Lipoprotein (a): an emerging risk factor for atherosclerosis

Lipoprotein (a) is an antigenic variant of low density lipoprotein and is present in the plasma of most people. Many epidemiologic studies from Europe and North America have found that when plasma levels of lipoprotein (a) exceed 0.20 g/L, there is a significantly higher risk of coronary and cerebrovascular atherosclerosis. Until recently, there has been little insight into the function of lipoprotein (a) or its potential atherogenic mechanism. Molecular biological studies have shown that the characteristic protein of lipoprotein (a), called apolipoprotein (a), strongly resembles plasminogen, the precursor of the natural anticoagulant plasmin. Furthermore, there is emerging evidence that lipoprotein (a) is the missing link between the lipoprotein and coagulation systems, acting perhaps as a vehicle which delivers cholesterol to the site of intravascular damage, or as an inhibitor of plasminogen activation at the site of an evolving thrombus.     

Obstructive sleep apnea: an emerging risk factor for atherosclerosis

Obstructive sleep apnea (OSA) is independently associated with death from cardiovascular diseases, including myocardial infarction and stroke. Myocardial infarction and stroke are complications of atherosclerosis; therefore, over the last decade investigators have tried to unravel relationships between OSA and atherosclerosis. OSA may accelerate atherosclerosis by exacerbating key atherogenic risk factors. For instance, OSA is a recognized secondary cause of hypertension and may contribute to insulin resistance, diabetes, and dyslipidemia. In addition, clinical data and experimental evidence in animal models suggest that OSA can have direct proatherogenic effects inducing systemic inflammation, oxidative stress, vascular smooth cell activation, increased adhesion molecule expression, monocyte/lymphocyte activation, increased lipid loading in macrophages, lipid peroxidation, and endothelial dysfunction. Several cross-sectional studies have shown consistently that OSA is independently associated with surrogate markers of premature atherosclerosis, most of them in the carotid bed. Moreover, OSA treatment with continuous positive airway pressure may attenuate carotid atherosclerosis, as has been shown in a randomized clinical trial. This review provides an update on the role of OSA in atherogenesis and highlights future perspectives in this important research area.     

Arterial stiffness as a risk factor for coronary atherosclerosis

The major pathophysiologic process of coronary atherosclerosis is a defect or injury of the arterial endothelial function. The rate of progression of coronary atherosclerosis is highly variable and mainly determined by risk contributors such as lipids, glucose, and smoking. Coronary plaque rupture is the precipitating factor for clot formation and acute coronary events. Measurement of arterial stiffness with different noninvasive techniques provides information about the functional and structural vascular changes at the level of the aorta, muscular conduit arteries, the peripheral branches, and the microvascular components. Arterial stiffness has been related to the Framingham and other cardiovascular risk scores. Large artery stiffness contributes to exercise-induced myocardial ischemia in patients with coronary artery disease. It can predict the outcome after coronary interventions. There is now evidence that arterial stiffness is a predictor for cardiovascular events in the general population, in patients with hypertension, end-stage renal disease, impaired glucose intolerance, and coronary artery disease. Future studies are warranted to demonstrate the value of follow-up of arterial stiffness as a marker of reduction of arterial wall damage during antihypertensive, antidiabetic, and lipid-lowering therapy. Promising study results show that measurement of arterial stiffness could become an important part of the routine assessment of patients in daily practice.     

Homocysteine as a novel risk factor for atherosclerosis.

Homocysteine is a sulfhydryl amino acid formed during metabolism of methionine. Increasing evidence suggests that homocyst(e)ine may act as an independent risk factor for ischemic heart disease, cerebrovascular disease, and peripheral arterial disease. Recent prospective data have shown that homocyst(e)ine levels in the top 20% of the population increase the risk for ischemic heart disease by approximately twofold. Homocyst(e)ine seems to promote the progression of atherosclerosis by causing endothelial dysfunction, increasing oxidant stress, and promoting vascular smooth muscle growth. Recent human studies using methionine loading to experimentally induce moderate hyperhomocyst(e)inemia have demonstrated rapid and profound impairment of resistance and conduit artery endothelial function. No data are available from randomized, controlled trials of the effects of lowering plasma homocyst(e)ine on atherosclerotic vascular events; however, screening for hyperhomocyst(e)inemia should be actively considered in individuals with progressive and unexplained atherosclerosis. Both fasting and postmethionine load homocyst(e)ine levels should be measured. B vitamins, including folic acid and vitamins B6 and B12 are the mainstay of treatment of patients with hyperhomocyst(e)inemia. Primary prevention strategies await the completion of long-term, randomized, prospective studies.     

