- Email: [email protected]
Postmenopausal hormone therapy and risk of stroke. The Heart and Estrogen-Progestin Replacement Study (HERS)
Results: Mean age was 77.8 years and 50% had CVD. Higher levels of IL-6 were associated with smoking, CHD, PVOD, CHF, diabetes, COPD. Increasing IL-6 was also related to decreasing ABIs, exercise tolerance, FEV1 and increasing BMI as a measure of obesity. After adjusting for cofounders, women in the highest IL-6 tertile were at higher risk for all-cause mortality, which was strongly influenced by the presence of CVD (increased risk of death fourfold). Adjustment for all chronic diseases, serum albumen and tertile of C-reactive protein (CRP) and the clinical parameters, including FEV1 and ABIs, and exercise tolerance did not change the results. While the predominant association of high levels of IL-6 and all-cause mortality was in the first 18 months of follow-up (RR 5.65 after adjustment for clinical variables), the RR was 1.62 from 19 to 36 months. Conclusions: IL-6 level is helpful in identifying a subgroup of older women and CVD patients with a high risk of death over 3 years. Systemic inflammation, as measured by IL-6, may be related to the clinical evolution of older patients with CVD. Perspective: Elevated cytokines, such as IL-6, are not simply markers of lymphocyte and macrophage activity. IL-6, IL-1, TNF-␣ and CRP, the hepatic acute-phase reactant to proinflammatory cytokines, can promote thrombosis, plaque instability and up-regulate the renin-angiotensin system. It is clear that markers of a heightened inflammatory state are associated with a higher mortality in adult men and women, the elderly and those with and without CVD but less clear is the clinical utility of measuring these markers. MR
Results: 44 or 10% of women had been treated for an anxiety disorder. Their scores of anxiety and depression were significantly worse, they had more autonomic symptoms (muscle tension) and avoidance behavior, but did not differ in regard to the response to nitroglycerin or presence of inducible ischemia. Back pain and angina during sleep were more common, otherwise the pains were characterized the same. The women with previous treatment for anxiety were three times more likely to be in the no CAD than obstructive CAD groups, and 25% had obstructive CAD compared to 37% of the 391 without a history of anxiety disorders. Conclusions: Among women with chest pain symptoms, a history of anxiety disorders is associated with a lower probability of significant CAD. Knowledge of an anxiety disorder history may assist in the clinical evaluation of women with chest pain. Perspective: The findings are not surprising considering the well-characterized but poorly understood Syndrome X, “angina with normal coronary arteriography,” described in the 1970s to be associated with anxiety and panic. The findings are also not very helpful to the clinician in need of an improved diagnostic decision tree in women with chest pain. Fully 30% of the women underwent elective coronary arteriography without a noninvasive test for ischemia, and the groups did not differ substantially in the quality of chest pain. Also, findings in WISE are preliminary, and it would not be appropriate to withhold noninvasive or invasive studies in women with a history of anxiety disorders. MR
Postmenopausal Hormone Therapy and Risk of Stroke. The Heart and Estrogen-Progestin Replacement Study (HERS)
History of Anxiety Disorders Is Associated With a Decreased Likelihood of Angiographic Coronary Disease in Women With Chest Pain: The WISE Study
Simon JA, Hsia J, Cauley JA, et al., for the HERS Research Group. Circulation 2001;103:638 – 42.
Rutledge T, Reis SE, Olson M, Owens J, et al. J Am Coll Cardiol 2001;37:780 –5.
Study Question: The risk of stroke associated with postmenopausal hormone replacement therapy (HRT) is not clear. This study sought to determine the effects of HRT on stroke and transient ischemic attacks (TIA) in postmenopausal women with coronary heart disease (CHD) enrolled in HERS, which evaluated the effects of 0.625 mg conjugated estrogen and 2.5 mg progestin in CHD. Methods: Postmenopausal women with CHD (n ⫽ 2763) were randomly assigned to HRT vs. placebo and followed for a mean of 4.1 years. Stroke and TIA were prespecified secondary outcomes in HERS. Results: Average age was 67 years, 68% were hypertensive, 23% diabetics, ASA was used in 79% and lipid levels were relatively normal. A total of 149 women (5%) had one or more strokes (85% ischemic) and 26 were fatal. HRT was not significantly associated with nonfatal or fatal strokes. Independent predictors of stroke included increasing age, hypertension, diabetes, current cigarette smoking, and atrial fibrillation. BMI was inversely related to stroke.
