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To obtain reliable data on the epidemiology of arteriosclerosis and the comorbidities in patients with hypertension (HP), coronary heart disease (CHD), type 2 diabetes mellitus (T2DM) and stroke, we evaluated the clinical significance of pulse wave velocity (PWV) as an indicator of arteriosclerosis and its comorbidities in Chinese patients. A total of 910 subjects, including 748 Chinese patients with one or more cardiovascular risk factors (80.2% male, mean age 73.69+/-5.03 years) and 162 healthy volunteers (78.4% male, mean age 73.60+/-5.32 years) were recruited into the study. PWV was measured in 910 subjects, and large artery arteriosclerosis was defined as PWV >or=12 m/s. Multivariable logistic regression analyses were performed to identify risk factors associated with arteriosclerosis. The prevalence of large artery arteriosclerosis in the patients overall was 67.4%, and the prevalence was higher in patients with than in those without HP (63.3% vs. 34.0%; odds ratio [OR]: 3.451), T2DM (24.8% vs. 11.1%; OR: 2.854), CHD (56.1% vs. 45.1%; OR: 1.246) and stroke (26.6% vs. 19.2%; OR: 1.236), but the OR values of CHD and stroke did not differ significantly (p>0.05). After multiple logistic regression analysis, female sex, older age, HP and T2DM were risk factors for large artery arteriosclerosis. In conclusion, PWV can be used as a routine measurement to scan arteriosclerosis in patients with HP or T2DM.

Rupture of an atherosclerotic plaque with subsequent thrombosis and myocardial ischemia is the patho-physiological mechanism in acute coronary syndromes. Tissue factor (TF) as the main initiator of the extrinsic coagulation cascade plays a central role in the pathogenesis of acute coronary syndromes. The extent of the thrombotic process is modulated by local vascular TF of the ruptured plaque as well as by circulating TF. In addition, TF alters signaling pathways and, thereby, contributes to inflammatory reactions and vascular remodeling. This review addresses current concepts of the role of TF in acute coronary syndromes and discusses potential consequences and therapeutic approaches.

Background: Arterial wave reflection is a major determinant of left ventricular function, coronary perfusion and cardiovascular risk. We investigated whether arterial wave reflection may detect atherosclerosis of peripheral arteries in patients with documented coronary artery disease (CAD)., Methods: Radial artery applanation tonometry and pulse wave analysis was performed in 184 patients with documented CAD at coronary angiography; central blood pressures and augmentation index (AI) were measured. Ankle-brachial (ABI) index and intima-media thickness (IMT) were used as indices of atherosclerosis of the lower limbs and the carotid arteries respectively., Results: Patients with abnormal IMT (> 0.7 mm, first tertile) or ABI (< 0.94, first tertile) had higher AI than patients with lower IMT or higher ABI (24 +/- 17 versus 17 +/- 16% and 23 +/- 18 versus 18 +/- 13%, respectively, P < 0.05). In multivariate analysis, increasing AI was associated with age, female gender, heart rate, mean blood pressure, hyperlipidaemia, and use of statins (regression coefficient (beta) = 0.50, beta = 0.15, beta = -0.60, beta = 0.23, beta = 0.16 and beta = -0.14, respectively, P < 0.05). Increasing AI was associated with an adjusted-odds ratio of 1.035 [95% confidence interval (CI), 1.005-1.066], P = 0.02 for an abnormal IMT and of 1.08 (95% CI, 1.024-1.146), P = 0.005 for ABI after adjustment for age, gender, heart rate, height, blood pressure, atherosclerotic risk factors, obesity and medication. No relation was found between AI and Gensini score or for the number of diseased coronary vessels., Conclusion: Augmentation index is a marker of extensive extracoronary atherosclerosis in patients with CAD.

Background: Increased arterial stiffness has been shown to be associated with coronary heart disease (CHD). However, it remains unclear as to whether the second derivative of the finger photoplethysmogram (SDPTG), a non-invasive method for the assessment of arterial stiffness, is useful for the estimation of risk of CHD in the general population., Methods and Results: The SDPTG in 211 subjects (age: 63+/-15 years, range: 21-91 years, 93 males) was recorded without apparent atherosclerotic disorders from a community. The relationship between the SDPTG indices (b/a and d/a) and coronary risk factors (n=211) or the Framingham risk score (n=158, age: 60+/-12 years, range: 30-74 years, 63 males) were analyzed. The SDPTG indices significantly correlated with the Framingham risk score in both genders (b/a; r(male) =0.43, r(female) =0.54 and d/a; r(male) =-0.38, r(female) =-0.58), as well as several coronary risk factors. In the receiver operating characteristics curve analyses, the b/a discriminated high-risk subjects for CHD, who were in the highest quintile of the Framingham risk score in each gender, with a sensitivity and specificity of 0.85 and 0.58 in males and 0.83 and 0.72 in females, respectively., Conclusions: These results suggest that the SDPTG is useful for the estimation of risk of CHD in the general population.

During inflammation, several cell types synthesize and secrete phospholipase A2 that catalyses lipid oxidation in LDL. Myeloperoxidase, a haeme protein secreted by activated phagocytes, oxidizes L-tyrosine to a tyrosyl radical that is a physiological catalyst for the initiation of lipid oxidation in LDL. Lipid oxidation results in the generation of aldehydes that substitute lysine residues in the apolipoprotein B-100 moiety. Lipid together with protein oxidation in LDL results in the generation of oxidized LDL. We, among others, have demonstrated an association between coronary heart disease (CHD) and increased plasma levels of oxidized LDL. Recently, we have demonstrated a higher prevalence of elevated oxidized LDL in persons with high-calculated CHD risk prior to events. The odds of having elevated oxidized LDL for persons with high-calculated CHD risk prior to events were even higher than for persons with diagnosed CHD. A likely explanation is that once CHD has been diagnosed the patients are more treated with a statin that appears to decrease oxidized LDL even beyond its cholesterol-lowering effect. We have identified several metabolic syndrome components (high triglycerides, low HDL-cholesterol, glucose intolerance and diabetes) that independently of LDL-cholesterol, predicted high levels of oxidized LDL. Finally, elevated oxidized LDL predicted myocardial infarction in the Health ABC cohort consisting of well-functioning elderly people, even after adjusting for age, gender, race, smoking, and the metabolic syndrome.

