Lower Incidence Of Coronary Artery Disease Research Articles

Apolipoprotein E genotype, lifestyle and coronary artery disease: Gene-environment interaction analyses in the UK Biobank population

Background and aimsThe APOE ε4 genotype has a higher risk for developing coronary artery disease (CAD), but there is preliminary evidence that antioxidative lifestyle factors interact with APOE genotype on CAD risk. Here, we assessed the effect modification of physical activity, oily fish and polyunsaturated fatty acid (PUFA) intake with APOE genotype on risk of incident CAD. MethodsThe present study comprised 345,659 white European participants from UK Biobank (mean age: 56.5 years, 45.7% men) without a history of CAD. Information regarding physical activity, oily fish intake and PUFA intake was collected through questionnaires, and information on incident CAD through linkage with hospital admission records. Analyses were performed using Cox proportional hazard models adjusted for age and sex. ResultsHigher physical activity level and oily fish intake were both associated with a lower incidence of CAD. However, these associations were similar across the different APOE genotypes (p-values for interaction > 0.05). Most notable, higher PUFA intake was associated with a lower CAD risk in APOE ε4 genotype carriers (hazard ratio: 0.76, 95% confidence interval: 0.63–0.92), and not in APOE ε3/ε3 genotype carriers (0.90; 0.79, 1.02), but without statistical evidence for effect modification (p-valueinteraction = 0.137). ConclusionsWhile higher physical activity and high fish and PUFA intake were associated with a lower risk of incident CAD, no evidence for interaction of these lifestyle factors with APOE genotype was observed in UK Biobank participants. Interventions intended to reduce cardiovascular risk might therefore be similarly effective across the APOE genotype carriers.

Hypocholesterolemia and dysregulated production of angiopoietin-like proteins in sickle cell anemia patients

Angiopoietin-like proteins (ANGPTL) are responsible for inhibiting lipoprotein lipase activity, and ANGPTL3 and ANGPTL4 deficiencies have been shown to lower lipoprotein levels in animal models and in humans carrying loss-of-function mutations. Sickle cell anemia (SCA) is a hereditary hemolytic anemia characterized by vaso-occlusive crises and end-organ damage, which is curiously associated with hypocholesterolemia and a low incidence of atherosclerosis, whose underlying mechanisms are unclear. We hypothesized that ANGPTL3 and ANGPTL4 dysregulation is responsible for the hypolipidemic phenotype in SCA. We measured circulating concentrations of ANGPTL3 and ANGPTL4 and correlated them with hemolytic biomarkers and lipoproteins in 40 patients with SCA and 30 control individuals. The association between hemolysis and low cholesterol levels in SCA was confirmed along with surprisingly higher levels of ANGPTL3 and ANGPTL4 in SCA patients than in controls. ANGPTL3 correlated with hemolysis markers LDH and reticulocyte counts, while ANGPTL4 did not. Our data show a paradoxical increase in production of ANGPTL3 and ANGPTL4 in SCA, which would be expected to cause hyperlipidemia, due to increased inhibition of lipoprotein lipase. ANGPTL3, exclusively produced by the liver, correlated with hemolysis markers, suggesting a possible hepatic response to hemolysis. Further functional studies and replication in larger cohorts are warranted to investigate the dysregulation of lipid metabolism in SCA.

Disadvantages of Current LDL-cholesterol Lowering and the Role of PCSK9 Inhibitors.

