Alcohol, lipid metabolism and coronary heart disease

Numerous epidemiological studies have unequivocally proven a protection from the development of coronary heart disease by moderate long-lasting alcohol consumption. During the past 20 years studies in different ethnic groups starting from an American cohort and spanning to the recently performed analysis in the MONICA-project gave evidence for a decreased morbidity and mortality from coronary heart disease at 1 to 3 drinks a day when compared to total abstainers. A part of the protection is thought to be mediated through alcohol effects on plasma lipoprotein metabolism. Substantial increases in high-density lipoprotein cholesterol and its subfractions occur and are believed to be responsible for as much as half of the alcohol-mediated benefits. In addition, moderate decreases in low-density lipoprotein cholesterol and probably also in lipoprotein(a), established cardiovascular risk factors, may contribute accordingly. Furthermore, antioxidants like flavonoids and polyphenols found in red wines by protecting low density lipoproteins from oxidative modification may explain the "French paradox", the decreased incidence of coronary heart disease in France despite a high consumption of saturated fats. Also, alcoholic vasodilation, decreases in platelet aggregability, changes in prostacyclin/thromboxane ratios and increased fibrinolytic activities are to be considered as additional benefits caused by moderate alcohol consumption.     

Polymorphism of the methionine synthase gene : association with homocysteine metabolism and late-onset vascular diseases in the Japanese population

Methionine synthase and 5,10-methylenetetrahydrofolate reductase (MTHFR) sequentially catalyze the remethylation of homocysteine to methionine. A point mutation in the encoding region of the methionine synthase gene, which results in substitution of an aspartic acid for a glycine residue (D919G), has been identified in patients of the cblG genetic complementation group; these patients exhibit significantly decreased methionine synthase activity. Nevertheless, the D919G mutation has also been reported to be common in the general population. In this study, we analyzed the distribution of methionine synthase D/G polymorphism in the Japanese population and examined the extent to which it is associated with altered homocysteine metabolism and late-onset vascular diseases. We studied 215 patients with coronary artery disease, 251 patients with histories of ischemic stroke, and 257 control subjects. The methionine synthase genotype was analyzed by polymerase chain reaction followed by HaeIII digestion; allele frequencies for the D919G variant of the enzyme proved to be similar in all 3 subject groups (control subjects, 0.17; coronary artery disease patients, 0. 17; and ischemic stroke patients, 0.19). Furthermore, in patients with ischemic stroke, plasma levels of homocyst(e)ine and folate were similar, irrespective of methionine synthase genotype. Thus, the methionine synthase D919G mutation was found to be common in the Japanese general population, and it appears unlikely that this polymorphism has a major effect on homocysteine metabolism and/or the onset of vascular diseases.     

Polymorphism in apolipoprotein(a) kringle IV 37(Met/Thr): frequency in a London population and its association with coronary artery disease

BACKGROUND: A raised concentration of lipoprotein(a) [Lp(a)] in human plasma has been considered as a risk factor for coronary artery disease (CAD). Apolipoprotein(a) and plasminogen genes are exceptionally similar to a variable number of plasminogen-like kringle IV repeats in the apo(a) gene. Polymorphisms have been previously identified in the apolipoprotein(a) kringle IV 37. HYPOTHESIS: In order to determine the frequency of the apolipoprotein(a) kringle IV 37 Met66-->Thr polymorphism in a London-based population and to assess the relationship of this polymorphism with CAD in Caucasian patients, we genotyped two groups of people of different ethnic origin (Caucasian and Afro-Caribbean) for the mutation using standard polymerase chain reaction (PCR) techniques. METHODS: The first group consisted of 182 unrelated Caucasian patients (107 men and 75 women, mean age 59.7 +/- 10.2 years) recruited at St. George's Hospital. They were defined as patients with 0, 1 or > or = 2 vessel disease patients depending on the degree of stenosis in none, one, or several major epicardial arteries. The second group comprised 64 unrelated patients of Afro-Caribbean origin attending a hypertension clinic at St. George's Hospital. RESULTS: It was shown that the prevalence of the Met66-->Thr mutation is markedly higher in Caucasians than in Afro-Caribbeans and that this mutation is not associated with either Lp(a) levels or severity of CAD.     