Patients with chronic kidney disease (CKD) on dialysis have 2- to 5-fold more coronary artery calcification than age-matched individuals with angiographically proven coronary artery disease. In addition to increased traditional risk factors, CKD patients also have a number of nontraditional cardiovascular risk factors that may play a prominent role in the pathogenesis of arterial calcification, including duration of dialysis and disorders of mineral metabolism. In histological specimens from the inferior epigastric artery of dialysis patients, we have found expression of the osteoblast differentiation factor core binding factor alpha-1 (Cbfa1) and several bone-associated proteins (osteopontin, bone sialoprotein, alkaline phosphatase, type I collagen) in both the intima and medial layers when calcification was present. In cultured vascular smooth muscle cells, the addition of pooled serum from dialysis patients (versus normal healthy controls) accelerated mineralization and increased expression of Cbfa1, osteopontin, and alkaline phosphatase to a similar magnitude as does beta-glycerophosphate alone. However, a lack of inhibitors of calcification may also be important. Dialysis patients with low levels of serum fetuin-A, a circulating inhibitor of mineralization, have increased coronary artery calcification and fetuin-A can inhibit mineralization of vascular smooth muscle cells in vitro. These data support that elevated levels of phosphorus and/or other potential uremic toxins may play an important role by transforming vascular smooth muscle cells into osteoblast-like cells, which can produce a matrix of bone collagen and noncollagenous proteins. This nidus can then mineralize if the balance of pro-mineralizing factors outweighs inhibitory factors.

Coronary heart disease (CHD) remains a persistent public health burden in the United States, and it is the cause of one of every five deaths each year. The link between lipids and CHD has been firmly established, first by epidemiologic studies and, more recently, by long-term outcomes trials that demonstrated that lowering low-density lipoprotein cholesterol (LDL-C) levels significantly reduced the risk of major coronary events. Based on this evidence, the National Cholesterol Education Program recommends lowering the LDL-C level to reduce CHD risk, particularly for patients at highest risk. Recently, evidence has emerged that suggests that C-reactive protein may be a mediator of atherosclerosis and its presence may be indicative of increased risk of CHD. Although these data are intriguing, their relevance has yet to be established in prospective outcomes trials. Until then, lipid lowering through lifestyle modification and the use of safe and effective modes of therapy should be the emphasis of CHD risk reduction strategies.

Background: Endothelial dysfunction leads to atherosclerosis and the hypothesis of the present study was that the systemic circulatory response during exercise would be a manifestation of endothelial dysfunction., Methods and Results: The circulatory response to exercise of 1,214 apparently healthy people (946 men, mean age 51.2 +/- 10.3; 268 women, mean age 52.7 +/- 10.1) was investigated, as well as the number of coronary risk factors. Systemic vascular resistance (SVR) was calculated from heart rate, blood pressure and oxygen uptake at rest and at maximal exercise during a ramp protocol using a bicycle ergometer. SVRs at rest (1,751-2,001 (dynes.s.cm(-5)) in women and 1,528-1,564 in men) did not significantly differ among the groups by number of coronary risk factors. At maximal exercise, however, they were lower in the group with fewer risk factors; that is, among women 929 (dynes.s.cm (-5)) with no risk factor to 1,305 with 5 risk factors; among men 793 with 1 risk factor to 1,170 with 6 risk factors., Conclusions: Those with more coronary risk factors showed a lower but lengthier reduction in SVR during exercise. This weak circulatory response to exercise is a manifestation of deteriorated circulatory function in coronary high-risk subjects.

Objectives: We sought to assess the prognostic utility of brachial artery reactivity (BAR) in patients at risk of cardiovascular events., Background: Impaired flow-mediated vasodilation measured by BAR is a marker of endothelial dysfunction. Brachial artery reactivity is influenced by risk factors and is responsive to various pharmacological and other treatments. However, its prognostic importance is uncertain, especially relative to other predictors of outcome., Methods: A total of 444 patients were prospectively enrolled to undergo BAR and follow-up. These patients were at risk of cardiovascular events, based on the presence of risk factors or known or suspected cardiovascular disease. We took a full clinical history, performed BAR, and obtained carotid intima-media thickness (IMT) and left ventricular mass and ejection fraction. Patients were followed up for cardiovascular events and all-cause mortality. Multivariate Cox regression analysis was performed to assess the independent association of investigation variables on outcomes., Results: The patients exhibited abnormal BAR (5.2 +/- 6.1% [mean +/- SD]) but showed normal nitrate-mediated dilation (9.9 +/- 7.2%) and normal mean IMT (0.67 +/- 0.12 mm [average]). Forty-nine deaths occurred over the median follow-up period of 24 months (interquartile range 10 to 34). Patients in the lowest tertile group of BAR (<2%) had significantly more events than those in the combined group of highest and mid-tertiles (p = 0.029, log-rank test). However, mean IMT (rather than flow-mediated dilation) was the vascular factor independently associated with mortality, even in the subgroup (n = 271) with no coronary artery disease and low risk., Conclusions: Brachial artery reactivity is lower in patients with events, but is not an independent predictor of cardiovascular outcomes in this cohort of patients.

Statin therapy prevents the first occurrence and recurrence of coronary events and reduces cardiovascular and general mortality in patients with coronary artery disease. These compounds modulate a variety of processes involved in the pathophysiology of arteriosclerosis and vascular graft disease by lipid-dependent and lipid-independent (pleiotropic) mechanisms. As a result, statins produce angiographic and clinical benefits in patients undergoing coronary bypass surgery. We review the present knowledge about the effects of statins on this pathologic condition and the evidence supporting an early treatment initiation.