Study Question: This study sought to determine whether a history of anxiety disorder is associated with a decreased likelihood of obstructive coronary stenosis in women with chest pain. Methods: The 435 women in this study were participants in Women’s Ischemia Syndrome Evaluation (WISE), an NHLBI multicenter study designed to characterize chest pain syndromes in women and identify the optimal work-up for suspected myocardial ischemia. Each completed psychological profiling and underwent quantitative coronary arteriography (QCA) for the evaluation of chest pain. Coronary disease was characterized using three methods: 1) maximal stenosis in one or more epicardial vessels as no CAD (⬍20%), nonobstructive CAD (20 – 49%) and obstructive CAD (⬎49%); 2) with discrete ranges adjusted for location and 3) the raw maximum stenosis by QCA. Approximately 70% of women underwent one or more noninvasive studies for ischemia.
ACC CURRENT JOURNAL REVIEW Jul/Aug 2001
27
Conclusions: Hormone therapy with estrogens and progestins in postmenopausal women with CHD had no significant effect on the risk for stroke or TIAs. Perspective: The incidence of stroke in HERS was over twice that in white women aged 45– 84 years (4/1000 personyears), a finding likely explained by the association of cerebral and carotid disease with CHD and shared risk factors. The findings are important since if the subset of patients with CHD for whom there is a risk of early thrombotic events can be distinguished, the long-term benefits of HRT on CHD risk reduction should be obtained without an increased risk of neurologic events. MR
creased thrombosis and decreased thrombolysis, an atherogenic lipid profile with small LDL particles and low HDL-C, abnormal endothelial function, carotid and coronary disease, and now silent cerebral lacunar infarcts, a marker of stroke risk (odds ratio ⬃ 10). While somewhat painful and frustrating, diet and exercise, which increase insulin sensitivity, have been recommended since biblical times to promote a long and healthy life. How did they know? MR
Chronic Infections and the Risk of Carotid Atherosclerosis. Prospective Results From a Large Population Study
Hyperinsulinemia and Hemostatic Abnormalities Are Associated With Silent Lacunar Cerebral Infarcts in Elderly Hypertensive Subjects
Kiechel S, Egger G, Mayr M, et al. Circulation 2001;103:1064 – 70. Study Question: This study sought to determine the relationship between chronic infection and carotid atherosclerosis. Methods: A random sample of 919 inhabitants (40 –79 years of age) of Bruneck, Italy underwent screening for coronary risk factors, serum markers of inflammation and infection and clinical evidence of chronic infections. A carotid ultrasound was performed at baseline and after 5 years of followup. Carotid disease was defined as minimal plaque, the average of plaque diameter at eight sites, average intimamedia thickness (IMT) and occurrence or progression to lesions ⬎40%. Results: Average age was 58 years, 25% were smokers, ⬃70% were in the lower socioeconomic tertile and other risk factors comparable to the US. 268 of the 826 subjects with complete data had diagnostic criteria for chronic infection, the most common of which were respiratory and urinary tract. After adjustment for age and sex, several serum markers of inflammation and infection correlated with chronic infection, including CRP (0.17 mg/dL vs. 0.52 mg/dL), endotoxin, soluble heat shock protein-60 and IgA to C. pneumoniae. New carotid plaque developed in 41% of all subjects and 25% of those plaque free at baseline. After adjustment for other variables, the odds ratio (OR) for new plaque attributable to chronic infection was 4.1, which was not influenced by smoking, aspirin or the absence of classic risk factors, but exaggerated in diabetes. New plaque was associated with any chronic infection and IgA to C. pneumoniae ⬎1/16, and most likely (OR ⫽ 5) when the CRP was ⬎60% percentile. There was no association between new plaque and CMV, herpes zoster or chronic active hepatitis B or C. Chronic infection was the strongest variable associated with new plaque, the others being ferritin, hypertension, LDL-C and age. Conclusions: This study provides solid evidence for a role of common chronic infections in human atherogenesis. Induction of systemic inflammation and autoimmunity may be potential pathophysiologic links.