LDL cholesterol (LDL-C) is a strong independent cardiovascular (CV) risk factor that can be easily influenced. Today, statins are the therapy of choice for the achievement of target LDL-C values. Although controlled clinical trials have demonstrated their effectiveness and safety, in practice we are often met with statin intolerance as well as a failure to achieve target LDL-C values in a significant portion of the patients despite maximal doses. In patients with high and very high CV risk, other antilipemic pharmacotherapy is often also insufficient. PCSK9 inhibitors (PCSK9-I) are new revolutionary drugs with a potent effect on LDL-C. The rapid development of PCSK9-I began in 2003 with the discovery of a PCSK9 gene mutation in patients with familial hypercholesterolemia. The product of this gene, proprotein convertase subtilisin/kexin type 9 (PCSK9), has an important role in the expression of LDL receptors and cholesterol metabolism. Animal models demonstrated that inactivation of the PCSK9 gene lowers LDL-C with regression of atherosclerotic changes in the aorta. Heterozygotes and homozygotes with the inactivation mutation of PCSK9 have lower LDL-C values and lower incidence of atherosclerosis. Among the various groups of PCSK9-I, monoclonal antibodies saw strong development (alirocumab, evolocumab, bococizumab). Phase 3 clinical trials on familial and primary hypercholesterolemia with statin intolerance or resistance have demonstrated a strong positive effect of alirocumab and evolocumab on LDL-C values (a reduction of 60%), with high safety and good tolerability. The OSLER study on evolocumab also demonstrated positive effects on CV outcomes. Multiple clinical trials on PCSK9-I are currently monitoring their effect on CV morbidity and mortality. Positive results from these studies would confirm the great potential of PCSK9-I for better prevention and treatment of CV diseases.

70. Epicardial fat quality effect on subclinical atherosclerosis

Epicardial fat quality measured as Hounsfield Unit (HU) by computed tomography has significant impact on atherosclerosis. Excessive epicardial adipose tissue (EAT) is considered a risk factor for coronary artery disease (CAD). There are limited data, however, about the quality of epicardial fat as a CAD risk factor. We investigated the relation between EAT volume and quality and subclinical CAD defined by positive coronary artery calcification (CAC) using computed tomography (CT). We reviewed 609 CT scans to assess the EAT volume, which was measured by manually tracing the parietal pericardial sac on axial images. Fat density was recorded in mean Hounsfield units (HU). Coronary calcium scores were measured using the Agatston method. The patients’ mean age was 50 ± 11 years, and 398 (65.4%) were men. The mean EAT volume was 65 ± 27 cm 3 , and it had a density of 87.0 ± 3.4 HU. Calcium was present in 135 (22%) of the patients: 97 (16% of the total) were men and 38 (6%) were women. There was no difference between the sexes in regard to EAT volume (66 ± 27 vs. 63 ± 26, p = 0.34) or density (87.4 ± 3.2 vs. 87.0 ± 3.6, p = 0.28). Obese patients (body mass index ⩾30 kg/m 2 had significantly higher EAT volumes than nonobese patients (73 ± 30 vs. 61 ± 29, p = 0.011), but no difference was seen in CAC (33 ± 97 vs. 27 ± 103, p = 0.34) or fat density (87.7 ± 4.0 vs. 88.0 ± 2.7, p = 0.48). Univariate regression analyses showed that higher fat attenuation (HU) was associated with a lower coronary atherosclerosis hazard ratio (HR) (0.871, 95% confidence interval [CI] 0.790–0.948, p p = 0.0001). The quality of EAT, measured as HU on CT, is a strong predictor of subclinical CAD as defined by coronary artery calcifications, with a higher HU associated with a lower incidence of atherosclerosis.

The Ankle-Brachial Index Is Related to Left Ventricular Ejection Fraction in Bonnet Macaques

Low ankle-brachial index (ABI) is a marker of peripheral arterial disease associated with higher cardiovascular risk. ABI has been found to be influenced by left ventricular ejection fraction (LVEF), but this relation is confounded by atherosclerosis. Objectives: Since nonhuman primates have a low incidence of atherosclerosis, we sought to evaluate the effect of LVEF on ABI in 24 healthy female bonnet macaques (age 83 ± 21 months). Methods: LVEF was determined by echocardiography during anesthesia with ketamine. ABI was determined using automatic blood pressure cuff. Results: Mean LVEF was 73 ± 6%. Mean ABI was 1.03 (range 0.78-1.17) with similar right and left lower limb values (p = 0.78). On univariate analysis, mean ABI was significantly correlated with LVEF (r = 0.58, p = 0.003) but not with age, crown-rump length or weight. Mean LVEF increased in a stepwise manner from lowest to highest ABI tertile (68 ± 6 vs. 73 ± 4 vs. 77 ± 5%, p = 0.008). On ordinal regression and forced multivariate linear analyses, ABI status was independently related to LVEF. Conclusions: ABI is influenced by left ventricular systolic function but not age, height, weight or mass index in bonnet macaques. Left ventricular systolic function should be accounted for when considering ABI measurements.