Mortality rates from coronary heart disease are lower in Swedish men and among Finnish migrants who have lived in Sweden for over 20 years than in men living in Finland. Sero-epidemiological studies, investigations of atheromatous plaque specimens, in vitro animal models and anti-chlamydial antibiotic trials have given support to the hypothesis that Chlamydia pneumoniae (Cpn) has a role in atherosclerosis. We investigated whether men with a similar genetic background but living permanently in Finland or Sweden have differences in the prevalence of Cpn seropositivity, and whether chronic Cpn infection is associated with markers of subclinical atherosclerosis. We measured anti-Cpn antibodies and ultrasonographic markers of subclinical atherosclerosis, including carotid intima-media thickness, carotid artery compliance and brachial artery flow-mediated dilatation, in a population of 76 migrant-discordant male twin pairs (152 men). The number of men with seropositivity to Cpn infection (defined as IgA>/=1:64 and IgG>/=1:128) was greater in Finland than in Sweden (21.5% compared with 10.5%; P =0.046). Cpn seropositivity accompanied by elevated C-reactive protein (CRP) levels (>1 mg/l) was associated with attenuated brachial artery flow-mediated dilatation (3.3+/-0.3%, compared with 5.5+/-0.4% in men with no signs of Cpn infection; P <0.001).Thus, among Finnish twin brothers discordant for migration to Sweden, the prevalence of Cpn seropositivity is higher for those living in Finland, and men with Cpn seropositivity combined with elevated CRP levels had attenuated endothelial function. These findings offer insight into the mechanism whereby chronic Cpn infection may increase the risk of coronary heart disease.

The objective of this communication is to provide evidence that the spasm of resistance vessel (S-RV) concept of ischemic heart disease (IHD) and other ischemic disorders provides a more consistent set of explanations for acute coronary syndromes than the accepted mechanism of plaque rupture and consequent thromboses. The concept avers that S-RV directly induces symptoms in the various syndromes of IHD, including acute coronary syndromes. The S-RV concept is considered to be an alternate paradigm to explain IHD, and interest only develops in such models when there is significant doubt about the validity of the accepted paradigm. This report is an update of a study reported in this Journal in 1999 and has 2 changes; evidence will be evaluated by formal verification/falsification (pass/fail) methods - the method used to evaluate paradigms, and this report focuses on the mechanism of acute coronary syndromes because of the importance of these syndromes. It is well accepted that acute coronary syndromes are due directly to plaque rupture/thromboses, and there is considerable evidence to support this obvious mechanism. In spite of the obviousness of this mechanism, the S-RV concept asserts that S-RV is a more rational mechanism to explain acute coronary syndromes. Consistent with this position, the results of the study favor the S-RV concept. The standard position was given 8 passes, 2 passes with associated possible limited failures, and 2 possible failures. In contrast, the S-RV concept was given 12 passes, and no failures. Hopefully, the results of this study, and other available information about the S-RV concept, will prompt interest in the concept - such as independent testing of its premises.

Age is the main clinical determinant of large artery stiffness. Central arteries stiffen progressively with age, whereas peripheral muscular arteries change little with age. A number of clinical studies have analyzed the effects of age on aortic stiffness. Increase of central artery stiffness with age is responsible for earlier wave reflections and changes in pressure wave contours. The stiffening of aorta and other central arteries is a potential risk factor for increased cardiovascular morbidity and mortality. Arterial stiffening with aging is accompanied by an elevation in systolic blood pressure (BP) and pulse pressure (PP). Although arterial stiffening with age is a common situation, it has now been confirmed that older subjects with increased arterial stiffness and elevated PP have higher cardiovascular morbidity and mortality. Increase in aortic stiffness with age occurs gradually and continuously, similarly for men and women. Cross-sectional studies have shown that aortic and carotid stiffness (evaluated by the pulse wave velocity) increase with age by approximately 10% to 15% during a period of 10 years. Women always have 5% to 10% lower stiffness than men of the same age. Although large artery stiffness increases with age independently of the presence of cardiovascular risk factors or other associated conditions, the extent of this increase may depend on several environmental or genetic factors. Hypertension may increase arterial stiffness, especially in older subjects. Among other cardiovascular risk factors, diabetes type 1 and 2 accelerates arterial stiffness, whereas the role of dyslipidemia and tobacco smoking is unclear. Arterial stiffness is also present in several cardiovascular and renal diseases. Patients with heart failure, end stage renal disease, and those with atherosclerotic lesions often develop central artery stiffness. Decreased carotid distensibility, increased arterial thickness, and presence of calcifications and plaques often coexist in the same subject. However, relationships between these three alterations of the arterial wall remain to be explored.

Diets rich in fruits and vegetables containing carotenoids have been of interest because of their potential health benefit against chronic diseases such as cardiovascular diseases (CVD) and cancer. Interest particularly in lycopene is growing rapidly following the recent publication of epidemiological studies that have associated high lycopene levels with reductions in CVD incidence. Two studies were conducted. In the first one, we examined the role of lycopene as a risk-lowering factor with regard to acute coronary events and stroke in the prospective Kuopio Ischemic Heart Disease Risk Factor (KIHD) Study. The subjects were 725 middle-aged men free of coronary heart disease and stroke at the study baseline. In a Cox's proportional hazards' model adjusting for covariates, men in the lowest quartile of serum levels of lycopene had a 3.3-fold (P < 0.001) risk of the acute coronary event or stroke as compared with others. In the second study, we assessed the association between plasma concentration of lycopene and intima-media thickness of the common carotid artery wall (CCA-IMT) in a cross-sectional analysis of the Antioxidant Supplementation in the Atherosclerosis Prevention (ASAP) study data in 520 asymptomatic men and women. In a covariance analysis adjusting for common cardiovascular risk factors, low plasma levels of lycopene were associated with an 18% increase of IMT in men as compared with men in whom plasma levels were higher than median (P = 0.003 for difference). In women, the difference did not remain significant after the adjustments. On the basis of these works, it is evident that the circulating levels of lycopene play some role with regard to cardiovascular health in Finland, at least in men. We conclude that circulating levels of lycopene, a biomarker of tomato-rich food, may play a role in early stages of atherogenesis and may have clinical and public health relevance.

The objective of this study was to investigate the pattern of serum non-esterified fatty acid (NEFA) fraction in association with atherosclerosis development. We have studied possible relationships between eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and arachidonic acid (AA) in the NEFA fraction and biochemical markers of endothelial activation or dysfunction. The study population consisted of 152 elderly men with high risk for coronary heart disease. The composition of fasting serum NEFA was analysed by gas-liquid chromatography. Endothelial activation was evaluated using biochemical analyses of some markers of endothelial function. A significant inverse linear association was found between serum non-esterified EPA and DHA, and soluble vascular cell adhesion molecule-1 (sVCAM-1) (P=0.02 and 0.001, respectively). An inverse linear association was found between serum non-esterified AA and sVCAM-1 (P=0.001) and von Willebrand Factor (P=0.005). The significant inverse associations for DHA and AA were independent from the serum content of other NEFAs. Taken together, negative associations were found between sVCAM-1 and the serum levels of non-esterified DHA, EPA and AA. The inverse relation between the levels of sVCAM-1 and very long-chain n-3 fatty acids might indicate an anti-inflammatory effect of the latter.

