure was higher, and they more often had an enlarged heart or left ventricular hypertrophy and more often took antihypertensive medication, digitalis or diuretic drugs. Serum cholesterol levels were not different between the two groups. After adjustment for other risk factors, these silent ST-T changes had a risk ratio of 2.0 for death from coronary heart disease and 1.6 for subsequent myocardial infarction or angina pectoris. CONCLUSIONS: Silent ST-T changes that are ischemic by the Minnesota code are probably both a marker of silent coronary heart disease and high blood pressure. They define a distinct group of patients with highly abnormal risk factor profile. Although not specific for coronary heart disease and often transient, they are associated with the development of every clinical manifestation of coronary heart disease and are independent predictors of reduced survival.

Safety and tolerability of cholesterol lowering with simvastatin during 5 years in the Scandinavian Simvastatin Survival Study.

BACKGROUND: Long-term safety is an important consideration in the selection and use of drugs, such as lipid-lowering agents, that are prescribed to reduce the risk of clinical events during long periods. METHODS: The Scandinavian Simvastatin Survival Study was designed to evaluate the effects of cholesterol lowering with simvastatin on mortality and morbidity in patients with coronary heart disease. The 4444 patients aged 35 to 70 years (mean, 58.9 years) with angina pectoris or previous myocardial infarction and serum cholesterol levels of 5.5 to 8.0 mmol/L (213-310 mg/dL) receiving a lipid-lowering diet were randomly assigned to take double-blind treatment with simvastatin, 20 to 40 mg once daily, or placebo. In addition to previously reported end-point events, detailed clinical and laboratory safety data were collected during a median follow-up period of 5.4 years (range in survivors, 4.9-6.2 years). RESULTS: The only clearly drug-related serious adverse event during the 5.4-year median follow-up period was a single reversible case of myopathy. The frequencies of persistent elevations of hepatic aminotransferase levels above 3 times the upper limit of normal and of nonviral hepatitis in the simvastatin and placebo treatment groups were not significantly different. Examination of the lens showed no between-group differences, and no previously unrecognized adverse effects of the drug were observed. There were no significant between-group differences in adverse events in any body system. In particular, the frequency of adverse events related to the central nervous system was similar in both groups. CONCLUSION: The safety profile of simvastatin, 20 to 40 mg daily, over 5 years was excellent.

Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S)

OBJECTIVE: To assess in diabetic patients with coronary heart disease (CHD) the effect of cholesterol lowering with simvastatin on mortality and the risk of CHD and other atherosclerotic events. RESEARCH DESIGN AND METHODS: A post hoc subgroup analysis was carried out on data from 202 diabetic patients and 4,242 nondiabetic patients with previous myocardial infarction or angina pectoris, serum total cholesterol 5.5-8.0 mmol/l, and serum triglycerides < or = 2.5 mmol/l who were participating in the Scandinavian Simvastatin Survival Study (4S). Participants in the 4S were randomly assigned to double-blind treatment with simvastatin, 20 mg daily, with blinded dosage titration up to 40 mg daily, according to cholesterol response during the first 6-18 weeks, or placebo. Endpoints were 1) total mortality, 2) major CHD events (CHD death or nonfatal myocardial infarction), 3) other acute atherosclerotic events, 4) myocardial revascularization procedures. RESULTS: Over the 5.4-year median follow-up period, simvastatin treatment produced mean changes in serum lipids in diabetic patients similar to those observed in nondiabetic patients. The relative risks (RRs) of main endpoints in simvastatin-treated diabetic patients were as follows: total mortality 0.57 (95% CI, 0.30-1.08; P = 0.087), major CHD events 0.45 (95% CI, 0.27-0.74; P = 0.002), and any atherosclerotic event 0.63 (95% CI, 0.43-0.92; P = 0.018). The corresponding RRs in nondiabetic patients were the following: 0.71 (95% CI, 0.58-0.87; P = 0.001), 0.68 (95% CI, 0.60-0.77; P < 0.0001), and 0.74 (95% CI, 0.68-0.82; P < 0.0001). CONCLUSIONS: The results strongly suggest that cholesterol lowering with simvastatin improves the prognosis of diabetic patients with CHD. The absolute clinical benefit achieved by cholesterol lowering may be greater in diabetic than in nondiabetic patients with CHD because diabetic patients have a higher absolute risk of recurrent CHD events and other atherosclerotic events.