In Vitro Effects of Extracts of Extra Virgin Olive Oil on Human Colon Cancer Cells

The Mediterranean diet is associated with a lower incidence of atherosclerosis, cardiovascular diseases, and some types of cancer. Recent interest has been focused on the biological activity of phenolic compounds present in extra virgin olive oils (EVOOs). Both in vivo and in vitro studies have shown that EVOO components have positive effects on metabolic parameters, such as plasma lipoproteins, oxidative damage, inflammatory markers, platelet function, and antimicrobial activity. We have investigated the possible interactions between 2 extracts of extra virgin olive oil and estrogen receptor β (ERβ) in an in vitro model of colon cancer. The qualification and quantification of the components of the 2 samples tested showed that phenolic compounds—hydroxytyrosol, secoiridoids, and lignans—are the major represented compounds. EVOO extracts were tested on a colon cancer cell line engineered to overexpress ERβ (HCT8-β8). By using custom made Oligo microarray, gene expression profiles of colon cancer cells challenged with EVOO-T extracts when compared with those of cells exposed to 17β-estradiol (17β-E2). This study demonstrated that the EVOO extracts tested showed an antiproliferative effect on colon cancer cells through the interaction with estrogen-dependent signals involved in tumor cell growth. Specifically, the ability of EVOO extracts to inhibit cell proliferation was superimposable to the activation of the ERβ receptor, similar to what was observed after 17β-E2 challenge.

Endothelium-dependent vasoactivity of the human internal mammary artery

Coronary artery disease is recognized as a major health problem worldwide, particularly because of the associated morbidity and mortality. Coronary artery bypass grafting has been an established mainstay in the treatment of this disease for almost half a century and is arguably the most intensively studied surgical procedure ever undertaken. Because of its unique properties, the human internal mammary artery has long been considered the best graft to use in this type of surgery. Previous studies have shown several advantages of this graft compared with others, that is, lower incidence of atherosclerosis. However, few comparative studies on the reactivity of this artery have been published. Moreover, these studies usually focus on isolated cardiovascular risk factors rather than combined risk factors. In fact, patients who require coronary revascularization usually present multiple risk factors, which can interfere with several pathways of regulation of vascular function, namely endothelial function. Several diseases and cardiovascular risk factors have been shown to interfere with endothelial function, promoting the production of vasoconstrictors, inhibiting the production of vasodilators, or both, and thus eventually leading to endothelial dysfunction. Therefore, it is of great interest to study the endothelial function, particularly of the human internal mammary artery, in the presence of combined cardiovascular risk factors and concomitant diseases. Many techniques have been developed to assess the endothelial function, in particular, studies on isolated arteries, as well as spectroscopic, electrochemical, and immunological methods, among others.

Low plasma levels of the soluble receptor for advanced glycation end products in HIV-infected patients with subclinical carotid atherosclerosis receiving combined antiretroviral therapy