Hyperhomocysteinemia is associated with arterial hypertension and endothelial dysfunction in healthy humans. Placebo-controlled vitamin intervention studies cannot distinguish intrinsic actions of homocysteine (tHcy) and folate concentrations on the endothelium. The present two-period crossover study investigates the effects of tHcy lowering through oral folic acid on antioxidant status and resistance vessel reactivity in patients with established coronary artery disease (CAD). We investigated 27 male patients with angiographically documented multivessel CAD aged 50 (range 46-56) years. Resistance vessel reactivity was assessed by measurement of postischemic reactive hyperemia (RH) in the forearm using venous occlusion plethysmography at baseline, after 6 weeks of treatment with 5 mg of oral folic acid, and after a washout period of another 6 weeks. Plasma folate increased 3.49-fold with a mean tHcy reduction of 21.3%. Peak reactivity of resistance vessels improved significantly (18.97-23.60 ml/min(-1) per 100 ml; P = 0.01) with unchanged total antioxidant status (TAS; 0.912-0.944 microM; P = 0.4). This effect was limited to subjects (n = 14) with a tHcy reduction >2 microM (median reduction, 14.4-9.6 microM, P < 0.001). In the 13 subjects with a below-median reduction, tHcy remained unaltered (9.7-9.6 microM, P = 0.88) and TAS increased significantly (0.923-1.055 microM, P = 0.006), whereas RH peak flow was not affected (20.22-22.99 ml/min(-1) per 100 ml, P = 0.28). Homocysteine lowering >2 microM through folic acid supplementation improves resistance vessel reactivity in patients with CAD. Our data support the hypothesis that homocysteine lowering may have intrinsic vasoprotective effects largely independent of folate.

Background: No-reflow associated with direct angioplasty (PCI) of patients with acute coronary syndromes (ACS) is associated with unfavorable results., Methods and Results: We used a new thrombectomy device to treat 51 lesions in 48 consecutive ACS patients (40 male and 8 female; mean age 63 years) and conducted a microscopic analysis of aspirates and blood samples retrieved from the culprit coronary artery. The first aspirate was collected before PCI and the second was collected separately after percutaneous transluminal coronary angioplasty or stenting, including samples from the no-reflow lumen. Light microscopy showed that the materials obtained from the pre-PCI aspiration consisted of thrombus in 37.5%, thrombus and atheroma in 35.0%, and atheromatous plaque in 27.5%. The materials collected from the post-PCI aspiration were thrombus in 8.3%, thrombus and atheroma in 41.7%, and atheromatous plaque in 50.0%. We then compared the 9 lesions (19.1%) with no-reflow to those without no-reflow. There was no difference in the pre-PCI aspirates. However, after PCI, there was more atheromatous plaque retrieved from patients with no-reflow (P<0.001) as well as significantly more platelet and fibrin complex, macrophages, and cholesterol crystals in the blood aspirated from no-reflow cases. Aspiration of these elements improved the no-reflow in 7 of 9 lesions to TIMI-3 flow., Conclusions: No-reflow after angioplasty may be caused by gruel that formed from an atheroma attributable to mechanical plaque disruption during intervention.

Atherothrombosis is a diffuse disease. Is it the same process whatever the territory? or are there specific features depending upon the location of the lesions? At the level of the plaque, from a pathophysiological standpoint, the available literature suggests a similar process whatever the territory (slow growth of the plaque, inflammation, rupture and erosion, thrombosis, embolization). The consequences of atherothrombosis may however vary from one territory to another; this may be related to differences in arterial circulations or in cell tolerance to ischemia or in adaptative mechanisms such as collateral growth.

Healthy endothelium plays a central role in cardiovascular control. Therefore endothelial dysfunction (ED), which is characterized by an imbalance between relaxing and contracting factors, procoagulant and anticoagulant substances, and between proinflammatory and antiinflammatory mediators, may play a particularly significant role in the pathogenesis of atherosclerosis and cardiovascular disease. ED is thought to be an early physiologic event in the development of atherosclerosis, occurring before morphologic changes in the vessel wall can be detected. It is closely related to different risk factors of atherosclerosis, to their intensity and their duration. The involvement of risk factors in ED is also supported by results of intervention studies that showed regression of ED with treatment of risk factors. Further, it was shown that ED is significantly and directly correlated with the occurrence of cardiac events. The common denominator whereby different risk factors cause ED is most probably increased oxidative stress and consequently decreased bioavailability of nitrogen oxide. Endothelial dysfunction promotes atherosclerosis and probably plays an important role in the development of thrombotic complications in late stages of the disease. As ED is a key underlying factor in the atherosclerotic process, markers of endothelial abnormalities have been proposed, but loss of endothelium-dependent vasodilation has became a broadly accepted indicator of endothelial dysfunction. Using these non-invasive tests it is possible to follow the dose-response of harmful effects or risk factors, and the effects of preventive procedures on vessel wall function.

Understanding of the pathophysiology of atherosclerosis has changed markedly over the past few decades. It is now widely accepted that inflammation plays a fundamental role in the genesis and development of atherosclerosis. Inflammatory mechanisms also appear to determine clinical presentation and disease outcome. Atherosclerotic lesions have high concentrations of inflammatory cells (T lymphocytes and activated macrophages) as well as an abundance of pro-inflammatory cytokines [interleukin (IL)-1, IL-6, IL-8, interferon-gamma, tumor necrosis factor-alpha, etc.] that modulate local inflammatory responses. These may also alter plaque stability and facilitate the development of acute cardiovascular events. The role of anti-inflammatory cytokines in this context remains to be studied. IL-10 is an anti-inflammatory cytokine synthesised by T-lymphocytes and macrophages and has other anti-inflammatory effects. IL-10 expression within human atherosclerotic plaques has been demonstrated and animal experiments have shown that low levels of IL-10 lead to the development of extensive and unstable atherosclerotic lesions. Currently available evidence suggests a potential protective role for IL-10 in atherosclerosis. This new perspective on coronary disease as a chronic inflammatory process may open new avenues for the management of ischemic heart disease.