Role of ADP-ribosylation in endothelial signal transduction and prostacyclin production.

ADP-ribosylation of proteins by the enzymatic transfer of ADP-ribose from NAD has been implicated in a number of biological processes. We report that inhibitors of ADP-ribosylation, most notably the novel inhibitor of arginine specific cellular mono(ADP-ribosyl) transferase, meta-iodobenzylguanidine (MIBG) as well as nicotinamide, L-arginine methyl ester (LAME) and guanyltyramine, inhibit histamine-induced endothelial production of inositol phosphates, release of arachidonic acid and production of prostacyclin (PGI2). Those same responses were unaffected by MIBG when triggered by thrombin or leukotriene C4. These findings suggest that ADP-ribosylation serves a role in histamine-induced production of prostacyclin and imply differences in transduction pathways employed by the different agonists.

Platelet factors and the human vascular wall. Part 2. Such factors are not required for endothelial cell proliferation and migration.

The effects of platelet factors on human umbilical venous endothelial cell DNA-synthesis at various serum concentrations were studied. While [3H]thymidine uptake of these cells was almost linearly related to the concentration of serum in the culture medium, no significant differences were found at any serum level between cultures treated with sera derived from either platelet-rich or platelet-poor plasma. The role of platelet factors in cellular migration into standardized mechanical "wounds" was also investigated following inhibition of the proliferative response by irradiation of endothelial monolayers. Repopulation of such "wounds" was not affected by platelet factors. We conclude that endothelial cells proliferate and migrate in vitro independently of platelet factors.

Platelet factors and the human vascular wall: variations in growth response between endothelial and medial smooth muscle cells.

In the present investigations, the effects of platelet factors on DNA-synthesis by human arterial and venous smooth muscle and venous endothelial cells were compared. Also studied was the role of such factors in restimulating quiescent endothelial cultures and in endothelial reaction to injury. Aortic smooth muscle cells grown in medium containing 10% human serum prepared from plasma poor in platelets (PPPS) reached 9.7%+/-SE 0.65 labelling index when continuously exposed to [3H] thymidine (1 muCi/ml). When lysate from gel-filtered platelets was added, the index was 19.4% +/- SE 1.13 (P less than 0.01) and in the presence of serum derived from platelet rich plasma (PRPS) it reached 24.6% +/- SE 1.22 (P less than 0.01). Similar results were obtained with smooth muscle cells from umbilical veins. In constrast, platelet factors did not significantly affect DNA-synthesis in endothelial cultures. They reached 25.6% +/- SE 1.97 when grown in medium containing PPPS as compared to 21.9% +/- Se 2.53 (P greater than 0.05), when exposed to PRPS. The ability of sera to stimulate DNA-synthesis in endothelial cultures rendered quiescent by 24 h exposure to medium containing 1.4% serum albumin (labelling index 1.83% +/- SE 0.14) was not affected by platelet factors. Platelet lysates alone were not sufficient to restimulate the quiescent cells (labelling index 3.03% +/- SE 1.06) (P greater than 0.05). Platelet factors did not affect the proliferative response following experimental mechanical injury to endothelial monolayers in vitro. We conclude that while platelet factors are essential for human vascular smooth muscle cells to achieve optimal growth, they are not indispensable for endothelial cell proliferation. It is suggested that these cellular differences in growth requirements may play an important role in human atherogenesis.

Involvement of MAP kinases in the control of cPLA(2) and arachidonic acid release in endothelial cells.

