Am J Cardiol. 2006 May 15;97(10):1427-8. Epub 2006 Mar 24

Ness J, Aronow WS.

Atherosclerotic vascular disease (AVD) and osteoporosis or osteopenia are common conditions among postmenopausal women and appear to be linked in a manner that is not fully understood. In a retrospective study that was conducted among 1,000 postmenopausal women who were seen in a general medicine clinic, AVD was more commonly seen among women with osteoporosis (92 of 154, 60%) than among those with osteopenia (63 of 179, 35%, p <0.001) or no osteoporosis or osteopenia (148 of 667, 22%, p <0.001). AVD was also more prevalent in women with osteopenia than in those with no osteoporosis or osteopenia (p <0.001). Modifiable risk factors for AVD were present to the same extent in women with osteoporosis, osteopenia, or no osteoporosis or osteopenia.

Atherosclerosis. 2006 May 3; [Epub ahead of print]

Lapointe A, Couillard C, Piche ME, Weisnagel SJ, Bergeron J, Nadeau A, Lemieux S.

OBJECTIVE: To investigate the relation between circulating ox-LDL and components of the metabolic syndrome (MS) in a sample of 124 postmenopausal women with varying glucose tolerance status. METHODS: This cross-sectional study included postmenopausal women not using hormone therapy. Ox-LDL concentrations were measured in plasma by a monoclonal antibody (mAb-4E6) based competition ELISA. LDL peak particle diameter (LDL-PPD) was measured by non-denaturating polyacrylamide gradient gel electrophoresis (PAGGE). Presence of the MS was determined according to the definition of the NCEP-ATPIII. RESULTS: Circulating ox-LDL concentrations were significantly associated with some factors of the MS such as triglyceride (r=0.48; p<0.0001), high-density lipoprotein cholesterol (r=-0.34; p=0.0001) and fasting plasma glucose concentrations (r=0.21; p=0.02). Ox-LDL concentrations were also associated with LDL cholesterol (r=0.54; p<0.0001), total cholesterol (r=0.48; p<0.0001), LDL apolipoprotein B (r=0.62; p<0.0001) and LDL-PPD (r=-0.18; p<0.05). Moreover, women with the MS had significantly higher ox-LDL concentrations (79.5+/-28.3U/l) compared to women without the MS (64.2+/-19.9U/l) (p<0.05). CONCLUSION: Ox-LDL concentrations are associated with individual components of the MS and are significantly higher in postmenopausal women with MS compared to healthy postmenopausal women.

Am J Clin Nutr. 2006 May;83(5):1039-46

Andersen LF, Jacobs DR Jr, Carlsen MH, Blomhoff R.

BACKGROUND: Coffee is the major source of dietary antioxidants. The association between coffee consumption and risk of death from diseases associated with inflammatory or oxidative stress has not been studied. OBJECTIVE: We studied the relation of coffee drinking with total mortality and mortality attributed to cardiovascular disease, cancer, and other diseases with a major inflammatory component. DESIGN: A total of 41 836 postmenopausal women aged 55-69 y at baseline were followed for 15 y. After exclusions for cardiovascular disease, cancer, diabetes, colitis, and liver cirrhosis at baseline, 27 312 participants remained, resulting in 410 235 person-years of follow-up and 4265 deaths. The major outcome measure was disease-specific mortality. RESULTS: In the fully adjusted model, similar to the relation of coffee intake to total mortality, the hazard ratio of death attributed to cardiovascular disease was 0.76 (95% CI: 0.64, 0.91) for consumption of 1-3 cups/d, 0.81 (95% CI: 0.66, 0.99) for 4-5 cups/d, and 0.87 (95% CI: 0.69, 1.09) for >/=6 cups/d. The hazard ratio for death from other inflammatory diseases was 0.72 (95% CI: 0.55, 0.93) for consumption of 1-3 cups/d, 0.67 (95% CI: 0.50, 0.90) for 4-5 cups/d, and 0.68 (95% CI: 0.49, 0.94) for >/=6 cups/d. CONCLUSIONS: Consumption of coffee, a major source of dietary antioxidants, may inhibit inflammation and thereby reduce the risk of cardiovascular and other inflammatory diseases in postmenopausal women.

Am J Med. 2006 May;119(5 Suppl 1):S24-30

Kurtz TW.