ObjectiveCombined antiretroviral therapy (cART) has significantly improved the survival rate and quality of life for HIV-infected subjects, but it contributes to the development of metabolic complications including coronary artery disease (CAD). Recent studies have reported that high plasma levels of the soluble receptor for advanced glycation end products (sRAGE) were associated with a lower incidence of CAD in non-HIV infected patients. However, there has been no report of an association of sRAGE and subclinical carotid atherosclerosis in HIV-infected patients receiving cART. MethodsWe examined the association of circulating sRAGE in HIV-infected patients with carotid intima–media thickness (IMT) and other metabolic variables. We prospectively enrolled 76 HIV-infected patients receiving cART for ≥6 months. ResultssRAGE had a significantly negative correlation with body mass index (r=−0.324, p=0.005), waist-to-hip ratio (r=−0.335, p=0.003), systolic blood pressure (BP) (r=−0.359, p=0.002), diastolic BP (r=−0.343, p=0.004), total cholesterol (r=−0.240, p=0.037), low-density lipoprotein-cholesterol (r=−0.284, p=0.024), log(homeostasis model assessment of insulin resistance [HOMA-IR]) (r=−0.380, p=0.002) and carotid IMT including max-IMT and mean-IMT (r=−0.358, p=0.001 and r=−0.329, p=0.004, respectively). By the use of multiple stepwise regression analyses, systolic BP (p=0.001) and log[HOMA-IR] (p=0.001) remained significant independently. ConclusionsThese results suggest that sRAGE may have a protective effect against subclinical atherosclerosis by preventing inflammatory responses mediated by the activation of cell surface RAGE in HIV-infected patients receiving cART.

Histomorphometric and sympathetic innervation of the human internal thoracic artery

INTRODUCTION:Internal thoracic artery (ITA) is an established arterial graft for the coronary artery by‐pass surgery. Special micro‐anatomical features of the ITA wall may protect it from age related pathological changes. One of the complications seen after coronary artery bypass grafting is vasospasm. Sympathetic nerves may be involved in vasospasm.OBJECTIVE:To ascertain the sympathetic innervation of the internal thoracic artery and to assess the effect of aging on this artery by histomorphometry.METHOD:Fifty‐four human internal thoracic artery samples were collected from 27 cadavers (19 male and 8 female) with ages of 19 to 83 years. Samples were divided into three age groups: G1, 19–40 years; G2, 41–60 years; G3, ≥61 years. Sections (thickness 5 µm) of each sample were taken and stained with hematoxylin–eosin and Verhoeff–Van Gieson stains. Five of fifty‐four samples were processed for tyrosine hydroxylase immunostaining.RESULTS:The thickness of the tunica intima was found to be constant in all age groups, whereas the thickness of the tunica media decreased in proportion to age. Verhoeff–Van Gieson staining showed numerous elastic laminae in the tunica media. Significant differences (p<0.0001) in the number of elastic laminae were found between G1 with G2 cadavers, between G2 and G3 cadavers and between G3 and G1 cadavers. Tyrosine hydroxylase immunostaining demonstrated sympathetic fibers, located mainly in the tunica adventitia and the adventitia–media border. The sympathetic nerve fiber area and sympathetic index were found to be 0.0016 mm2 and 0.012, respectively.DISCUSSION:Histology of the ITA showed features of the elastic artery. This may be associated with lower incidence of Atherosclerosis or intimal hyperplasia in ITA samples even in elderly cases. Low sympathetic index (0.012) of ITA may be associated with fewer incidences of sympathetic nervous systems problems (vasospasm) of the ITA.CONCLUSION:Sympathetic nerve fibers are present in the adventitia of the internal thoracic artery. This is an elastic artery, although anatomically it is considered to be medium‐sized. The sympathetic index may be used for analysis of sympathetic nerve fiber‐related problems of the internal thoracic artery.

Biological Activities of Phenolic Compounds Present in Virgin Olive Oil

The Mediterranean diet is associated with a lower incidence of atherosclerosis, cardiovascular disease, neurodegenerative diseases and certain types of cancer. The apparent health benefits have been partially ascribed to the dietary consumption of virgin olive oil by Mediterranean populations. Much research has focused on the biologically active phenolic compounds naturally present in virgin olive oils to aid in explaining reduced mortality and morbidity experienced by people consuming a traditional Mediterranean diet. Studies (human, animal, in vivo and in vitro) have demonstrated that olive oil phenolic compounds have positive effects on certain physiological parameters, such as plasma lipoproteins, oxidative damage, inflammatory markers, platelet and cellular function, antimicrobial activity and bone health. This paper summarizes current knowledge on the bioavailability and biological activities of olive oil phenolic compounds.

Prevalence of Coronary Heart Disease in Patients with Hemophilia: a Nationwide Study in Brazil.