The -700/-310 fragment of the apolipoprotein A-IV gene combined with the -890/-500 apolipoprotein C-III enhancer is sufficient to direct a pattern of gene expression similar to that for the endogenous apolipoprotein A-IV gene

Spatial gene expression in the intestine is mediated by specific regulatory sequences. The three genes of the apoA-I/C-III/A-IV cluster are expressed in the intestine following cephalocaudal and crypt-to-villus axes. Previous studies have shown that the -780/-520 enhancer region of the apoC-III gene directs the expression of the apoA-I gene in both small intestinal villi and crypts, implying that other unidentified elements are necessary for a normal intestinal pattern of apoA-I gene expression. In this study, we have characterized transgenic mice expressing the chloramphenicol acetyltransferase gene under the control of different regions of the apoC-III and apoA-IV promoters. We found that the -890/+24 apoC-III promoter directed the expression of the reporter gene in crypts and villi and did not follow a cephalocaudal gradient of expression. In contrast, the -700/+10 apoA-IV promoter linked to the -500/-890 apoC-III enhancer directed the expression of the reporter gene in enterocytes with a pattern of expression similar to that of the endogenous apoA-IV gene. Furthermore, linkage of the -700/-310 apoA-IV distal promoter region to the -890/+24 apoC-III promoter was sufficient to restore the appropriate pattern of intestinal expression of the reporter gene. These findings demonstrate that the -700/-310 distal region of the apoA-IV promoter contains regulatory elements that, in combination with proximal promoter elements and the -500/-890 enhancer, are necessary and sufficient to restrict apoC-III and apoA-IV gene expression to villus enterocytes of the small intestine along the cephalocaudal axis.     

Plasma lipid, apolipoprotein and Lp(a) levels in elderly normolipidemic women: relationships with coronary heart disease and longevity

The relation between plasma lipids and coronary heart disease (CHD) in the elderly is still debated, as well as the proposed role of lipoproteins as markers of longevity. In this study both normolipidemic elderly and middle-aged women with CHD showed higher triglycerides and apolipoprotein B levels and lower high-density lipoprotein (HDL)-cholesterol and apolipoprotein A-I levels in comparison with age-matched subjects without CHD. In the middle-aged group, hypertension and HDL-cholesterol levels and, in the elderly group, only HDL-cholesterol levels were independently associated with CHD. No significant difference was found between a group of healthy centenarians and elderly and middle-aged subjects without CHD. These data suggest that plasma lipids are also related to CHD in the elderly and that, even if at present we are not able to consider them as predictors of longevity, some lipoprotein features may contribute to select subgroups of subjects in which other factors play a further role in life expectancy.     

Association between apolipoprotein(a) phenotypes and coronary heart disease at a young age

Fentanyl is a basic amine shown to have extensive first-pass pulmonary uptake. To evaluate the role of the pulmonary endothelium in this uptake process, the simultaneous pharmacokinetics of [3H]fentanyl and two marker drugs, blue dextran, and [14C]antipyrine, were evaluated in a flow-through system of pulmonary endothelial cells. Fentanyl equilibrium kinetics were determined in a static culture system. The flow-through system consisted of monolayers of bovine pulmonary artery endothelial cells cultured on solid microcarrier beads placed in a chromatography column and perfused at 1.0 ml/min (37 degreesC). Fentanyl and the markers were injected into the perfusate at the top of the column and samples were collected from the eluate at 9-s intervals for 10 min. The pharmacokinetic analyses were based on determinations of mean transit time and flow. Fentanyl was partitioned into the pulmonary endothelial cells 60 times more than the tissue water space marker antipyrine. In the static system, monolayers of bovine pulmonary artery endothelial cells were cultured in 3.8-cm2 wells to which were added 0 to 946 micromol (0-500 microgram/ml) of unlabeled fentanyl citrate and 0.14 micromol of [3H]fentanyl. After a 10-min incubation, solubilized cells were assayed for [3H]fentanyl. Pulmonary endothelial cells contained a higher relative fentanyl concentration at lower fentanyl supernatant concentrations than would be expected if uptake occurred by diffusion alone. These observations can be explained with a model of fentanyl uptake that includes both passive diffusion and saturable active uptake. This suggests that the extensive first-pass pulmonary uptake of fentanyl observed in vivo is due largely to vascular endothelial drug uptake by both a passive and a saturable active uptake process.     