Context: Microvascular processes have been hypothesized to play a greater role in the development of coronary heart disease (CHD) in women than in men; however, prospective clinical data are limited., Objective: To examine the association between retinal arteriolar narrowing, a marker of microvascular damage from hypertension and inflammation, and incident CHD in healthy middle-aged women and men., Design, Setting, and Participants: The Atherosclerosis Risk in Communities Study, an ongoing prospective, population-based cohort study in 4 US communities initiated in 1987-1989. Retinal photographs were taken in 9648 women and men aged 51 to 72 years without CHD at the third examination (1993-1995). To quantify retinal arteriolar narrowing, the photographs were digitized, individual arteriolar and venular diameters were measured, and a summary arteriole-to-venule ratio (AVR) was calculated., Main Outcome Measure: Risk of CHD associated with retinal arteriolar narrowing., Results: During an average 3.5 years of follow-up, 84 women and 187 men experienced incident CHD events. In women, after controlling for mean arterial blood pressure averaged over the previous 6 years, diabetes, cigarette smoking, plasma lipid levels, and other risk factors, each SD decrease in the AVR was associated with an increased risk of any incident CHD (relative risk [RR], 1.37; 95% confidence interval [CI], 1.08-1.72) and of acute myocardial infarction (RR, 1.50; 95% CI, 1.10-2.04). In contrast, AVR was unrelated to any incident CHD in men (RR, 1.00; 95% CI, 0.84-1.18) or to acute myocardial infarction (RR, 1.08; 95% CI, 0.85-1.38)., Conclusion: Retinal arteriolar narrowing is related to risk of CHD in women but not in men, supporting a more prominent microvascular role in the development of CHD in women than in men. Future work is needed to confirm these findings.

The detection, treatment, and follow-up of subclinical vascular disease are becoming clinically essential components of cardiovascular disease prevention in the elderly. Noninvasive measurements are available for different vascular beds, including carotid, coronary, aortic, and peripheral arterial circulation. Current interest in these measures is aimed at improving the accuracy of risk prediction for coronary heart disease and cardiovascular disease. Indirect physical examination and imaging evaluations detect significant obstruction of flow in the peripheral arteries. Doppler measures of ankle-arm blood pressure index represent a simple, indirect test that has been shown to be predictive of incident cardiovascular disease independent of risk factors. Newer, high-resolution tests allow direct detection and quantitation of the burden of atherosclerosis and vascular disease within the arterial wall, independent of flow obstruction. Carotid intimal-medial thickness predicts incident coronary heart disease and stroke in the elderly, even after adjustment for traditional risk factors. Coronary calcium can be accurately detected by computed tomography and is a strong predictor of the incidence of coronary heart disease events. Evidence is accruing that coronary calcium screening will play a role in prevention in the elderly. Magnetic resonance imaging is currently under study as a promising modality for detection and quantification of aortic and carotid plaque. Ongoing studies will provide important information regarding the appropriate role of the many newer, high-resolution tests of subclinical atherosclerosis in disease prediction, treatment, and tracking of disease progression in the elderly., ((c)2002 CVRR, Inc.)

Objective: During the process of atherosclerosis the endothelium changes both structurally and functionally. We examined whether shedding of endothelin-converting enzyme (ECE), a metalloprotease responsible for endothelin production, is concomitant with tissue-type plasminogen activator (t-PA), and how atherosclerosis affects ECE release., Design: Fourteen healthy volunteers and 24 patients with angiographically verified coronary heart disease (CHD) were investigated. ECE and t-PA releases were measured by a provocation test (20-min venous occlusion)., Results: Serum ECE activities were comparable in both groups before the venous occlusion test (in CHD patients 205 +/- 24 vs in healthy controls 204 +/- 40 pmol/ml/h, p = NS). However, delta-ECE (= the difference between, after, and before the venous occlusion test) was significantly lower in CHD patients than in controls (203 +/- 36 vs 338 +/- 43 pmol/ml/h, p = 0.02, respectively). Delta-t-PA was similar in both groups (22.3 +/- 4.4 vs 14.5 +/- 4.6 ng/ml, p = NS, respectively). Furthermore, t-PA and ECE values correlated in the CHD group in all pre-, post-venous occlusion test, and delta-venous occlusion test values (r = 0.56, p = 0.009; r = 0.62, p = 0.003; r = 0.54, p = 0.01, respectively)., Conclusion: Vascular ECE release can be stimulated, and it is concomitant with t-PA release. A common location in endothelium may explain this simultaneous shedding. However, ECE levels do not rise in patients with CHD as markedly as in healthy patients. Atherosclerosis may explain reduced shedding of ECE.

Purpose: There have been few studies of the natural history of peripheral arterial disease (PAD), and none have used serial noninvasive laboratory examinations for the objective quantification of disease progression. The relationship between the site of initial symptoms of PAD (lower-extremity disease [LED] vs cerebrovascular disease [CVD]) and the site of subsequent symptomatic progression (LED vs CVD vs coronary heart disease [CHD]) has not been examined., Methods: This is a long-term, blinded prospective clinical research study of the relationship of PAD progression to multiple clinical, laboratory, and noninvasive vascular laboratory parameters. Patients with symptomatic LED, CVD, or both underwent comprehensive risk-factor assessment and were seen every 6 months for follow-up examinations. In addition to history and physical examination, all subjects underwent serial noninvasive lower-extremity and carotid artery testing. The relationship between the initial symptomatic site(s) and subsequent progression was examined by means of multivariate proportional hazards analysis, which was adjusted for age, diabetes mellitus, hypertension, smoking, cholesterol, homocysteine level, lowest initial ankle/brachial index (ABI), worst carotid stenosis, ABI progression, and carotid stenosis progression, because each of these factors was significantly associated with one or more aspects of progression., Results: There were 397 study subjects (mean age, 66 years; 38% women) with a mean follow-up period of 48.5 months. LED was initially present in 88% of subjects and CVD in 37% of subjects (both were present in 25% of subjects). There were 78 deaths, 47 (60%) of which were caused by cardiovascular disease (18% mortality rate after 5 years by means of life table). Progression of disease as documented by means of vascular laboratory findings occurred in 90% of subjects by means of life table after 5 years (ABI progression, 31%; carotid stenosis progression, 40%). Symptomatic clinical progression of disease occurred in 52% of subjects by means of life table after 5 years (LED progression, 22%; CVD progression, 23%; CHD progression, 31%). By means of multivariate analysis, no significant relationship was found between the site of initial symptoms of PAD and the site(s) of subsequent symptomatic clinical progression (LED vs CVD vs CHD; P = not significant for all hazard ratios)., Conclusion: Patients with symptomatic PAD experience symptoms of ongoing LED, CVD, and CHD with a frequency that is not influenced by the site(s) of their original symptoms. The hypothesis that lesions and resulting symptoms of systemic atherosclerosis occur at various anatomic sites as a matter of random chance should be tested with other studies.