Abstract 3495Poster Board III-432 BackgroundIt is well known that patients with hemophilia (both A and B) have a lower incidence of coronary artery disease (CAD). However, patients with hemophilia may develop atherosclerosis, and with increases in life expectancy it is possible that the incidence of CAD may increase in these patients. There are no studies analyzing the prevalence of CAD in patients with hemophilia and possible risk factors. AimsTo determine the prevalence of CAD in patients with hemophilia treated in Brazil. MethodsAll patients with hemophilia in Brazil receive therapy with Factor VIII or Factor IX at government-designed hemophilia centers. We thus contacted all centers in Brazil by e-mail and information from databases concerning health information for all patients was reviewed by the responsible physician at each center. A questionnaire about risk factors for CAD and history of coronary events was sent to patients that had a positive history of CAD. ResultsThere are 6,881 patients registered with a diagnosis of hemophilia A and 1,291 patients with a diagnosis of hemophilia B in Brazil. Fifty-six percent of hemophilia centers answered the query, and information on 71.7% of patients with hemophilia A (4,934 patients) and 61.4% of patients with hemophilia B (792 patients) was reviewed. There were only 3 patients (0.05%) with a positive history of CAD. Their clinical characteristics are summarized in Table 1. During surgical treatment for CAD, replacement with Factor VIII and Factor IX was done by continuous infusion to increase Factor activity to 80-100%. Antiplatelet therapy was used in all patients at some point, and one patient (#1) developed hemarthrosis after two months of ASA. Patient #3 did not start antiplatelet therapy after CABG, and developed thrombosis of the graft. ASA and clopidogrel were started after percutaneous coronary angioplasty. ConclusionWe found a very low incidence of CAD in hemophiliac patients, even after doing a nationwide survey that included more than 5,000 patients. No information about risk factors can be gleaned due to the small number of patients. Surgical treatment after increasing factor activity appears to be safe in such patients. Despite a theoretical risk for increased bleeding, therapy with antiplatelet agents appears to be necessary in hemophiliac patients with CAD.Table 1Clinical features of patients with CAD and HemophiliaUPIAge, yearsTypeComorbiditiesAcute EventsMedical TherapySurgical Therapy151ADiabetes MellitusMIASACABG262ANoneUAASAPercutaneous angioplasty with stent337BHIV+ receiving HAARTUAClopidogrel ASACABG Percutaneous angioplasty with stentAbbreviations: UPI, unique patient identifier; MI, myocardial infarction; ASA, acetylsalycilic acid; CABG, coronary artery bypass graft; UA, unstable angina; HAART, highly active anti-retroviral therapy Disclosures:No relevant conflicts of interest to declare.

Total oxidant‐scavenging capacities of plasma from glycogen storage disease type Ia patients as measured by cyclic voltammetry, FRAP and luminescence techniques

It has been suggested that the very low incidence of atherosclerosis in glycogen storage disease type Ia (GSD Ia) subjects might be attributed to elevated levels of uric acid, one of the potent low molecular- weight antioxidants found in plasma. The present communication describes a use of two analytical methods-cyclic voltammetry and ferric reducing ability of plasma-and also two chemiluminescence methods to evaluate the total oxidant-scavenging capacities (TOSC) of plasma from GSD Ia patients. Our results verified the elevation of TOSC in GSD Ia patients and we propose the inclusion of luminescence and cyclic voltammetry assays as reliable methods for estimating TOSC in a variety of clinical disorders. Our findings with the cyclic voltammetry method add support to the assumption that the elevated uric acid levels might be the main contributor to plasma antioxidant capacity and possible protection against atherosclerosis.

Chemistry and Health of Olive Oil Phenolics

The Mediterranean diet is associated with a lower incidence of atherosclerosis, cardiovascular disease, and certain types of cancer. The apparent health benefits have been partially attributed to the dietary consumption of virgin olive oil by Mediterranean populations. Most recent interest has focused on the biologically active phenolic compounds naturally present in virgin olive oils. Studies (human, animal, in vivo and in vitro) have shown that olive oil phenolics have positive effects on certain physiological parameters, such as plasma lipoproteins, oxidative damage, inflammatory markers, platelet and cellular function, and antimicrobial activity. Presumably, regular dietary consumption of virgin olive oil containing phenolic compounds manifests in health benefits associated with a Mediterranean diet. This paper summarizes current knowledge on the physiological effects of olive oil phenolics. Moreover, a number of factors have the ability to affect phenolic concentrations in virgin olive oil, so it is of great importance to understand these factors in order to preserve the essential health promoting benefits of olive oil phenolic compounds.