Social networks and coronary heart disease among Japanese men in Hawaii

A group of 4653 men of Japanese ancestry living in Hawaii were studied for the association of measures of social networks with both the prevalence and incidence rates of coronary heart disease (Honolulu Heart Program, 1971-1979). Prevalence rates for myocardial infarction, angina, and total coronary heart disease were inversely associated with the social network scales in bivariate analyses with age, and in multivariate analyses including 12 other risk factors. With the incidence data, the associations were less evident. Bivariate analysis with age revealed inverse associations for nonfatal myocardial infarction and total coronary heart disease with only one of the social network scales. With multivariate analyses, there was no significant association of any subgroup of coronary heart disease with any scale, although there was a borderline association (p = 0.08) of nonfatal myocardial infarction with one scale. No individual question was significantly associated with either prevalence or incidence rates for coronary heart disease. There was also little evidence of reduced risk of incident coronary heart disease associated with the social network scale for men in high risk categories of serum cholesterol, blood pressure, and cigarette smoking.     

The significance of endothelial injury in the pathogenesis of coronary heart disease

In this study, the number of circulating endothelial cells (CEC) was counted and used as an indicator of the injury of vascular endothelial cells (VEC) in 27 cases with coronary heart disease (CHD), in vivo, CECs were identified with fluorescein-labeled anti-human antibody to factor VIII related antigen. The contents of MDA representing lipid peroxides were also measured in these cases. Meanwhile the number of CEC in normal people was counted as control and compared with that in patients before and after therapy. The results were as follows: The number of CEC and content of MDA in the patients were higher than that in normal people and these two induces were significantly correlated (r = 0.802). The CEC number reflects the severity of CHD. The present investigation suggests that VEC injury induced by the lipid peroxide may play an important role in the pathogenesis of the CHD and CEC counting can be used as a reference for judging the severity and the prognosis of the CHD.     

Association of chronic infection of Chlamydia pneumoniae and coronary heart disease in the Japanese

The association of Chlamydia pneumoniae with atherosclerosis of coronary and carotid arteries and the aorta has been demonstrated by seroepidemiology and by detection of the organism in atheromata. We investigated the frequency of C. pneumoniae seropositivity in patients with acute myocardial infarction (AMI). C. pneumoniae-specific antibodies were measured by the microimmunofluorescence test in 160 AMI patients and 160 control subjects matched for age and gender. The odds ratios (ORs) were 2.2 (95% confidence interval (CI), 1.2 to 3.9) for immunoglobulin (Ig)G and 2.7 (95% CI, 1.7 to 4.3) for IgA. After adjustment for other cardiovascular risk factors of age, gender, hypertension, diabetes, cigarette smoking and serum cholesterol, the ORs were essentially unchanged. This study confirmed that the observations of an association between antibody against C. pneumoniae and coronary heart disease in Western nations is also present in Japan. Our results are comparable to the previous seroepidemiological studies reporting ORs of 2.0 or greater.     

Association between electrocardiographic ischemic abnormalities and ischemic heart disease risk factors in a Japanese population