Cytosolic Phospholipase A(2) (cPLA(2)) has been implicated in receptor-mediated release of arachidonic acid from membrane phospholipids, the limiting step in prostacyclin and other eicosanoid production. Its activity is controlled by Ca(++) levels and enzymatically regulated phosphorylation. The purpose of this study was to assess the importance of phosphorylation of cPLA(2) in human umbilical vein endothelial cells and to identify the kinases involved. Inhibitors were used to study the pathways leading to phosphorylation and activation of mitogen activated protein kinases (MAP-kinases) and cPLA(2), as well as release of arachidonic acid and prostacyclin production after stimulation with different agonists. We have found that agonists that release arachidonic acid, including histamine, thrombin, AlF(4)(-), and pervanadate, all activate the MAP kinases ERK, p38 and JNK and cause phosphorylation of cPLA(2). Agonist specific differences in the signal transduction pathways included variable contribution of tyrosine phosphorylation, protein kinase C and ERK activity, and different effects of pertussis toxin. Treatment with PD98059 (inhibitor of ERK-activation) or SB203580 (inhibitor of p38) caused partial decrease in arachidonic acid release and cPLA(2) activity. In contrast the nonspecific protein kinase inhibitor staurosporin completely inhibited cPLA(2) activity. We conclude that in endothelial cells arachidonic acid release is largely mediated by cPLA(2) through agonist-specific pathways. The MAP kinases ERK and p38 both have demonstrable but not major effect on agonist stimulated arachidonic acid release and the data suggest that an additional unidentified kinase also has a role.

Glucose tolerance and blood pressure in a population-based cohort study of males and females: the Reykjavik Study.

OBJECTIVE: To investigate the relationship between fasting and postprandial glucose levels and the risk of hypertension, both cross-sectionally in different age and body mass index (BMI) groups, and prospectively. DESIGN: Long-term prospective health survey in the Reykjavik area, of a large representative population sample of males and females in various age groups, conducted since 1967. METHODS: Values from 8285 males and 9183 females were included in the cross-sectional analysis. The prospective analysis included 2639 males and 2346 females, with two consecutive observations for each individual, with a 3- to 8-year interval. RESULTS: After controlling for year of examination, age, BMI and various other risk factors, we found a strongly significant relationship between the blood glucose level, both fasting and 90 min after an oral glucose load, and risk for hypertension. The strength of the correlation between postprandial glucose value and blood pressure was similar in different age and BMI groups, except for in the males, in whom there was a stronger correlation with diastolic blood pressure with higher BMI. The 90-min glucose level was also predictive for development of hypertension 3-8 years later. The predictive power was somewhat stronger for females. Fasting glucose level was predictive for hypertension only for the females. Concurrent weight gain had a very strong independent explanatory power for development of hypertension. CONCLUSIONS: This study confirms the role of metabolic factors in hypertension. The correlation between impaired glucose tolerance and hypertension was found to be remarkably consistent throughout adult life, for both sexes and all values of BMI. Fasting glucose was predictive of hypertension in the females, and blood glucose at 90 min after the glucose-tolerance test was predictive of future development of hypertension in both sexes.

Prognostic role of cardiovascular risk factors for men with cardiomegaly (the Reykjavik Study).

The Reykjavik Study is a large population-based cohort study, starting in 1967. A total of 9,139 men, born in the years 1907 to 1934, have been followed for 4 to 24 years. Heart size was determined by chest roentgenogram in 2 planes and cardiomegaly, defined as a relative heart size exceeding 550 ml/m2, was detected in 517. Multivariate Cox regression analysis was used to estimate the independent contribution of variables measured at each participant's first visit to the risk of both all-cause and coronary artery disease (CAD) mortality. Cardiomegaly was detected in 3.7% of men aged < 40 years and in 21.2% of those > 75 years. One half of these men had hypertension, one third had manifestations of CAD, and 37% had neither. Among men with cardiomegaly, the presence of CAD had marked deleterious effect on prognosis. Serum total cholesterol and systolic blood pressure were significant independent risk factors of CAD mortality with risk ratio of 1.008 per mg/dl serum cholesterol (95% confidence interval 1.00 to 1.01; p = 0.004) and 1.015/mm Hg (95% confidence interval 1.000 to 1.300; p = 0.043), respectively. Smoking > 25 cigarettes/day carried a 2.3-fold risk (95% confidence interval 1.3 to 4.4; p = 0.008) of all-cause mortality. The traditional risk factors for CAD, serum cholesterol, high blood pressure, and smoking maintain their detrimental effect on prognosis among patients with cardiomegaly. These findings have implications for secondary prevention, signifying that in the presence of cardiomegaly, complacency is not justified in controlling major risk factors for CAD.

