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Life Extension Magazine April 2013


Plasma homocysteine predicts progression of atherosclerosis.

MINI ABSTRACT: Three emerging risk factors potentially useful in predicting future cardiac events are electron-beam computed tomography (EBT), homocysteine(HCY), and C-reactive Protein (CRP). We evaluated a cohort of 133 serial asymptomatic patients, who underwent two consecutive EBT scans (8-84 months apart) and a comprehensive cardiac risk factor assessment, including measurements for lipids, ultrasensitive CRP and homocysteine. Individuals with elevated HCY (> or =12 micromol/L) demonstrated a mean increase in CC progression of 35% per year, while those with HCY <12 micromol/L (median) progressed at 17% per year (p = 0.0008). Patients with a level equal to or lower than the median value of CRP (0.8 mg/L) had a median yearly progression of 22%, compared to 21% for those with CRP value = 0.9-11 mg/L (p = ns). Presence of elevated HCY (>12 micromol/L) strongly and independently predicts progression of coronary plaque burden. BACKGROUND: Despite the availability of effective preventive therapies, coronary artery disease (CAD) remains the leading cause of morbidity and mortality. Use of traditional cardiovascular risk factors is imprecise and predicts less than one half of future cardiovascular events. Three ‘emerging risk factors’, as potential means of identifying subclinical atherosclerosis and predicting future cardiovascular events, are electron-beam computed tomography, homocysteine, and C-reactive protein. Given the evidence that HCY and CRP are involved in atherogenesis, we hypothesized that significant progression of EBT calcium score (a measure of atherosclerotic plaque burden) is associated with higher levels of these markers. METHODS: We evaluated 133 asymptomatic patients (100 men, 33 women; mean age was 61 +/- 9 years) who underwent previous EBT calcium score testing at Harbor-UCLA 8-80 months prior to enrollment (mean follow-up 20 months). Exclusion criteria included those with known or symptomatic CAD and chronic renal disease. During enrollment, we measured risk factors, serum HCY, serum lipids, ultrasensitive-CRP, and repeat EBT calcium scan. Statistical analysis was performed using probable Chi square method, and Student’s t-test. RESULTS: Individuals with elevated HCY (> or =12 micromol/L) demonstrated a mean increase in CC progression of 35% per year, while those with HCY <12 micromol/L (median) progressed at 17% per year (p = 0.0008). Patients with a level equal to or lower than the median value of CRP (0.8 mg/L) had a median yearly progression of 22%, compared to 21% for those with CRP value = 0.9-11 mg/L (p = ns). Neither cholesterol values, body mass index, gender, age nor presence of individual risk factors predicted progression of coronary calcium. CONCLUSION: Presence of elevated HCY (>12 micromol/L) strongly and independently predicts progression of coronary plaque burden.

Atherosclerosis. 2005 Jul;181(1):159-65

Depression as a risk factor for mortality after coronary artery bypass surgery.

BACKGROUND: Studies that have shown clinical depression to be a risk factor for cardiac events after coronary artery bypass graft (CABG) surgery have had small sample sizes, short follow-up, and have not had adequate power to assess mortality. We sought to assess whether depression is associated with an increased risk of mortality. METHODS: We assessed 817 patients undergoing CABG at Duke University Medical Center between May, 1989, and May, 2001. Patients completed the Center for Epidemiological Studies-Depression (CES-D) scale before surgery, 6 months after CABG, and were followed-up for up to 12 years. FINDINGS: In 817 patients there were 122 deaths (15%) in a mean follow-up of 5.2 years. 310 patients (38%) met the criterion for depression (CES-D > or =16): 213 (26%) for mild depression (CES-D 16-26) and 97 (12%) for moderate to severe depression (CES-D > or =27). Survival analyses, controlling for age, sex, number of grafts, diabetes, smoking, left ventricular ejection fraction, and previous myocardial infarction, showed that patients with moderate to severe depression at baseline (adjusted hazard ratio [HR] 2.4, [95% CI 1.4-4.0]; p=0.001) and mild or moderate to severe depression that persisted from baseline to 6 months (adjusted HR 2.2, [1.2-4.2]; p=0.015) had higher rates of death than did those with no depression. INTERPRETATION: Despite advances in surgical and medical management of patients after CABG, depression is an important independent predictor of death after CABG and should be carefully monitored and treated if necessary.

Lancet. 2003 Aug 23;362(9384):604-9

Fibrinogen: associations with cardiovascular events in an outpatient clinic.