This cross-sectional study was undertaken to investigate the association of electrocardiographic (ECG) ischemic abnormalities with ischemic heart disease (IHD) risk factors in a Japanese population. Resting ECGs of 1201 subjects (572 men and 629 women, aged 30 to 89 years), were coded independently by two coders according to the Minnesota Code. Blood pressure (BP) was recorded using a standard sphygmomanometer, and non-fasting serum total cholesterol and high-density lipoprotein cholesterol were measured. Codes 1.1 and 1.2 were classified as myocardial infarction and codes 1.3, 4.1-4.4, 5.1-5.3 and 7.1 were classified as ischemia. Prevalence of ECG with evidence of IHD (IHD ECG) was defined as myocardial infarction and ischemia together. Levels of risk factors were compared between subjects with IHD ECGs and those without IHD ECGs. Multiple logistic regression analysis was used to ascertain the associations between IHD ECG and risk factors. The prevalence of myocardial infarction in the total population was 1.5% and 0.7% in men and women, respectively and the prevalence of IHD ECGs was 10% and 11.3% in men and women, respectively. Systolic blood pressure (SBP) was consistently higher in subjects with IHD ECGs in the total population of both sexes (P < 0.001, P = 0.001 for men and women respectively). Diastolic blood pressure (DBP) was higher only in men with IHD ECGs (P = 0.002). In middle-aged men (aged 30-59 years), total cholesterol was considerably higher in subjects with IHD ECGs, although this relationship was statistically not significant. In multiple logistic regression analysis, SBP was independently associated with IHD ECGs in both sexes (P = 0.001). Associations between IHD ECGs with total cholesterol, alcohol intake and smoking were not statistically significant. This study showed that electro-cardiographic IHD evidences in Japanese are predominantly associated with blood pressure level in both sexes.     

Helicobacter pylori infection and coronary heart disease in the North Glasgow MONICA population

AIM: Recent evidence suggests that Helicobacter pylori infection is associated with coronary heart disease. We investigated whether H. Pylori infection is related to prevalent coronary heart disease, in a random sample of 1428 men and women aged 25-74 years. METHODS AND RESULTS: Coronary heart disease was assessed by questionnaire and electrocardiography (ECG). Standard risk factors for coronary heart disease, fibrinogen concentration and serum concentrations of H. pylori-specific IgG antibody were measured. H. pylori seropositivity increased with age (P < or = 0.001) and was significantly more prevalent in men than women. H. pylori infection was associated with current smoking and a higher systolic blood pressure in men but not in women. There was no significant increase in the odds ratio in those seropositive for H. pylori with regard to any manifestation of coronary heart disease, after adjustment for age, standard cardiovascular risk factors and social class. Likewise, age-adjusted plasma fibrinogen was no higher in seropositives. CONCLUSION: Seropositivity to H. pylori is associated with a trend towards a greater prevalence of coronary heart disease. However, that association is likely to be spurious and can be adequately explained by the much stronger association of H. pylori infection with age and social class, both of which are linked with coronary heart disease.     

Do lipid lowering drugs reduce the risk of coronary heart disease?

Historically, a wide range of drugs have been used to treat hyperlipidemias. These include fibrates whose main action is to lower plasma triglycerides; bile-acid sequestering resins introduced to reduce plasma cholesterol; and more recently a family of statins designed to inhibit the rate-limiting enzyme of cholesterol biosynthesis, HMG-CoA reductase. Early trials employing rather small numbers of subjects with established coronary artery disease (CAD) demonstrated that lipid reduction was often but not always associated with a lowered incidence of clinical end-points, including death and non-fatal myocardial infarction. However, significant angiographic benefit was rarely demonstrated in these investigations. More recent trials based on statins have shown a reduction in clinical events not only in patients with CAD, but also in healthy subjects given these drugs for primary prevention. Differences in design, duration, the role of confounders such as risk factors other than lipids, and the frequently poor correlation between angiographic changes and clinical outcomes are discussed.     

Distribution of dehydroepiandrosterone sulfate and relationships between its level and serum lipid levels in a rural Japanese population

The feasibility of thoracoscopy for viewing the chest cavity and performing pulmonary lobectomy was assessed in 8 mongrel dogs. Previously, selective intubation had been performed in another group of dogs (n = 8) in order to monitor respiratory physiology and assess its safety. Each hemithorax was intubated using a double-barrelled endotracheal tube with one barrel placed in the left main bronchus and the other in the bifurcation of the trachea. The thoracoscope was introduced through a cannula inserted through a 2-cm incision at the ventral third of the left 5th intercostal space. The cranial, dorsal, and caudal surfaces of the pleura, lobes of the left lung, and the mediastinum were examined. A 2nd cannula was located in the dorsal 3rd of the 5th intercostal space with a prior incision and used for the introduction of forceps to separate the viscera. To biopsy, a 3rd cannula was inserted at the dorsal third of the 8th intercostal space with a prior incision, through which a 12-mm diameter stapler was introduced. Should a lobectomy be necessary, a 4th cannula is located in the middle third of the 4th intercostal space. Excision of the left caudal pulmonary lobe was performed through the incision made for the 12-mm diameter cannula (8th intercostal space); a twisting movement facilitated removal. Thoracoscopy is a procedure that can be used in dogs and is particularly suitable for examination, collection of biopsy specimens, and even lung lobectomies.     