Predictive value of apolipoproteins in a prospective survey of coronary artery disease in men.

Some studies have suggested that measurements of apolipoproteins may be valuable in the clinical assessment of susceptibility to coronary artery disease, over and above the lipoprotein lipids. Only a few of these studies have been prospective in nature and further knowledge is therefore needed to clarify the issue. The independent prognostic value of apolipoproteins (apo-B, apo-AI and apo[a]) with regard to coronary artery disease was estimated from a prospective survey among 1,332 randomly selected Icelandic men, aged 45 to 72 years, participating in a health survey from 1979 to 1981. The group was followed for 8.6 years, and during that period 104 men had fatal or nonfatal myocardial infarction. The Cox's proportional hazards model was used to estimate the significance of independent variables. The results of multivariate analysis showed that apo(a) was a significant independent risk factor (odds ratio 1.22 for 1 SD), but apo-AI was a stronger negative risk factor (odds ratio 0.70 for 1 SD). Apo-B was a highly significant risk factor in a univariate analysis, but not in a multivariate analysis when serum cholesterol was included. Previous population surveys in Iceland have confirmed the importance of cigarette smoking, cholesterol, triglycerides and blood pressure as risk factors for coronary artery disease. The present results illustrate additional importance of apo-AI and apo(a) concentrations in predicting coronary artery disease among Icelandic men, whereas apo-B did not contribute anything further to the prediction than serum total cholesterol.

Follow-up study of patients randomized in the Scandinavian simvastatin survival study (4S) of cholesterol lowering.

The Scandinavian Simvastatin Survival Study (4S) and other randomized clinical trials have demonstrated that cholesterol-lowering treatment with statins improves prognosis in patients with coronary atherosclerosis compared with placebo. The effect of therapy with statins beyond the typical 5 to 6 years' duration of the trials, in particular regarding the risk of cancer, has not been investigated. This study examines the long-term effects of simvastatin for up to 8 years on cause-specific mortality in patients with coronary heart disease (CHD). We performed an observational, government registry-based study of mortality in the groups originally randomized to simvastatin or placebo in the 4S over an additional 2-year follow-up period, so that the median total follow-up period was 7.4 years (range 6.9 to 8.3 in surviving patients). Randomization took place at outpatient clinics at 94 clinical centers in Denmark, Finland, Iceland, Norway, and Sweden from 1988 to 1989. Of 4,444 patients with CHD, 2,223 and 2,221 were randomized to treatment with placebo or simvastatin therapy, respectively. Patients received treatment with simvastatin, starting at 20 mg/day, with titration to 40 mg/day at 12 or 24 weeks if total cholesterol was >5.2 mmol/L (200 mg/dl), or placebo. After the double-blind period, most patients in both treatment groups received simvastatin as open-label prescription. Of the 1,967 patients originally treated with placebo and surviving the double-blind period, 97 (4.9%) died during the following 2 years. In the group randomized to simvastatin the corresponding number was 74 of the 2, 039 survivors (3.6%). Adding these deaths to those occurring during the original trial, the total was 353 (15.9%) and 256 (11.5%) deaths in the groups originally randomized to placebo and simvastatin, respectively. The relative risk was 0.70 (95% confidence interval 0. 60 to 0.82, p = 0.00002). The total number of cancer deaths was 68 (3.1%) in the placebo group and 52 (2.3%) in the simvastatin group (relative risk 0.73, 95% confidence interval 0.51 to 0.05, p = 0. 087), and the numbers of noncardiovascular and other deaths were similar in both groups. We therefore conclude that treatment with simvastatin for up to 8 years in patients with CHD is safe and yields continued survival benefit.