BACKGROUND: Fibrinogen, known to influence the coagulation process, is an independent risk factor for coronary artery disease (CAD). However, its association with myocardial infarction (MI) and its predictive potential for short-term mortality, in an ongoing clinical practice, has not been characterized. OBJECTIVES: In a high-risk outpatient practice we sought to demonstrate whether baseline fibrinogen levels related to MI rather than CAD alone, and whether baseline serum fibrinogen levels predicted mortality over a short-term follow-up. METHODS AND RESULTS: From a total of 2,126 patients with baseline fibrinogen measurements (mean age, 56 +/- 12 years, 35% female), 1,187 patients with CAD (n = 606 with MI) and 939 patients without CAD were evaluated in an active preventive cardiology unit of a large city hospital. Logistic regression models were used to determine the association of fibrinogen with differing CAD presentations. Fibrinogen quartile showed a significant correlation with CAD both univariately and after adjustment for Framingham risk score (odds ratio [OR] = 1.22, P <.001). Fibrinogen levels were significantly associated with the presence of CAD and history of MI (adjusted OR = 1.25, P =.001). Fibrinogen did not show a significant association to CAD when MI was not considered in the analysis (OR = 1.01, P =.82). In this same clinical cohort, after a mean follow-up of 24 +/- 13 months, 41 patients had died. Consistent with the observed association with MI, fibrinogen quartile showed a graded independent relation to mortality in a cohort of both men and women (hazard ratio = 1.81, P <.001). CONCLUSIONS: In the clinical setting of an outpatient clinic, fibrinogen was directly associated with the presence of MI and was revealed to be an independent short-term predictor of mortality.

Am Heart J. 2002 Feb;143(2):277-82

Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events.

BACKGROUND: Both C-reactive protein and low-density lipoprotein (LDL) cholesterol levels are elevated in persons at risk for cardiovascular events. However, population-based data directly comparing these two biologic markers are not available. METHODS: C-reactive protein and LDL cholesterol were measured at base line in 27,939 apparently healthy American women, who were then followed for a mean of eight years for the occurrence of myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes. We assessed the value of these two measurements in predicting the risk of cardiovascular events in the study population. RESULTS: Although C-reactive protein and LDL cholesterol were minimally correlated (r=0.08), base-line levels of each had a strong linear relation with the incidence of cardiovascular events. After adjustment for age, smoking status, the presence or absence of diabetes mellitus, categorical levels of blood pressure, and use or nonuse of hormone-replacement therapy, the relative risks of first cardiovascular events according to increasing quintiles of C-reactive protein, as compared with the women in the lowest quintile, were 1.4, 1.6, 2.0, and 2.3 (P<0.001), whereas the corresponding relative risks in increasing quintiles of LDL cholesterol, as compared with the lowest, were 0.9, 1.1, 1.3, and 1.5 (P<0.001). Similar effects were observed in separate analyses of each component of the composite end point and among users and nonusers of hormone-replacement therapy. Overall, 77 percent of all events occurred among women with LDL cholesterol levels below 160 mg per deciliter (4.14 mmol per liter), and 46 percent occurred among those with LDL cholesterol levels below 130 mg per deciliter (3.36 mmol per liter). By contrast, because C-reactive protein and LDL cholesterol measurements tended to identify different high-risk groups, screening for both biologic markers provided better prognostic information than screening for either alone. Independent effects were also observed for C-reactive protein in analyses adjusted for all components of the Framingham risk score. CONCLUSIONS: These data suggest that the C-reactive protein level is a stronger predictor of cardiovascular events than the LDL cholesterol level and that it adds prognostic information to that conveyed by the Framingham risk score.

N Engl J Med. 2002 Nov 14;347(20):1557-65

Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women.