The frequency of a common mutation of the methionine synthase gene in the Australian population and its relation to smoking and coronary artery disease

BACKGROUND: Modest elevations in levels of circulating homocysteine are common in patients with vascular disease. Methionine synthase is a vitamin B12-dependent enzyme catalysing the re-methylation of homocysteine to methionine; reduced methionine synthase activity results in elevated level of homocysteine. DESIGN: A case-control study. METHODS: We explored the frequency and distribution of a 2756A-->G (D919G) mutation of the methionine synthase gene, detected by polymerase chain reaction genotyping, in 745 Australian Caucasian patients aged < or = 65 years (550 men and 195 women) with and without angiographically documented coronary artery disease (CAD). RESULTS: The frequency distributions of AA, AG and GG genotypes were 61.9%, 33.8% and 4.3%, respectively, and were in Hardy-Weinberg equilibrium. There was no correlation between the methionine synthase mutation and CAD from simple chi2 comparison. However, the interactive term of life-time smoking dose with methionine synthase genotypes was predictive of both the number of significantly diseased vessels (> or =50% luminal obstruction; chi2 = 12.518, P=0.0019), and the presence or absence of significant CAD (chi2=7.045, P=0.027). A stepwise logistic regression analysis showed that smokers who were also GG homozygotes had more severe CAD compared with smokers of other genotypes. The methionine synthase genotypes were not associated with any of the other established CAD risk factors assessed in our study. CONCLUSIONS: We conclude that the methionine synthase 2756A-->G mutation is common, with homozygosity occurring in approximately 4% of white Australians, and that it has an interactive effect with life-time smoking dose to increase the severity of CAD. Smokers who are also GG homozygotes have additionally elevated CAD risk.     

Apolipoprotein E and A-IV polymorphisms in the Estonian population

A 41-year-old man was admitted to our hospital with chief complaints of painless tumor in the left scrotal contents and loss of body weight. As the tumor was suspected of being a neoplastic lesion, left radical inguinal orchiectomy was carried out. Histopathological examination showed metastatic adenocarcinoma of the bile duct. Metastatic carcinoma to the testicle, epididymis, and their tunics is unusual and testicular metastases from adenocarcinoma of the bile duct is extremely rare. A case of testicular metastases from carcinoma of the bile duct is reported and the literature reviewed.     

Changes in population cholesterol levels and coronary heart disease deaths in seven countries

BACKGROUND: Are trends in coronary heart disease deaths based on risk factor changes? OBJECTIVE: To study the relationship between trends in coronary deaths and changes in blood cholesterol in the Seven Countries Study. MATERIAL AND METHODS: Sixteen cohorts of men aged 40-59 years from seven countries (U.S.A., Finland, the Netherlands, Italy, Croatia (former Yugoslavia), Serbia (former Yugoslavia), Greece, Japan) were units for the analyses of serum cholesterol measured at entry and after 5 and 10 years, and for mortality over 25 years. RESULTS: In the populations, the ecological relationship of mean serum cholesterol at entry to late coronary heart disease death rates during the 10- to 25-year follow-up was weak, with an R-square of 0.31. Cholesterol measurements made at year 10, and an indicator of cholesterol change during the first 10 years, increased the association (R-square, 0.49). A negative and significant interaction was shown between baseline population cholesterol levels and their 10-year change. As an indicator of acceleration in mortality, cholesterol change over 10 years was also positively correlated (partial R-square 0.44) with the ratio of 25-year to 5-year deaths. CONCLUSIONS: In the Seven Countries Study, late coronary heart disease death rates are largely "explained' by changes in blood cholesterol levels during the early phases of the study, mainly due to increases in lower cholesterol levels among some cohorts.     