Natural history of chronic left ventricular aneurysm; a population based cohort study.

In order to evaluate the morbidity and mortality of chronic left ventricular aneurysm a population based cohort study was carried out. All cardiac catheterizations performed in Iceland during the years 1983-1985 were examined (n = 1261). Sixty seven patients with left ventricular aneurysm defined as: (1) normal diastolic contour with segmental dyskinesis (n = 6), (2) abnormal diastolic contour with (a) akinetic (n = 36) or (b) dyskinetic (n = 25) segments in systole, were included. Sixty seven patients with normal diastolic contour and akinetic segments in systole served as controls. The groups had similar mean age, sex ratio, number of diseased vessels and left ventricular end diastolic pressure. Mean ejection fraction was significantly lower in the aneurysm group (46 vs 56%, p = 0.00005). Collaterals were detected significantly more often in controls (88 vs 72%, p = 0.03). At follow up in 1989, 19 in the aneurysm group had died as compared to 12 in the control group. Life table analysis revealed significant differences between survival curves. The relative risk ratio was 2.18 with 95% confidence interval of 1.00-4.74 (p less than 0.05). However, when the amount of myocardial damage was taken into account the differences in survival were no longer statistically significant (relative risk ratio 1.77 with 95% confidence interval of 0.79-3.99). We conclude that the reduced survival probability of patients with chronic left ventricular aneurysm in comparison to controls with akinetic scars is accounted for by the more extensive myocardial damage and not by the presence of aneurysm per se.

Predominance of aortic calcification as an atherosclerotic manifestation in women: the Reykjavik study.

Since 1967 the Reykjavík study has monitored coronary artery disease and its risk factors in randomly selected cohorts. From 1979 to 1984, 3246 men and 3545 women aged 45-74 years were studied. Routine biplane chest X rays were assessed by a radiologist who noted the presence or absence of aortic calcification (AC), but had no detailed knowledge of the subjects. Overall, AC was diagnosed in 283 (8%) women, but in only 54 of the men (1.7%). In the women, the prevalence of AC increased from 2.0% at age 45-49 years to 17.1% at the age of 70-74 years, while in men it was 0 and 8.3%, respectively. In women, multivariate analysis of risk factors showed AC to be positively related to systolic and negatively related to diastolic blood pressure, indicating a potential relation to pulse pressure. Furthermore, AC was independently associated with age, drug treatment for hypertension, nonfasting blood sugar, use of antidiabetic drugs, total serum cholesterol levels, and the amount of smoking. Too few men had AC for multivariate assessment of risk factors. In addition, in women AC was also related to a previous myocardial infarction (p < 0.05), mortality from coronary artery disease (p < 0.01), and the presence of intermittent claudication (p < 0.01). In men, however, AC was related only to total mortality (p < 0.05). Thus, these data show AC to be more prevalent in women, independently associated with recognized atherosclerotic risk factors, and a potential marker for coronary and peripheral artery disease.

A marked decline in the prevalence and incidence of intermittent claudication in Icelandic men 1968-1986: a strong relationship to smoking and serum cholesterol--the Reykjavik Study.

The epidemiology of peripheral vascular disease has been studied much less extensively than the epidemiology of coronary heart disease (CHD). The prospective Reykjavik Study gave an opportunity to monitor secular trends from 1968 to 1986 of clinical intermittent claudication (IC) amongst Icelandic males, aged 34-80 and to assess the importance of possible risk factors. Both prevalence and incidence of IC decreased sharply after 1970 in all age groups, and this decline occurred a few years earlier than the decline of CHD in Iceland. The only significant risk factors for intermittent claudication, in addition to age, were smoking which increased the risk of IC 8- to 10-fold and serum cholesterol level. Approximately one-half of the striking decline in the incidence of IC can be explained by decreased smoking and cholesterol levels amongst Icelandic men. A follow-up study verified that IC patients stood twice the risk of cardiovascular and total mortality as non-IC patients, indicating that IC is a high risk group which should receive all possible preventive measures.