The metabolic syndrome is characterized by the clustering of insulin resistance, dyslipidemia, and hypertension and is associated with increased risk of cardiovascular disease and type 2 diabetes mellitus. However, older antihypertensive agents such as thiazide diuretics and beta-blockers have potentially adverse effects on glucose and lipid metabolism and may even the exacerbate the metabolic syndrome and increase risk of type 2 diabetes. Recent clinical trials have suggested that antihypertensive agents that inhibit the renin-angiotensin system may reduce risk for new-onset type 2 diabetes, but only a few of these studies were placebo controlled, and in most cases, the absolute antidiabetic effects were relatively modest. Evidence is accumulating that telmisartan (Micardis), in addition to blocking the angiotensin II type 1 receptor, activates the peroxisome proliferator-activated receptor (PPAR)-gamma a well-known target for treatment of the metabolic syndrome and diabetes. By contrast, other angiotensin-receptor blockers are largely devoid of activity on PPAR-gamma. Telmisartan is a partial agonist of PPAR-gamma and has a superior tolerability profile without causing the fluid retention and edema associated with full agonists of PPAR-gamma such as pioglitazone and rosiglitazone. Recent studies have indicated that in addition to antidiabetic properties, PPAR-gamma activators may also provide protection against atherosclerosis and coronary events. Thus, the ability of telmisartan both to activate PPAR-gamma and to block the angiotensin receptor may provide added value not only in the treatment of the metabolic syndrome and prevention of type 2 diabetes but also in prevention and treatment of atherosclerotic cardiovascular disease

From The British Journal of Diabetes and Vascular Disease

Fibrates: Therapeutic Review

M. John Chapman

Abstract. As agonists of the peroxisome proliferator-activated receptor (PPAR), fibrates are established, effective and well-tolerated agents in the management of atherogenic dyslipidaemia. Key actions of fibrates include a reduction in elevated triglyceride levels (by up to 50%) and a rise in high-density lipoprotein cholesterol (HDL-C) concentrations (typically by 5-15%). Fibrates promote a shift from small, dense low-density lipoprotein (LDL) to larger more buoyant particles, which are less susceptible to oxidation and possess higher binding affinity for removal by the non-atherogenic LDL receptor pathway. Thus, fibrates can correct lipid abnormalities commonly observed in patients with type 2 diabetes and metabolic syndrome. Clinical evidence has demonstrated the value of fibrate therapy in secondary and primary prevention settings, as well as in patients with type 2 diabetes. However, FIELD, the largest fibrate study to date in diabetic patients, predominantly in a primary prevention setting, showed a non-significant 11% reduction in the primary end point of coronary heart disease death and non-fatal myocardial infarction with fenofibrate, although total cardiovascular events, corresponding to the secondary end point, were significantly reduced by 11% (p=0.035). It is possible that risk reduction with fenofibrate may have been attenuated by the two-fold greater drop-in use of statin therapy in the placebo group. However, the interesting results of fenofibrate on attenuation of microangiographic symptomatology potentially suggest a new recommendation for fibrate therapy, although further studies are required to validate these findings.

From Diabetes Care

Trend in the Prevalence of the Metabolic Syndrome and Its Impact on Cardiovascular Disease Incidence: The San Antonio Heart Study

Carlos Lorenzo, MD; Ken Williams, MS; Kelly J. Hunt PHD;Steven M. Haffner, MD

Objective. With the current obesity epidemic, one would expect a prevalence increase in the metabolic syndrome. Therefore, in the San Antonio Heart Study, a population-based study with worsening obesity, we examined the metabolic syndrome and its effect on incident cardiovascular disease (CVD).

Research Design and Methods: We enrolled 5,158 subjects in two cohorts: 1979-1982 and 1984-1988. We reexamined 3,682 (71.4%) subjects in 1987-1990 (cohort 1) and 1991-1996 (cohort 2) and assessed a 7.5-year incidence of CVD in 4,635 (90.0%) participants. We used the metabolic syndrome definition of the National Cholesterol Education Program-Adult Treatment Panel III. Results: At baseline, the metabolic syndrome was less prevalent in cohort 1 than in cohort 2: in men, 20.4 vs. 29.3% (P < 0.001); in women, 16.3 vs. 26.3% (P < 0.001). The prevalence increased in men and women of both Mexican-American and non-Hispanic white ethnic groups between 1979-1982 and 1991-1996 (P for trend <0.001 for each of the groups). There was an excess of incident CVD in cohort 2 relative to cohort 1 (odds ratio 1.37 [95% CI 1.02-1.84]) after adjustment for age, sex, ethnic origin, socioeconomic status, history of CVD, diabetes, total cholesterol, smoking, and family history of heart attack. Further adjustment for the metabolic syndrome reduced this difference (1.26 [0.93-1.71]) because the metabolic syndrome predicted incident CVD (1.58 [1.14-2.18]).

Conclusions: In San Antonio, Texas, an increase in the prevalence of the metabolic syndrome between 1979-1982 and 1984-1988 contributes to explain a higher CVD incidence.