Homocysteinemia, hypertension, and family history of diabetes in a smoking male population in Saudi Arabia

AbstractArabs have a lower incidence of atherosclerosis than other ethnicities, but few studies have examined homocysteine (HCYS) as a risk factor for cardiovascular disease in this population. Here, we investigated the association between serum HYCS levels and risk factors for cardiovascular disease (smoking, hypertension, and family history of diabetes) in Saudi males. A total of 50 smokers and 72 nonsmokers completed a general health questionnaire. In addition, their lipid profiles were measured using routine methods and HCYS levels by high-performance liquid chromatograph with electrochemical detection. Regression analysis showed negative associations between HCYS and glucose (r = −0.22; P &lt; 0.05) as well as family history of diabetes (r = −0.21; P &lt; 0.05). HCYS levels were similar between hypertensive and nonhypertensive smokers, but they were significantly elevated in hypertensive nonsmokers (P = 0.027) and lower in smokers with family history of diabetes (P = 0.01). Levels of HCYS among nonsmokers inversely correlated with history of diabetes and elevated glucose. Nonsmokers’ HCYS levels were significantly elevated in the presence of hypertension and correlated with diastolic blood pressure. Thus, HCYS may be a predictor of hypertension among nonsmokers. Until further trials are conducted, we recommend vitamin B6/folic acid supplementation for the Saudi hypertensive population as an adjuvant therapy.

The stromal derived factor-1 mutated allele (SDF1-3′A) is associated with a lower incidence of atherosclerosis in HIV-infected patients

HIV-infected patients have higher rates of subclinical atherosclerosis. The chemokine stromal derived factor 1 (SDF-1) is the natural ligand for the CXCR4 HIV co-receptor, is highly expressed in atherosclerotic plaques, and the plasma concentration is lower in individuals homozygous for the mutant allele (SDF1-3'A). We tested the influence of SDF1-3'A on atherosclerosis in HIV-infected patients. We performed carotid ultrasonography and determined the SDF1-3'A DNA polymorphism in 183 HIV-infected patients. Classical cardiovascular risk factors and antiretroviral therapy were also recorded. From these patients, we selected a group of 134 patients taking protease inhibitor-based antiretroviral therapy and in whom the lipid profile over an 18-month follow-up was collated. We found atherosclerosis in 113 (61.7%) and a lower number of patients with the SDF-1 mutated allele in the group with carotid atherosclerosis compared to those without (41.6% versus 57.1%; P = 0.04). Using a logistic regression analysis, age and dyslipidaemia were significantly associated with atherosclerosis but the SDF1-3'A allele exerted a protective effect on the development of atherosclerosis (odds ratio, 0.45; 95% confidence interval, 0.14-1.02; P = 0.05). Further, we observed that, in the selected group of patients there were lower plasma low-density lipoprotein cholesterol concentrations [mean +/- SEM, 2.06 +/- 0.34 mmol/l] throughout follow up in those patients without carotid lesions and who also carried the mutated SDF1-3'A allele (P = 0.04). The SDF1-3'A allele is associated with a lower presence of subclinical carotid atherosclerosis in an HIV-infected population.

Testosterone for secondary prevention in men with ischaemic heart disease?