Anticardiolipin antibodies as a risk factor of atherosclerosis in intermittent claudication

Anticardiolipin antibodies have been associated as a risk factor of atherosclerosis. The aim of this study was to evaluate the association between anticardiolipin antibodies and intermittent claudication. Forty consecutive patients (33 men, 7 women; age range: 45-84 years, mean 65.5) who were seen in the angiology and vascular surgery department with intermittent claudication were evaluated. Exclusion criteria included prior revascularization, angioplasty, or a history of thrombosis of a lower limb. Forty individuals (23 men, 17 women; age range: 58-82 years, mean 67.1) who attended a support group for senior citizens and who were apparently healthy formed the control group. Anticardiolipin antibodies were evaluated by means of enzyme-linked immunosorbent assay (ELISA) for quantitative measurement of immunoglobulin G (IgG) and IgM antibodies against cardiolipins in serum. IgG levels were considered normal when < 7, borderline from 7 to 10, and elevated at > 10 GPL units/mL; IgM levels were normal when < 4, borderline from 4 to 7, and elevated at > 7 MPL, as recommended by the test manufacturers. Statistical analysis used the relative risk test with a confidence interval of 95%. Twenty-three patients from the study group and 6 individuals from the control group were found to have elevated levels of anticardiolipin antibodies giving a relative risk of 3.833 (ranging from 1.749 to 8.4; p value < 0.0001). In conclusion, patients who have elevated levels of anticardiolipin antibodies present a 3.8 times greater risk of developing intermittent claudication.     

Insulin resistance as a risk factor for subclinical atherosclerosis in rheumatoid arthritis

BackgroundInsulin resistance (IR) is strongly associated with systemic inflammation. Insulin resistance is known to be increased in patients with rheumatoid arthritis (RA) and has been shown to be a risk factor for both clinical cardiovascular disease and subclinical atherosclerosis.Aim of the workTo study the relationship between insulin resistance, disease activity and subclinical atherosclerosis in RA patients.Patients and methodsForty RA patients and twenty age and sex matched healthy individuals as controls were included. Patients with diabetes mellitus, obesity and hypertension were excluded. Fasting plasma sugar and serum insulin were done, RA disease activity was assessed using the disease activity score (DAS28) and IR was evaluated by the homeostasis model assessment (HOMA2). Carotid artery intima media thickness (IMT) was evaluated using ultrasound.ResultsRA patients had significantly higher erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) positivity, fasting plasma sugar and fasting serum insulin, HOMA2-IR levels than the controls. IR was present in 33 (82.5%) RA patients while it was present in only one (10%) of the controls (p = 0.001). RA patients with IR had significantly longer disease duration (p = 0.003), higher disease activity (p = 0.000), greater carotid IMT (p = 0.000), and more carotid plaques (p = 0.043) than those without insulin resistance. RA patients with increased IMT had significantly longer disease duration (p = 0.002), higher DAS28 score (p = 0.000) and higher HOMA2-IR (p = 0.000) than those with normal IMT.ConclusionsIn RA patients, IR significantly correlated with both disease activity and disease duration. Our study pointed out a significant association between IR and subclinical atherosclerosis in RA.     