Hardening of the pulse, first described thousands of years ago by Chinese healers, was known even then to be an adverse prognostic sign. In Western medicine, the association of aging, increased large-arterial stiffness, and systolic hypertension has been recognized for more than a century. Yet the adverse consequences of age-related arterial stiffness still receive little attention in everyday clinical practice, perhaps because clinicians assume that nothing can be done about the process. Recent developments, however, suggest that improved clinical recognition of age-related vascular stiffening will lead to better therapy and improved outcomes for patients with hypertension.

Plaque disruption promoted by local inflammation and oxidative stress seems to be the triggering mechanisms of acute coronary syndromes. Oxidized low-density lipoproteins (LDL) play a key role in the inflammatory process. Within the inflammatory region, angiotensin-converting enzyme (ACE) accumulation has been described, leading to enhanced production of angiotensin II which stimulates adhesion molecule formation and increases oxidative stress. According to recent clinical trials, drugs like statins or ACE inhibitors seem promising and could stabilize the plaque, probably by attenuation of the inflammatory process. Finally, as thrombus formation also plays a role in these acute coronary syndromes, another approach is the use of antithrombotic therapy.

Objectives: To review the available information on the action of hormones on the mechanisms involved in thrombotic risk., Results and Conclusions: Thrombosis plays a crucial role in the genesis and progression of both coronary heart disease (CHD) and venous thromboembolic disease (VTED), the two main forms of cardiovascular disease. Two main determinants of the thromboembolic phenotype, hypercoagulable state and altered endothelium, accumulate much of the work performed on the influence of hormones on thrombosis. Information has accumulated mainly for oestrogens, but increasing evidences support a role for progestogens. The sensitivity of each of the three components of the hemostatic balance, the coagulation cascade, the anticoagulant system and fibrinolysis, to oestrogens has been widely examined in the literature. Functional tests suggest that HRT is accompanied by a procoagulant state. Much of the work has concentrated on changes induced on reputable indicators of risk for either CHD or VTED. Distinct indicators of increased coagulability, such as resistance to activated C protein, antithrombin or tissue factor pathway inhibitor have been selected for VTED, whereas factor VII, fibrinogen, and defective fibrinolysis, for CHD. Different states of genetic susceptibility have been involved in both forms of the disease. The status of health of endothelium, defines another scenario for attention in CHD. A long-term anti-atherogenic action of oestrogens, which may be associated with short-term risk in cases of atherosclerosis-induced endothelial dysfunction, may most adequately explain much of the clinical observation. In both CHD and VTED, the procoagulant changes initiate soon after HRT administration.

This study examined the relationships between paraoxonase genotypes, coronary artery reactivity, and indices of low-density lipoprotein oxidation in healthy men. Impairment in coronary flow reserve, as assessed by positron emission tomography, is associated with lipoprotein oxidation, which is affected by high-density lipoprotein bound enzyme, paraoxonase. Paraoxonase has two common polymorphisms (M/L55 and R/Q192) that change the activity of the enzyme. Forty-nine healthy men (mean age 35 +/- 4 years) were divided by paraoxonase genotype into low (Q192/Q192, or M55/M55, M55/L55) and high-active (R192/Q192, R192/R192, or L55/L55) groups and related to the myocardial blood flow, to the susceptibility of low-density lipoprotein to oxidation, and the autoantibody titer against oxidized low-density lipoprotein. The blood flow was measured by positron emission tomography at rest and during adenosine infusion. The low-active Q192/Q192 genotype was associated with higher resting blood flow corrected for rate-pressure product compared to the high-active R192/R192 and R192/Q192 genotypes (P=0.011). The blood flow stimulated by adenosine was not significantly different in the low- and high-active genotype groups. Paraoxonase genotypes had no effect on low-density lipoprotein susceptibility to oxidation or autoantibody formation against oxidized low-density lipoprotein. Genotypes of paraoxonase may not clearly contribute to the early changes in coronary reactivity. Coronary vasomotor tone at rest appears to be modulated by paraoxonase R/Q192 polymorphism through mechanism(s) unrelated to low-density lipoprotein oxidation.

Hypertension and hypercholesterolemia, two major risk factors for atherosclerotic disease, frequently coexist in patients with hypertension and CAD. Data from clinical studies suggest the existence of lipoprotein-neurohormonal interactions that may adversely affect vascular structure and reactivity. Data from preclinical studies suggest that RAS may be upregulated by abnormal lipids, most likely via production of ox-LDL. On the other hand, activation of RAS leads to release of ROS and transcriptional upregulation of LDL and ox-LDL uptake in macrophages, smooth muscle cells and endothelial cells. These findings extend our understanding of the interplay among risk factors to synergistically increase cardiovascular risk, and of the anti-atherosclerotic effects of local ACE inhibition to reduce cardiovascular risk. Trials aimed at modifying RAS along with drugs lowering total- and LDL-cholesterol levels and inhibitors of oxidative modification of LDL-cholesterol will address the clinical relevance of this biological interaction.