Atherosclerotic coronary artery disease (CAD) is a leading cause of mortality and morbidity in the western world. It is a chronic progressive condition, and treatment is required indefinitely. Men are more than twice as likely as women to develop CAD:1 this ratio is consistent in all populations and is not related to differences in risk factors. Pre-menopausal females have a lower incidence of CAD, but this rises after the menopause, so that the risk of CAD rapidly approaches that of males after about 10 years. One explanation for these epidemiological observations is that female hormones protect against the development of CAD. Observational studies of hormone replacement therapies in women have suggested some benefit,2 but large randomized controlled trials have failed to show protective effects.3,,4 Little attention has been paid to the role of testosterone in the pathogenesis of CAD. Males do not have a menopause equivalent, but sex hormones do fall with advancing age.5,,6 The more elderly population, in which the prevalence of CAD is highest, has relatively low testosterone levels. Furthermore, males with CAD have lower testosterone levels than men with normal coronary angiograms males of the same age.7 Moreover, there is evidence that testosterone therapy delays the onset of cardiac ischaemia,8 probably as a consequence of a coronary vasodilator mechanism,8 improving the symptom of angina.8,,10 The ability of testosterone replacement therapy to alter disease progression to reduce events or mortality has not been examined. In this article, we review the effects of testosterone therapy on factors known to influence cardiovascular risk, and propose a justification for further studies into its use for males with coronary disease as secondary prevention. Testosterone has well-established functions in the adult male. It induces secondary sexual characteristics, and is …

Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part I: aging arteries: a "set up" for vascular disease.

Our population is aging; in the United States today there are 35 million people 65 years of age or older. That number will double by the year 2030 (Figure 1). Although epidemiological studies have discovered that lipid levels, diabetes, sedentary lifestyle, and genetic factors are risk factors for coronary disease, hypertension, congestive heart failure, and stroke, the quintessential cardiovascular diseases within our society, advancing age unequivocally confers the major risk. The incidence and prevalence of these diseases increase steeply with advancing age (Figure 2). Not only does clinically overt cardiovascular disease increase dramatically with aging, but so do subclinical or occult diseases, such as silent coronary atherosclerosis. Figure 3 (top) shows that a substantial percentage of older, community-dwelling, otherwise healthy volunteers have evidence of inducible ischemia during combined thallium/ECG treadmill stress testing, and their prognosis is poor compared with their counterparts without subclinical coronary disease (Figure 3, bottom). Figure 1. The demographic imperative. Numbers of persons 65 years of age or older (light bars) and 85 years of age or older in the United States from 1900 through 2030. Data taken from the US Census Bureau data with projections for 2030. Figure 2. A, Prevalence of hypertension, defined as systolic blood pressure ≥140, diastolic blood pressure ≥90, or current use of medication for purposes of treating high blood pressure. Data are based on National Health and Nutrition Examination Survey III (1988–1991) (Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hypertension in the US adult population: results from the Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension . 1995;25:305–313). B, Incidence of atherothrombotic stroke (per 1000 subjects per year) by age in men (light bars) and women (dark bars) from the Framingham Heart Study. Data from Wolf PA. Lewis A. Conner lecture: contributions of epidemiology to the …

New methods to evaluate endothelial function: Non-invasive method of evaluating endothelial function in humans.

Evidence has accumulated that impairment of vascular endothelial function is the initial step in the development of atherosclerosis. One important finding is impairment of the release of endothelium-dependent relaxing factor, which is now thought to be nitric oxide or its related substances, from endothelial cells. Flow-mediated dilatation has been known to be endothelium-dependent, and this can be detected during reactive hyperemia by high-resolution ultrasound in superficial arteries. Several coronary risk factors have been reported to be significantly related with decreased flow-mediated dilatation. We studied the association between the accumulation of coronary risk factors (hyperlipidemia, diabetes mellitus, hypertension, and current smoking habitus) and vascular endothelial function. The lower incidence of atherosclerosis in women before the menopause than that in men is an established epidemiological observation. Short-term estrogen therapy improves endothelial function in postmenopausal women. However, there are few reports on its long-term effects on endothelial function. Furthermore, we determined whether a reduced dosage of estrogen may maintain its beneficial effects. A similar improvement was also observed while women were on hormone replacement therapy even at the reduced dosage. Our results indicate that even at half the dose of estrogen, hormone replacement therapy may improve endothelial function in postmenopausal women.

Vitamin E in cardiovascular disease: has the die been cast?