CONTEXT: Elevated nonfasting triglycerides indicate the presence of remnant lipoproteins, which may promote atherosclerosis. OBJECTIVE: To test the hypothesis that very high levels of nonfasting triglycerides predict myocardial infarction (MI), ischemic heart disease (IHD), and death. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study of 7,587 women and 6,394 men from the general population of Copenhagen, Denmark, aged 20 to 93 years, followed up from baseline (1976-1978) until 2004. MAIN OUTCOME MEASURES: Hazard ratios (HRs) for incident MI, IHD, and total death according to baseline nonfasting triglyceride level categories of 1 to 1.99 mmol/L (88.5-176.1 mg/dL), 2 to 2.99 mmol/L (177.0-264.6 mg/dL), 3 to 3.99 mmol/L (265.5-353.0 mg/dL), 4 to 4.99 mmol/L (354.0-441.6 mg/dL), and 5 mmol/L or more (> or =442.5 mg/dL) vs triglyceride levels of less than 1 mmol/L (<88.5 mg/dL). RESULTS: With increasing levels of nonfasting triglycerides, levels of remnant lipoprotein cholesterol increased. During a mean follow-up of 26 years, 1,793 participants (691 women and 1,102 men) developed MI, 3,479 (1,567 women and 1,912 men) developed IHD, and 7,818 (3,731 women and 4,087 men) died. For MI, among women, the age-adjusted HRs and multifactorially adjusted HRs (aHRs) for each respective category per 1-mmol/L increase in nonfasting triglyceride levels were 2.2 (aHR, 1.7), 4.4 (aHR, 2.5), 3.9 (aHR, 2.1), 5.1 (aHR, 2.4), and 16.8 (aHR, 5.4); for both, P for trend < .001. For MI, among men, the values were 1.6 (aHR, 1.4), 2.3 (aHR, 1.6), 3.6 (aHR, 2.3), 3.3 (aHR, 1.9), and 4.6 (aHR, 2.4); for both, P for trend < .001. For IHD, among women, the values were 1.7 (aHR, 1.4), 2.8 (aHR, 1.8), 3.0 (aHR, 1.8), 2.1 (aHR, 1.2), and 5.9 (aHR, 2.6); for both, P for trend < .001. For IHD, among men, the values were 1.3 (aHR, 1.1), 1.7 (aHR, 1.3), 2.1 (aHR, 1.3), 2.0 (aHR, 1.2), and 2.9 (aHR, 1.5); P for trend < .001 for age-adjusted and P for trend = .03 for multifactorially adjusted. For total death, among women, the values were 1.3 (aHR, 1.3), 1.7 (aHR, 1.6), 2.2 (aHR, 2.2), 2.2 (aHR, 1.9), and 4.3 (aHR, 3.3); for both, P for trend < .001. For total death, among men, the values were 1.3 (aHR, 1.2), 1.4 (aHR, 1.4), 1.7 (aHR, 1.5), 1.8 (aHR, 1.6), and 2.0 (aHR, 1.8); for both, P for trend < .001. CONCLUSION: In this general population cohort, elevated nonfasting triglyceride levels were associated with increased risk of MI, IHD, and death in men and women.

JAMA. 2007 Jul 18;298(3):299-308

Endothelial function: a critical determinant in atherosclerosis?

Common conditions predisposing to atherosclerosis, such as hypercholesterolemia, hypertension, diabetes, and smoking, are associated with endothelial dysfunction. Endothelial function has largely been assessed as endothelium-dependent vasomotion, at least in part based on the assumption that impaired endothelium-dependent vasodilation also reflects the alteration of other important functions of the endothelium. An important rationale for this approach has been the observation that endothelium-derived nitric oxide (NO), a major mediator of endothelium-dependent vasodilation, has important anti-inflammatory and antithrombotic properties, ie, inhibiting leukocyte adhesion, limiting platelet adhesion and aggregation, and the expression of plasminogen activator inhibitor-1 (PAI-1), a prothrombotic protein. Accumulating data suggest that the degree of impairment of endothelium-dependent vasomotion has profound and independent prognostic implications. A common mechanism underlying endothelial dysfunction relates to increased vascular production of reactive oxygen species. Recent studies also suggest that inflammation per se and C-reactive protein in particular may directly contribute to endothelial dysfunction. These findings raise the question of whether assessment of endothelial function can be used in the clinical setting to identify patients at high risk. New insights into mechanisms of endothelial dysfunction, such as a better understanding of the regulation of important vascular sources of oxygen radicals, may lead to novel therapeutic strategies with the potential to improve prognosis.

Circulation. 2004 Jun 1;109(21 Suppl 1):II27-33

Hypercholesterolemia and hypertension have synergistic deleterious effects on coronary endothelial function.

OBJECTIVE: Coronary endothelial dysfunction is associated with an increase in cardiac events. Hypercholesterolemia (HC) and hypertension (HT) are both associated with endothelial dysfunction, and their coexistence is associated with an increased incidence of cardiac events in epidemiological studies. However, pathogenic mechanisms are poorly understood. Here we studied the effects of coexisting HC and HT on coronary endothelial function. METHODS AND RESULTS: Four groups of pigs were studied after 12 weeks of a normal diet (n=9), a 2% HC diet (n=9), HT (achieved by unilateral renal artery stenosis, n=8), or HC+HT (n=6). Coronary endothelial function was tested, in epicardial arteries and arterioles, by using organ chamber techniques. Oxidative stress was measured in coronary artery tissue. Vasodilatory response to bradykinin and calcium ionophore was significantly impaired in animals with HC+HT compared with each risk factor alone (P<0.05 for both). In animals with coexistent HC and HT, the increase in oxidative stress was more pronounced compared with each risk factor alone (P<0.05). Furthermore, chronic antioxidant supplementation significantly improved coronary artery vasoreactivity. CONCLUSIONS: These results suggest that HC and HT have a synergistic deleterious effect on coronary endothelial function, associated with increased oxidative stress. This interaction may contribute to the increased incidence of coronary heart disease and cardiac events seen when HC and HT coexist.

Arterioscler Thromb Vasc Biol. 2003 May 1;23(5):885-91

Emerging importance of HDL cholesterol in developing high-risk coronary plaques in acute coronary syndromes.