Coronary artery disease (CAD) is associated more closely with atherosclerosis in the popliteal than in the brachial artery. This case-control study aimed at clarifying whether endothelial dysfunction of patients with CAD can be detected non-invasively in the popliteal artery by means of ischemia-induced flow-mediated dilation (FMD) and cold pressor reaction (CPR), and how it compares with the brachial artery. We further investigated a new mode of evaluation of the CPR. Eleven cases with CAD were compared with 16 matched healthy controls. Popliteal and brachial arterial diameter was monitored by ultrasound for 20 min following ischemia and cold pressor. For CPR, the difference between maximum and minimum diameter was defined as maximum vasomotion. In the popliteal artery, maximum vasomotion and FMD were significantly smaller in cases than in controls, the difference being more pronounced than in the brachial artery, where only maximum vasomotion was significantly smaller. After exclusion of current smokers, only the difference in maximum vasomotion of both arteries remained significant. We conclude that maximum vasomotion may be more sensitive for detection of endothelial dysfunction than FMD. Endothelial dysfunction in patients with CAD is more pronounced in the popliteal artery than in the brachial artery.

Lp(a) may represent a link between the fields of atherosclerosis and thrombosis. Elevated Lp(a) levels > 300 mg/l have been associated with the presence of atherosclerotic disease. This prospective study initiated in 1995 and, until June 1999 enrolled 218 subjects divided in two groups: G1: subjects with/without angiographically proven coronary artery disease(CAD), n = 124 and GII: controls, n = 94 The objective of this study was to assess the influence of high Lp(a) serum levels on the CAD. Secondary end point was to demonstrate a correlation between the level serum Lp(a) and the severity of angiographic coronary findings. we found that The cases had significantly (p = 0.004) higher Lp(a) levels than the controls and that correlation exist between the value of Lp(a) serum levels and severity of angiographic findings. However, we do recommend Lp(a) screening for patients with early CA1:) or a family history of CAD.

Purpose: In earlier studies it was shown that patients with vascular disturbances (e.g. sudden hearing loss) had white-noise field campimetry abnormalities despite normal visual fields. The aim of this study was to clarify whether patients with coronary heart disease (CHD) have such disturbances in the white-noise field campimetry, too., Patients and Methods: Twenty-four patients (m:f = 23:1; mean age 58 +/- 9 years) with an angiographically documented CHD and 30 healthy controls (m:f = 29:1; mean age 54 +/- 7 years) were examined. In order to evaluate the morphological and functional ocular status, we examined the following parameters: morphological status, visual acuity, intraocular pressure, perimetry (Tübinger Automatic Perimeter 2000 ct, Oculus) and white-noise field campimetry (Tübinger Electronic Campimeter, Oculus)., Results: Fifteen patients had had a cardiac infarction. Twenty-one patients, but only 6 controls had alterations in perilimbal vessels of the conjunctiva and sixteen patients had a tortuousity of retinal vessels. The visual acuity, the intraocular pressure, the cup/disc ratio and the visual fields were within normal ranges. However, twenty patients and 5 controls were abnormal in the white-noise field campimetry., Discussion: Although patients with CHD appeared unaffected in the standard eye examinations, the disturbances in the white-noise field campimetry indicated a functional visual impairment. Together with the changes in the perilimbal vessels of the conjunctiva and the retinal vessels, a disturbed ocular microcirculation as the underlaying cause could be discussed.

Older women with low bone density have an increased risk of fracture, cardiovascular disease, and mortality. However, it is not known whether this association is caused by ongoing bone loss or by lower bone mass earlier in life. To determine whether rate of bone loss is associated with total and cause-specific mortality, we prospectively studied 6046 women aged 65 years or older who had serial bone mineral density (BMD) measurements as a part of the Study of Osteoporotic Fractures. Rates (mean +/- SD) of loss of BMD at the heel (for a mean of 5.7 years) and hip (for a mean of 3.5 years) were estimated. Cause-specific mortality was ascertained from death certificates and hospital records. BMD loss at the heel was 5.9 +/- 6.0 mg/cm2 per year (1.5 +/- 1.5%) and BMD loss at the hip was 4.1 +/- 10.2 mg/cm2 per year (0.6 +/- 1.4%). During an average follow-up of 3.2 years after the second measurement of BMD, 371 deaths occurred. Each SD increase in BMD loss at the hip was associated with a 1.3-fold (95% CI, 1.1-1.4) increase in total mortality, adjusted for age, baseline BMD, diabetes, hypertension, incident fractures, smoking, physical activity, health status, weight loss, and calcium use. In particular, hip BMD loss was associated with increased mortality from coronary heart disease (relative hazard [RH] = 1.3 per SD; 95% CI, 1.0-1.8) and pulmonary diseases (RH = 1.6 per SD; 95% CI, 1.1-2.5). The findings were similar for bone loss at the heel, except there was no significant association with pulmonary mortality. These results raise the possibility that bone loss may share common etiologies with coronary and pulmonary diseases.

Cholesterol-lowering and its relationship to acute coronary syndromes is the focus of this article. The pathophysiology of plaque formation and plaque rupture are briefly discussed as is the current thinking on the impact of cholesterol-lowering on these processes. How cholesterol affects endothelial function and plaque passivation (the complex process of stabilizing the active plaque at risk of rupture) are key elements. A few hallmark clinical trials and their impact on coronary heart disease (CHD) clinical event rates are discussed as is the impact of statin therapy on CHD management. A brief description of the National Cholesterol Education Program and its recommendations for primary and secondary prevention are included.

Low ankle/brachial blood pressure index (ABI) is a marker of generalized atherosclerosis in the elderly, although its association with coronary heart disease (CHD) has not been well established. The purpose of this report is to examine the relation between ABI and the risk of CHD in a sample of elderly men. Findings are based on the ABI that was measured in 2,863 Japanese-American men aged 71 to 93 years at an examination that occurred from 1991 to 1993 in the Honolulu Heart Program. All men were free of total CHD at that time and followed for nonfatal myocardial infarction and death from CHD over a 3- to 6-year period. During follow-up, 186 had a coronary event. Age-adjusted incidence declined significantly from 15.3% in men with an ABI <0.8 to 5.4% in men with an ABI >/=1.0 (p <0.001). The effect of ABI on disease was similar across a variety of risk factor strata, although it seemed strongest in the presence of hypertension and in past and current cigarette smokers. Adjustment for other risk factors failed to diminish the relation between ABI and CHD. We conclude that a low ABI increases the risk of CHD in elderly men. If findings can be extended to other elderly population segments, simple measurement of ABI in an outpatient setting could be an important tool for assessing the risk of CHD in the elderly.