Ann Pharmacother. 2006 Apr 11; [Epub ahead of print]

Cavallari LH, Helgason CM, Brace LD, Viana MA, Nutescu EA.

BACKGROUND: There is substantial interpatient variability in response to aspirin after an ischemic stroke or transient ischemic attack (TIA), as assessed by ex vivo effects of aspirin on platelet aggregation. The factors contributing to this variability are not well defined. OBJECTIVE: To determine whether demographic, social, or clinical characteristics are associated with ex vivo response to aspirin in patients with a history of stroke or TIA. METHODS: Eighty-one patients who were taking aspirin for secondary stroke prevention and underwent ex vivo platelet aggregation studies were identified. The medical records of eligible patients were reviewed by clinicians who specialize in the management of stroke patients. Characteristics were compared between 45 patients who had a complete response to aspirin and 36 patients who exhibited an incomplete (partial) response to aspirin based on the results of platelet aggregation testing. RESULTS: The median (range) aspirin dose was similar in complete (325; 81-1950 mg/day) and partial (325; 81-1300 mg/day) responders. There was no association between aspirin response and age, race, body mass index, medical history, smoking status, or use of statin or hormone replacement therapy. However, sex was significantly associated with response to aspirin, with more women in the partial versus complete responder group (75% vs 49%; p = 0.02). CONCLUSIONS: Our data suggest that aspirin may be less effective at inhibiting platelet aggregation in women compared with men who have a history of ischemic stroke or TIA.

Am J Clin Nutr. 2006 Apr;83(4):774-9

Kasim-Karakas SE, Tsodikov A, Singh U, Jialal I.

BACKGROUND: Inflammation contributes to atherogenesis. Dietary fats may be proinflammatory. OBJECTIVE: The objective was to determine whether energy intake modulates the effects of low-fat, high-carbohydrate intakes on inflammatory markers. DESIGN: Twenty-two healthy postmenopausal women with a mean (+/-SD) age of 61 +/- 11 y, who were not receiving hormone replacement therapy, were fed eucaloric diets to reduce their fat intake from 35% to 15% of energy. Next, the women consumed a 15%-fat ad libitum diet under free-living conditions. Serum highly sensitive C-reactive protein, interleukin 6, HDL serum amyloid A, and adiponectin concentrations were measured at the end of the eucaloric and ad libitum low-fat, high-carbohydrate intakes. RESULTS: The eucaloric diet decreased adiponectin from 16.3 +/- 2.1 to 14.2 +/- 2.0 mg/L (P < 0.05) and increased triacylglycerol from 131 +/- 11 to 164 +/- 14 mg/dL (P < 0.01). The ad libitum low-fat diet caused 6 kg weight loss and decreased highly sensitive C-reactive protein from 4.3 +/- 0.6 to 2.5 +/- 0.5 mg/L (P < 0.01), decreased HDL serum amyloid A from 10.3 +/- 1.8 to 5.7 +/- 1.3 mg/L (P < 0.001), increased adiponectin from 14.2 +/- 2.0 to 16.3 +/- 1.7 mg/L (P < 0.05), and decreased triacylglycerol from 164 +/- 14 to 137 +/- 15 mg/dL (P < 0.05). CONCLUSION: During the eucaloric phase, the low-fat, high-carbohydrate diet exerted unfavorable effects on the inflammatory markers. In contrast, the ad libitum low-fat, high-carbohydrate intake caused weight loss and affected inflammatory markers favorably. Thus, the energy content of a low-fat, high-carbohydrate diet determines changes in inflammatory markers.

J Clin Endocrinol Metab. 2005 Dec 29; [Epub ahead of print]

Masi CM, Hawkley LC, Berry JD, Cacioppo JT.

Context: Lower systolic blood pressure (SBP) and lower rates of coronary heart disease among premenopausal women compared with similarly aged men and postmenopausal women suggest female sex hormones may confer cardiovascular protection. 2-hydroxyestradiol, a product of 17beta-estradiol oxidative metabolism, inhibits proliferation of vascular smooth muscle cells in vitro. The other major product of 17beta-estradiol oxidative metabolism, 16alpha-hydroxyestradiol, does not demonstrate similar inhibitory effects. Concentrations of 2-hydroxyestrone (2-OHE) and 16alpha-hydroxyestrone (16-OHE) in urine reflect the relative activity of the 2- and 16alpha-hydroxylation pathways of 17beta-estradiol. Objective: The objective of this study was to determine the relationship between systolic blood pressure and the ratio of 2-OHE to 16-OHE in urine. Design and Participants: This was a cross-sectional study of 80 postmenopausal women living in Cook County, IL. Setting: This study was performed in an academic clinical laboratory. Main Outcome Measure: The main outcome measure was systolic blood pressure. Results: Women taking hormone replacement therapy (HRT) had higher levels of urinary 2-OHE and 16-OHE but their mean 2/16-OHE ratio and SBP did not differ from women not taking HRT. In a multivariate regression model which controlled for age, BMI, race/ethnicity, and antihypertensive medication use, a SD increase in the 2/16-OHE ratio was associated with a 6.7 mm Hg decrease (P < 0.05) in SBP. Conclusions: The ratio of urinary 2-OHE to 16-OHE is a significant predictor of SBP among postmenopausal women and may reflect the effects of 2-hydroxyestradiol, a potent inhibitor of vascular smooth muscle cell proliferation.