Vasectomy as a risk factor for atherosclerosis (author's transl)

Recent investigations have implicated vasectomy as a possible risk factor for the development of atherosclerosis in animals. Physicians are undecided as to the true importance of the information and how they should act upon it when counselling their patients. In an attempt to explore the problem in humans, we performed a case-controlled study in 55 men under age 50 with documented coronary disease and in a matched control group of brothers and 1st cousins who were asymptomatic. Within the limitations of the study, no association of coronary disease with prior vasectomy was found: 25.5% (14/55) of the mean in each group were vasectomized. Further work is needed to evaluate whether certain individuals such as hypertensives or hyperlipidemics may be at greater risk and whether a longer delay between vasectomy and symptoms of atherosclerosis may be required than were present in this study. (author's)     

DNA damage and repair in atherosclerosis

There is increasing evidence that human atherosclerosis is associated with damage to the DNA of both circulating cells, and cells of the vessel wall. Reactive oxygen species are the most likely agents inducing DNA damage in atherosclerosis. DNA damage produces a variety of responses, including cell senescence, apoptosis and DNA repair. This review summarises the evidence for DNA damage in atherosclerosis, the cellular responses to damage and the mechanisms of signalling DNA damage.     

The emerging role of asymmetric dimethylarginine as a novel cardiovascular risk factor

There is abundant evidence that the endothelium plays a crucial role in the maintenance of vascular tone and structure. One of the major endothelium-derived vasoactive mediators is nitric oxide (NO). Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase. ADMA inhibits vascular NO production at concentrations found in pathophysiological conditions (i.e., 3-15 micromol/l); ADMA also causes local vasoconstriction when it is infused intraarterially. The biochemical and physiological pathways related to ADMA are now well understood: dimethylarginines are the result of the degradation of methylated proteins; the methyl group is derived from S-adenosylmethionine. Both ADMA and its regioisomer, SDMA, are eliminated from the body by renal excretion, whereas only ADMA, but not SDMA, is metabolized via hydrolytic degradation to citrulline and dimethylamine by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). DDAH activity and/or expression may therefore contribute to the pathogenesis of endothelial dysfunction in various diseases. ADMA is increased in the plasma of humans with hypercholesterolemia, atherosclerosis, hypertension, chronic renal failure, and chronic heart failure. Increased ADMA levels are associated with reduced NO synthesis as assessed by impaired endothelium-dependent vasodilation. In several prospective and cross-sectional studies, ADMA evolved as a marker of cardiovascular risk. With our increasing knowledge of the role of ADMA in the pathogenesis of cardiovascular disease, ADMA is becoming a goal for pharmacotherapeutic intervention. Among other treatments, the administration of L-arginine has been shown to improve endothelium-dependent vascular function in subjects with high ADMA levels.     

Non-alcoholic fatty liver disease as an atherosclerosis risk factor

Currently, along with cardiovascular disease, changes in lipid and carbohydrate metabolism in the syndrome of insulin resistance seen pathology of the liver. The aim of our study was to determine the prognostic significance of nonalcoholic fatty liver disease (NAFLD) to assess the risk of early manifestations of atherosclerotic disease of carotid arteries. The correlation between the presence of NAFLD and signs of early atherosclerosis in the insulin resistance syndrome. The resulting ranked a number of prognostic factors influencing the degree of change in the walls of the carotid arteries, making it possible to construct estimates of individual risk of atherosclerosis development in clinically healthy patients. The clinical significance of the results is the need for more thorough examination of patients with NAFLD to assess risk factors for progression of pathology not only the liver, and cardiovascular disease.     

Intravenous iron therapy as a possible risk factor for atherosclerosis in end-stage renal disease

Atherosclerosis is a disease of the arterial wall, with increasing wall thickness representing an early event in the progression of the disease. It has been suggested that iron overload, as assessed by increased serum ferritin concentration, may be a risk factor for atherosclerosis. The aim of this study was to investigate the relationship between the influence of intravenous (IV) iron therapy and ferritin levels and carotid intima media thickness (C-IMT) in dialysis patients. Sixty patients (51 +/- 14) years were divided into two groups according to their IMT obtained by ultrasound; group I (high risk) and group II (low risk). The parameters assessed were serum creatinine, urea, calcium, phosphorus, hemoglobin, albumin, uric acid, iron, ferritin, and lipid levels. Thirty-eight patients (88%) in group I and 5 patients (12%) in group II received IV iron therapy while 5 patients (29%) in group I and 12 patients (71%) in group II (P < 0.001) did not receive IV iron therapy. Ferritin levels were higher in group I than in group II (581 +/- 303 and 306 +/- 224) (P < 0.001). C-IMT measurements correlated with serum ferritin and with the intravenous iron dose received during the 24 months preceding the study (r = 0.315, P = 0.015; r = 0.471, P = 0.001). The findings indicate that IV iron therapy and elevated serum ferritin levels may cause an increase in the incidence of atherosclerosis.     