Endothelial health is a key factor in normal cardiovascular homeostasis, and recent studies have revealed several important functions of the vascular endothelium that protect against atherothrombosis. These include control over arterial tone, coagulation, fibrinolysis, and vascular growth. Consequently, endothelial dysfunction has been implicated as an important event in the pathogenesis of atherosclerosis, coronary vasoconstriction, hypertension, and myocardial ischaemia. Therefore, there has been considerable research interest in diagnostic assays for the assessment of endothelium. This review outlines the current status of markers of endothelial dysfunction, particularly those related to vasomotor control, as well as circulating markers of vascular health.

Impaired endothelial function has been reported to be the initial step in atherosclerosis. Some coronary risk factors independently relate to impaired endothelial function. However, few studies have examined the association between coronary risk factors and endothelial function in patients who have multiple risk factors without clinical atherosclerosis. This study was undertaken to elucidate the relationship between accumulation of coronary risk factors and vascular endothelial dysfunction. We examined 101 subjects with one or more coronary risk factors 56.8 +/- 1.0 years old and 40 age-matched control subjects without coronary risk factors. We measured brachial artery diameter non-invasively using a 7.5-MHz ultrasound machine at rest, during reactive hyperemia caused by endothelium-dependent vasodilatation, and after sublingual administration of nitroglycerin, which causes endothelium-independent vasodilatation. The percentage change in flow-mediated diameter (%FMD; deltaD/D x 100), in subjects with one or more coronary risk factors was significantly lower than that in control subjects(4.8 +/- 0.3% vs. 6.7 +/- 0.5%, p < 0.01). Endothelium-independent vasodilatation by nitroglycerin did not differ between the two groups. Endothelial function was impaired according to the accumulation of coronary risk factors. On multiple regression analysis, the number of risk factors, age, and brachial artery diameter at rest showed significant correlation with %FMD. Our results suggest that an accumulation of coronary risk factors was significantly related to impairment of endothelial function.

SLE is a multifaceted disease; over the past 20 years, as survival has improved dramatically, new challenges have emerged. It is now clear from the results of studies at several centers that SLE is associated with at least a fivefold increased risk of CAD, which is accelerated at its onset and seems to abolish a female premenopausal protection against CAD. Several groups have also found by various techniques that subclinical disease occurs at a frequency of about 35% to 40%. The pathogenesis of atherosclerosis in this context seems to be a complex interaction of factors associated with the disease, its therapy, and traditional risk factors. Indeed, experimental models suggest a synergy of these different dimensions in plaque formation. Hypercholesterolemia has been identified as predictive of both future CAD events and sub-clinical disease. This is mainly the case in those patients in whom hypercholesterolemia is a sustained phenomenon. In addition, SLE itself seems to be a strong risk factor for CAD over and above the effects of the known traditional CAD risk factors. There is a lot that is still unknown about the pathogenesis of CAD in SLE. Current knowledge is sufficient to justify the belief that an aggressive approach to management of traditional CAD risk factors in patients with SLE is likely to have a major impact on morbidity and mortality in this population. For this to happen, patients must be educated about this issue and be encouraged to play an active role in lifestyle modifications. In addition, clinicians who care for patients with SLE need to assume a primary role in screening and coordinating the management of CAD risk factors in these high-risk patients.

Background: Diffuse coronary atherosclerosis is the substrate for plaque rupture and coronary events. Therefore, in patients with mild arteriographic coronary artery disease without significant segmental dipyridamole-induced myocardial perfusion defects, we tested the hypothesis that fluid dynamically significant diffuse coronary artery narrowing is frequently manifest as a graded, longitudinal, base-to-apex myocardial perfusion abnormality by noninvasive PET., Methods and Results: In this study, 1001 patients with documented coronary artery disease by coronary arteriography showing any visible coronary artery narrowing underwent rest-dipyridamole PET perfusion imaging. Quantitative severity of dipyridamole-induced, circumscribed, segmental PET perfusion defects was objectively measured by automated software as the minimum quadrant average relative activity indicating localized flow limiting stenoses. Quantitative severity of the graded, longitudinal, base-to-apex myocardial perfusion gradient indicating fluid dynamic effects of diffuse coronary artery narrowing was objectively measured by automated software as the spatial slope of relative activity along the cardiac longitudinal axis., Conclusions: In patients with mild arteriographic disease without statistically significant dipyridamole-induced segmental myocardial perfusion defects caused by flow-limiting stenoses compared with normal control subjects, there was a graded, longitudinal, base-to-apex myocardial perfusion gradient significantly different from normal control subjects (P=0. 001) that was also observed for moderate to severe dipyridamole-induced segmental perfusion defects (P=0.0001), indicating diffuse disease underlying segmental perfusion defects; 43% of patients with or without segmental perfusion defects demonstrated graded, longitudinal, base-to-apex perfusion abnormalities beyond +/-2 SD of normal control subjects, indicating diffuse coronary arterial narrowing by noninvasive PET perfusion imaging.

Endothelium plays a pivotal role in the development of atherosclerosis. Endothelial dysfunction participates in the course of acute coronary event. Using high-resolution ultrasound technique, endothelial dysfunction has been demonstrated in patients with atherosclerosis and risk factors for coronary disease, such as hypertension, diabetes mellitus, hypercholesterolemia and being smokers. In the present study, using this non-invasive method, the endothelial function of the brachial artery of patients with coronary heart disease (CHD) (n = 71) and control subjects (n = 34) was investigated. The results showed that endothelium-dependent and -independent vasodilatation were impaired in patients with CHD (2.61+/-2.91 vs. 8.10+/-7.81%, 17.20+/-7.93 vs. 23.19+/-8.89%, respectively) (P<0.001). Flow-mediated dilation (FMD) was significantly positively correlated with nitroglycerine-induced dilation (P<0.001). On univariate and multivariate analysis, the extent of FMD was significantly correlated with serum HDL-C levels (P<0.01). In conclusion, our study indicates both endothelial and underlying smooth muscle functions were impaired in patients with CHD. Decreased HDL-C levels may impair endothelial function.