Reuters Health

The adverse effects of postmenopausal hormone therapy documented in the Women's Health Initiative (WHI) study may actually reflect flaws in the study design, investigators report. They suggest that more appropriate, cyclical therapy in younger women actually reduces the risk of heart disease, as prior studies had shown. Dr. Edward L. Klaiber, from the University of Massachusetts Medical Center in Worcester, and his associates point out in their report, published in the December issue of Fertility and Sterility, that the WHI enrolled women whose age ranged from 50 to 79 years, many of whom would be expected to already have subclinical coronary artery atherosclerosis before starting hormone therapy. "If women start taking estrogen later after their arteries have already become narrowed by disease, estrogen may be harmful causing blood clots in diseased vessels resulting in heart attacks and strokes," the authors suggest. Another flaw was that the WHI investigators tested continuous combined conjugated equine estrogen plus medroxyprogesterone acetate (Prempro) in women with a uterus because they considered it to be more convenient for women to use. Those taking combined, continuous hormone therapy had more cases of cardio- and cerebrovascular events, so the study was discontinued because the overall health risks appeared to outweigh the benefits. However, other research has suggested that progestin reverses the cardioprotective effects of estrogen. Dr. Klaiber's team points out that a previous study, the Nurses' Health Study, included women aged 30 to 55 years. Their results showed a 40% to 50% reduction in the number of heart attacks among those taking estrogen. "A cyclic, rather than continuous regimen of micronized progestin would provide adequate protection from endometrial hyperplasia while interfering least with the positive beneficial effects of estrogen on the cardiovascular and cerebrovascular systems," they write. Moreover, Dr. Klaiber's group attributes the small increased risk of breast cancer observed in the WHI to the effect of prolonged, combined hormonal therapy on pre-existing cancers. Finally, the researchers note that the serum estrogen levels were not measured during the WHI, and that dosages should be adjusted to maintain levels within the normal premenopausal, physiologic range. They point out that the Kronos Longevity Research Institute is funding a large study testing the benefits of estrogen administered to recently menopausal women ages 40 to 55 years. "It is imperative," they say, "that a large scale study evaluating forms of hormone therapy other than continuous combined estrogen plus progestin be undertaken to evaluate their risks and benefits."

Fertil Steril 2005;6:1589-1601

Reuters Health

The Framingham risk estimation (FRE) method of assessing cardiovascular risk appears to underestimate women's risk for significant atherosclerosis when they have a family history of early heart disease, investigators at Johns Hopkins Medical Institutions report. "Because FRE weighs age so strongly and doesn't take into account family history or increased waist circumferences or lack of exercise, we think that it misses a lot of women who should be more aggressively treated with medication and lifestyle changes," senior investigator Dr. Roger S. Blumenthal told Reuters Health. The Baltimore-based research team used multidetector computed tomography (MDCT) to determine coronary artery calcification in 102 women ages 30 to 59 years who had siblings with coronary heart disease occurring before age 60. According to their report in the December issue of the American Heart Journal, only two of the subjects had FRE scores indicating an intermediate risk of having a cardiovascular event, i.e., a 10% to 19% risk over 10 years. However, 32% had significant subclinical atherosclerosis, with coronary artery calcium scores > 75th percentile for their age and gender. In terms of actual coronary artery calcium scores, 12 % had a score > 100, indicating moderately high cardiovascular risk; and 6% had scores > 400, indicating extensive atherosclerotic plaque burden. "These women almost surely should be on aspirin and cholesterol lowering therapy," Dr. Blumenthal said. "If we relied only on FRE we would miss them." He recommends for patients with a family history of premature heart disease that their physician either incorporate imaging studies, such as cardiac CT, or measure blood levels of C reactive protein along with standard blood work for blood sugar and lipids. The additional advantage of an imaging study, he pointed out, is that "you have more ammunition to help motivate them to exercise more days/week and more vigorously, improve their diet and accept a more aggressive medical regimen." "Our hope," he added, "is that investigators will update FRE to incorporate family history, since we now know that for these patients the risk is double what the current equation predicts."

Am Heart J 2005;150:1276-1281.