Orthostatic hypotension as a risk factor for incident heart failure: the atherosclerosis risk in communities study

Heart failure causes significant morbidity and mortality. Distinguishing risk factors for incident heart failure can help identify at-risk individuals. Orthostatic hypotension may be a risk factor for incident heart failure; however, this association has not been fully explored, especially in nonwhite populations. The Atherosclerosis Risk in Communities Study included 12363 adults free of prevalent heart failure with baseline orthostatic measurements. Orthostatic hypotension was defined as a decrease of systolic blood pressure ≥20 mmHg or diastolic blood pressure ≥10 mmHg with position change from supine to standing. Incident heart failure was identified from hospitalization or death certificate disease codes. Over 17.5 years of follow-up, orthostatic hypotension was associated with incident heart failure with multivariable adjustment (hazard ratio: 1.54 [95% CI: 1.30-1.82]). This association was similar across race and sex groups. A stronger association was identified in younger individuals ≤55 years old (hazard ratio: 1.90 [95% CI: 1.41-2.55]) than in older individuals >55 years old (hazard ratio: 1.37 [95% CI: 1.12-1.69]; interaction P=0.034). The association between orthostatic hypotension and incident heart failure persisted with exclusion of those with diabetes mellitus, coronary heart disease, and those on antihypertensives or psychiatric or Parkinson disease medications. However, exclusion of those with hypertension somewhat attenuated the association (hazard ratio: 1.34 [95% CI: 1.00-1.80]). We identified orthostatic hypotension as a predictor of incident heart failure among middle-aged individuals, particularly those 45 to 55 years of age. This association may be partially mediated through hypertension. Orthostatic measures may enhance risk stratification for future heart failure development.     

History of obesity as a risk factor for both carotid atherosclerosis and microangiopathy

As a westernized lifestyle becomes widespread in Japan, the number of individuals with obesity, as well as type 2 diabetes, is rapidly increasing. In this investigation, we studied the prevalence of obesity and its association with the development of diabetic macroangiopathy and microangiopathy. The clinical records of 634 patients in our hospital with type 2 diabetes were surveyed. The relationship between obesity and diabetic retinopathy and nephropathy and macroangiopathy (carotid artery intima-media thickness, IMT) was examined using univariate and multivariate analysis. A body mass index (BMI) > or = 25 kg/m2 was used as the diagnostic criterion for obesity. The prevalence of obesity at the time of the survey was 35% and a history of obesity was reported in 70% of the survey population. Multiple regression analysis revealed that the maximum BMI was significantly correlated with IMT thickening. The prevalence of nephropathy in previously obese patients was significantly higher than in non-obese patients. The maximum BMI was significantly associated with the development of retinopathy and nephropathy, as shown by logistic regression analysis. This suggests that a history of obesity may be an important risk factor for the development of micro- and macroangiopathy in Japanese with type 2 diabetes.     

Inflammation and emerging risk factors in diabetes mellitus and atherosclerosis

Type 2 diabetes mellitus and atherosclerosis are complex and progressive conditions that share several common antecedents. Recent data suggest that inflammation may play a central role in the origins and complications of cardiovascular disease and, possibly, type 2 diabetes mellitus. C-reactive protein and plasminogen activator inhibitor-1 are circulating markers of low-grade inflammation, thrombosis, and vascular injury. Together with homocysteine, they have been associated with the underlying inflammatory processes and are considered to be "nontraditional" risk factors of atherosclerosis. The role of their measurement in clinical practice remains unclear. In this article, we review the available evidence demonstrating a link between inflammation, cardiovascular disease, and diabetes. We discuss how therapeutic agents used for both cardiovascular disease and diabetes modulate the inflammatory responses and possibly attenuate the complications of these two chronic disorders that cause significant morbidity and mortality.