Cardiovascular disease is the principal cause of death in industrialized countries. Hyperlipidemia, with high low-density lipoprotein cholesterol and triglycerides, and low high-density lipoprotein cholesterol levels (<40 mg/dL in men and <45 mg/dL in women), is a known major cardiovascular risk factor. Statins are considered the most potent and effective agents to reduce low-density lipoprotein cholesterol, but they have a variable effect on high-density lipoprotein cholesterol and triglycerides. Different clinical trials with statins have shown a decrease in low-density lipoprotein cholesterol by 35% and a reduction of the incidence of coronary events by as much as 30%. However, 60 to 70% of events still occur, despite remarkable reduction of low-density lipoprotein cholesterol concentration. Recent National Cholesterol Education Program guidelines highlighted the importance of high-density lipoprotein cholesterol concentration in the prevention and treatment of cardiovascular disease. High-density lipoprotein cholesterol is considered an independent risk factor and has an inverse relation with coronary events. The association of low levels of high-density lipoprotein cholesterol with an increased incidence of cardiovascular events implies a critical role of high-density lipoprotein in the protection against atherosclerotic disease and in the progression of coronary atherosclerotic disease. High-density lipoprotein cholesterol appears to exert this protective effect through multiple mechanisms. High-density lipoprotein is not only involved in reverse cholesterol transport, but also prevents endothelial dysfunction; inhibits the homing of monocytes, apoptosis, platelet activation, and factor X activation; and has antioxidant properties. In this article the authors review the available experimental and clinical evidence supporting the importance of high-density lipoprotein cholesterol as a protective factor in coronary artery disease, and the strategies developed to increase high-density lipoprotein cholesterol.

Curr Opin Cardiol. 2003 Jul;18(4):286-94

Molecular mechanisms of impaired endothelial function associated with insulin resistance.

Dysfunction of the endothelium in large- and medium-sized arteries plays a central role in atherogenesis. The insulin resistance syndrome encompasses more than a subnormal response to insulin-mediated glucose disposal. Patients with this syndrome also frequently display elevated blood pressure, hyperlipidemia, and dysfibinolysis, even without any clinically manifested alteration in plasma glucose concentrations. Of note endothelial dysfunction and atherosclerosis also have been demonstrated in patients with hypertension, which is one of the features of the syndrome of insulin resistance. Insulin-induced vasodilation, which is mediated by the release of nitric oxide (NO) release, is impaired in obese individuals who display insulin resistance. Although it is tempting to speculate that loss of endothelium-dependent vasodilation and increased vasoconstriction might be etiological factors of elevated blood pressure, the factors contributing to NO-mediated endothelial dysfunction in the insulin-resistant state are not fully defined. Experimental evidences suggest that (6R)-5,6,7,8-tetrahydrobiopterin (BH(4)), the natural and essential cofactor of NO synthases (NOS), plays a crucial role not only in increasing the rate of NO generation by NOS but also in controlling the formation of superoxide anion (O(2)(-)) in the endothelial cells. Under insulin-resistant conditions where BH(4) levels are suboptimal, in addition to a reduced synthesis of NO, an accelerated inactivation of NO by O(2)(-) within the vascular wall was observed. Furthermore, oral supplementation of BH(4) restored endothelial function and relieved oxidative tissue damage, through activation of eNOS in the aorta of insulin-resistant rats. These results indicate that abnormal pteridine metabolism contributes to causing endothelial dysfunction and the enhancement of vascular oxidative stress in the insulin-resistant state.

Curr Drug Targets Cardiovasc Haematol Disord. 2004 Mar;4(1):1-11

Minireview: adiposity, inflammation, and atherogenesis.

Adipose tissue is a dynamic endocrine organ that secretes a number of factors that are increasingly recognized to contribute to systemic and vascular inflammation. Several of these factors, collectively referred to as adipokines, have now been shown regulate, directly or indirectly, a number of the processes that contribute to the development of atherosclerosis, including hypertension, endothelial dysfunction, insulin resistance, and vascular remodeling. Several adipokines are preferentially expressed in visceral adipose tissue, and the secretion of proinflammatory adipokines is elevated with increasing adiposity. Not surprisingly, approaches that reduce adipose tissue depots, including surgical fat removal, exercise, and reduced caloric intake, improve proinflammatory adipokine levels and reduce the severity of their resultant pathologies. Systemic adipokine levels can also be favorably altered by treatment with several of the existing drug classes used to treat insulin resistance, hypertension, and hypercholesterolemia. Greater understanding of adipokine regulation, however, should result in the design of improved treatment strategies to control disease states associated with increase adiposity, an important outcome in view of the growing worldwide epidemic of obesity.

Endocrinology. 2003 Jun;144(6):2195-200