Cardiovascular disease, in particular coronary artery disease (CAD), remains the most important cause of morbidity and mortality in developed countries and, in the near future, more so in the developing world. Atherosclerotic plaque formation is the underlying basis for CAD. Growth of the plaque leads to coronary stenosis, causing a progressive decrease in blood flow that results in angina pectoris. Acute myocardial infarction and unstable angina were recently recognised as related to plaque rupture, not progressive coronary stenosis. Acute thrombus formation causes an abrupt coronary occlusion. The characteristics of the fibrin cap, contents of the plaque, rheological factors and active inflammation within the plaque contribute to plaque rupture. Oxidative processes are important in plaque formation. Oxidized low density lipoproteins (LDL) but not unoxidized LDL is engulfed by resident intimal macrophages, transforming them into foam cells which develop into fatty streaks, the precursors of the atherosclerotic plaque. Inflammation is important both in plaque formation and rupture. Animal studies have shown that antioxidants reduce plaque formation and lead to plaque stabilisation. In humans, high intakes of antioxidants are associated with lower incidence of CAD, despite high serum cholesterol levels. This observation suggests a role for inflammation in CAD and that reducing inflammation using antioxidants may ameliorate these processes. Men and women with high intakes of vitamin E were found to have less CAD. Vitamin E supplementation was associated with a significant reduction in myocardial infarction and cardiovascular events in the incidence of recurrent myocardial infarction. In the hierarchy of evidence in evidence-based medicine, data from large placebo-controlled clinical trials is considered necessary. Results from various mega-trials have not shown benefits (nor adverse effects) conferred by vitamin E supplementation, suggesting that vitamin E has no role in the treatment of CAD. These results do not seem to confirm, at the clinical level, the effect of antioxidants against active inflammation during plaque rupture. However, a closer examination of these studies showed a number of limitations, rendering them inconclusive in addressing the role of vitamin E in CAD prevention and treatment. Further studies that specifically address the issue of vitamin E in the pathogenesis of atherosclerosis and in the treatment of CAD need be performed. These studies should use the more potent antioxidant property of alpha-tocotrienol vitamin E.

Remarkably high prevalence of small dense low-density lipoprotein in Japanese men with coronary artery disease, irrespective of the presence of diabetes

To examine how prevalence of the small dense LDL phenotype (LDL particle diameter ≤25.5 nm) is associated with coronary artery disease (CAD) in type 2 diabetic and non-diabetic Japanese men, an ethnic group with a low incidence of CAD, 85 non-diabetic men and 45 type 2 diabetic men with angiographically documented CAD, and 142 control men and 76 type 2 diabetic men without CAD were studied. Mean LDL particle diameter was determined using 2–16% polyacrylamide gel electrophoresis. LDL particle diameters in CAD patients were much smaller than those in controls (25.2±0.7 vs. 26.0±0.4 nm, mean±S.D., P<0.0001). LDL size was smaller in diabetic subjects (25.6±0.6 nm) and became even smaller in diabetics with CAD (25.0±1.0 nm). Prevalence of small dense LDL was markedly higher in both non-diabetic and diabetic CAD patients than that in non-diabetic and diabetic patients without CAD (71, 76, 23 and 42%, respectively). CAD patients had lower HDL-cholesterol and apo A1 levels, and higher triglyceride levels than those in diabetic and non-diabetic CAD-free patients, while total- and LDL-cholesterol levels were even lower in CAD group, and remnant-like particle-cholesterol, lipoprotein (a) and insulin levels were comparable among four groups. LDL size was significantly associated with triglyceride, HDL-cholesterol and glycemic control. Logistic regression analysis revealed that the small dense LDL phenotype was significantly associated with the incidence of CAD independent of low levels of HDL-cholesterol or high levels of triglyceride in both non-diabetic and diabetic cases. These results suggest that high prevalence of small dense LDL is a leading cause of CAD in both diabetic and non-diabetic Japanese men. Type 2 diabetes shows a greater capacity to reduce LDL size, which may contribute to the high incidence of CAD in the diabetic population.