Cholestyramine and a fat-free diet lower apolipoprotein A-IV mRNA in jejunum and cholestyramine lowers apolipoprotein A-I mRNA in ileum of rats

To investigate the effect of bile acids or dietary lipid on the expression of intestinal apolipoproteins, the mRNA levels of apolipoprotein A-I and A-IV in the intestine from rats fed a diet containing cholestyramine or a fat-free diet were compared with those from rats fed a control diet containing 25% casein and 5% corn oil. Plasma total cholesterol concentration was lower after 16 h in rats fed a diet containing cholestyramine or a fat-free diet than in rats fed a control diet. In rats fed the fat-free diet, HDL cholesterol concentration also was lower than in those fed the control diet. The pool of bile acid in intestinal contents was significantly lower in rats fed cholestyramine than in both other groups. The relative abundance of jejunal apolipoprotein A-I mRNA did not differ between groups. Jejunal apolipoprotein A-IV mRNA abundance was significantly lower than in controls in rats fed the fat-free and cholestyramine-containing diets. Abundance of apolipoprotein A-I mRNA in ileal mucosa was comparable to controls in rats fed a fat-free diet but was significantly lower in rats fed cholestyramine. Ileal apolipoprotein A-IV mRNA tended to be lower in rats fed cholestyramine and a fat-free diet than in controls. We propose that decreased absorption of dietary lipid may modulate changes in jejunal apolipoprotein A-IV mRNA level and low levels of bile acids in the lumen may modulate changes in ileal apolipoprotein A-I mRNA level.     

Angiotensin I-converting enzyme gene polymorphism in a low-risk European population for coronary artery disease

PURPOSE: Physiologic and non-physiologic tumor motion complicates the use of tight margins in three-dimensional (3D) conformal radiotherapy. Setup reproducibility is an important non-physiologic cause of tumor motion. The objective of this study is to evaluate and compare patient setup reproducibility using the reusable T-bar and the disposable expanded foam immobilization device (EFID) in radiation therapy for lung cancer. METHODS AND MATERIALS: Two hundred forty-four portal films were taken from 16 prospectively accrued patients treated for lung cancer. Patients were treated with either a pair of anterior and posterior parallel opposing fields (POF), or a combination of POF and a three-field isocentric technique. Each patient was treated in a supine position using either the T-bar setup or EFID. Six patients were treated in both devices over their treatment courses. Field placement analysis was used to evaluate 3D setup reproducibility, by comparing positions of bony landmarks relative to the radiation field edges in digitized simulator and portal images. Anterior-posterior, lateral, and longitudinal displacements, as well as field rotations along coronal and sagittal planes were measured. Statistical analyses of variance were applied to the deviations among portal films of all patients and the subgroup treated with both immobilization methods. RESULTS: For the T-bar immobilization device, standard deviations of the setup reproducibility were 5.1, 3.7, and 5.1 mm in the anterior-posterior, lateral, and longitudinal dimensions, respectively. Rotations in the coronal plane and the sagittal plane were 0.9 degrees and 1.0 degrees, respectively. For the EFID, corresponding standard deviations of set up reproducibility were 3.6 mm, 5.3 mm, 5.4 mm, 0.7 degrees and 1.4 degrees, respectively. There was no statistically significant difference (p = 0.22) in the 3D setup reproducibility between T-bar and EFID. Subgroup analysis for the patients who were treated with both immobilization devices did not reveal a difference either. There was no consistent systematic error from simulator to treatment unit identified for either immobilization device. CONCLUSION: Although the optimal immobilization technique and patient positioning for thoracic radiotherapy have yet to be determined, this study indicates that T-bar is comparable with EFID in its setup reproducibility. In view of the inherent advantages of T-bar, it has become a standard immobilization device at our institution. The observed range of displacements in field positioning with either immobilization device implies that one cm (two standard deviations [SD] of setup error) will be a more appropriate margin to allow for setup variability in radiation therapy for lung cancer.