Long-term prognosis of different forms of coronary heart disease: the Reykjavik Study.

BACKGROUND: While coronary heart disease (CHD) is a serious and often fatal disease the prognosis is variable and major effort has been invested in risk stratification. The purpose of this study was to examine the relation between long-term prognosis and risk factors in different clinical categories of CHD. METHODS: A general population sample of 9141 men, aged 34-79 at entry into the study was divided into six groups with respect to manifestations of CHD at entry: I. Symptomatic infarction. II. Silent or unrecognized infarction. III. Angina pectoris with ischaemic changes on ECG. IV. Angina without ischaemic changes. V. Angina by Rose questionnaire but not confirmed by a physician. VI. No manifestations of CHD. RESULTS: The risk factor profile varied considerably between the different categories and by life-table analysis marked differences in survival were demonstrated between the groups. The risk factors maintained their detrimental effects on prognosis in the presence of CHD. Thus, age, serum total cholesterol, impaired glucose tolerance and smoking were found by Cox's regression to be statistically significant independent risk factors of CHD mortality among men having manifestations of CHD (groups I-V). Furthermore, the composite risk score, a measure of the overall risk factor exposures had marked effect on the prognosis of the various CHD groups. When the comprehensive risk factor score for both CHD mortality and all-cause mortality was accounted for marked differences persisted in the long-term prognosis. Compared to those without CHD the infarct groups had about a 7.6- and 3.7-fold risk of dying from CHD and all causes respectively. Those with angina had from 2.5- to 3.2-fold risk of CHD mortality and 1.7- to 2.2-fold risk of all-cause mortality depending on the subgroup of angina, again compared to those without manifestations of CHD. CONCLUSION: Different categories of CHD had different risk factor profiles and the long-term prognosis resulted from a complex interplay between those factors and the diagnostic category of CHD. The risk factors maintained their detrimental effects on prognosis in the presence of CHD and after accounting for the comprehensive risk factor score marked differences persisted in the long-term prognosis, being worst for those having suffered a myocardial infarction, either symptomatic or silent.

Acute thoracic inlet obstruction in achalasia with adenoid cystic and squamous cell carcinoma.

Respiratory symptoms due to compression of the trachea by the dilated esophagus in achalasia are extremely rare. A patient is presented whose respiratory manifestations included engorged neck veins and a neck swelling that fluctuated with respiration. He also had two malignant tumors in his dilated esophagus, a squamous cell carcinoma and an adenoid cystic carcinoma.

Different mechanisms of homologous and heterologous desensitization of thrombin-induced endothelial prostacyclin production.

Several workers have described desensitization of endothelial prostacyclin production but conflicting evidence has been published regarding the mechanism of desensitization, whether it is homologous (agonist specific) or heterologous, and whether inactivation of cyclooxygenase is involved. The purpose of the present study was to determine the relation between the intensity of a first thrombin stimulus and the subsequent response to a repeat thrombin, histamine, ionophore A23187 or aluminium fluoride (AlF4) stimulation and to determine possible targets of desensitization. Following thrombin stimulation of confluent cultured human umbilical vein endothelial cells (HUVEC) only homologous desensitization of inositol phosphate production was observed. Both homologous and heterologous desensitization of arachidonic acid release and prostacyclin production occurred, the latter towards both histamine and the ionophore A23187. For any given dose of the first stimulant there was a much greater effect on the homologous response than on the heterologous response. These differences suggest different mechanisms. The homologous desensitization probably involves the receptor whereas the present results suggest that the target of heterologous desensitization is distal to calcium mobilization in the signal transduction pathway. The possibilities include decreased activity of phospholipase A2 or a decreased pool of accessible arachidonic acid.