Kario K, Matsuo T, Kobayashi H, Hoshide S, Shimada K. J Am Coll Cardiol 2001;37:871–7. Study Question: Silent lacunar cerebral infarcts (sLCI), which are strong predictors of subsequent strokes, can be detected by magnetic resonance imaging (MRI) in about 40% of normotensive older adults. This study sought to determine the incidence of lacunar infarcts in an elderly hypertensive population and the association with hyperinsulinemia and hemostatic factors. Methods: 123 asymptomatic hypertensive men and women ⬎54 years old (range 55– 88 years) were studied off antihypertensive and lipid lowering medication for at least 2 weeks. Patients with coronary disease, CHF, atrial fibrillation, previous stroke, diabetes, liver and kidney disease were excluded. All underwent a brain MRI with sLCI lesions classified as none, few (1–2), and multiple (⬎2) and location as subcortical or basal ganglia. Other studies included 24-hour ambulatory BP monitoring, ECG, an oral glucose and insulin tolerance test, lipids and hemostatic/thrombolytic factors including von Willebrand factor (vWF). Results: The average age was 68 years, 30% were male, 30% smoked, LVH was present in 20%, and the average blood pressure was 169/97 mm Hg. At least one sLCI was detected in 80 subjects (65%) and multiple in 39%. The presence of one or more sLCI was associated with older age, higher mean 24-hour blood pressures, 2-hour post-glucose insulin levels, prothrombin fragment 1 ⫹ 2, PAI-1 and vWF. Insulin resistance was associated with subcortical infarcts, while hemostatic abnormalities were more often found in those with multiple sLCI, particulary in the basal ganglia. Conclusions: In older asymptomatic hypertensive subjects, hyperinsulinemia is associated with lacunar-type silent cortical infarcts, particularly white matter, while hemostatic abnormalities more often predispose to multiple sLCI in the basal ganglia. Perspective: Insulin resistance has been associated with hypertension, truncal obesity, higher levels of CRP, in-
ACC CURRENT JOURNAL REVIEW Jul/Aug 2001
28
Results: 44 or 10% of women had been treated for an anxiety disorder. Their scores of anxiety and depression were significantly worse, they had more autonomic symptoms (muscle tension) and avoidance behavior, but did not differ in regard to the response to nitroglycerin or presence of inducible ischemia. Back pain and angina during sleep were more common, otherwise the pains were characterized the same. The women with previous treatment for anxiety were three times more likely to be in the no CAD than obstructive CAD groups, and 25% had obstructive CAD compared to 37% of the 391 without a history of anxiety disorders. Conclusions: Among women with chest pain symptoms, a history of anxiety disorders is associated with a lower probability of significant CAD. Knowledge of an anxiety disorder history may assist in the clinical evaluation of women with chest pain. Perspective: The findings are not surprising considering the well-characterized but poorly understood Syndrome X, “angina with normal coronary arteriography,” described in the 1970s to be associated with anxiety and panic. The findings are also not very helpful to the clinician in need of an improved diagnostic decision tree in women with chest pain. Fully 30% of the women underwent elective coronary arteriography without a noninvasive test for ischemia, and the groups did not differ substantially in the quality of chest pain. Also, findings in WISE are preliminary, and it would not be appropriate to withhold noninvasive or invasive studies in women with a history of anxiety disorders. MR
Postmenopausal Hormone Therapy and Risk of Stroke. The Heart and Estrogen-Progestin Replacement Study (HERS)
History of Anxiety Disorders Is Associated With a Decreased Likelihood of Angiographic Coronary Disease in Women With Chest Pain: The WISE Study
Simon JA, Hsia J, Cauley JA, et al., for the HERS Research Group. Circulation 2001;103:638 – 42.
Rutledge T, Reis SE, Olson M, Owens J, et al. J Am Coll Cardiol 2001;37:780 –5.
Study Question: The risk of stroke associated with postmenopausal hormone replacement therapy (HRT) is not clear. This study sought to determine the effects of HRT on stroke and transient ischemic attacks (TIA) in postmenopausal women with coronary heart disease (CHD) enrolled in HERS, which evaluated the effects of 0.625 mg conjugated estrogen and 2.5 mg progestin in CHD. Methods: Postmenopausal women with CHD (n ⫽ 2763) were randomly assigned to HRT vs. placebo and followed for a mean of 4.1 years. Stroke and TIA were prespecified secondary outcomes in HERS. Results: Average age was 67 years, 68% were hypertensive, 23% diabetics, ASA was used in 79% and lipid levels were relatively normal. A total of 149 women (5%) had one or more strokes (85% ischemic) and 26 were fatal. HRT was not significantly associated with nonfatal or fatal strokes. Independent predictors of stroke included increasing age, hypertension, diabetes, current cigarette smoking, and atrial fibrillation. BMI was inversely related to stroke.
Study Question: This study sought to determine whether a history of anxiety disorder is associated with a decreased likelihood of obstructive coronary stenosis in women with chest pain. Methods: The 435 women in this study were participants in Women’s Ischemia Syndrome Evaluation (WISE), an NHLBI multicenter study designed to characterize chest pain syndromes in women and identify the optimal work-up for suspected myocardial ischemia. Each completed psychological profiling and underwent quantitative coronary arteriography (QCA) for the evaluation of chest pain. Coronary disease was characterized using three methods: 1) maximal stenosis in one or more epicardial vessels as no CAD (⬍20%), nonobstructive CAD (20 – 49%) and obstructive CAD (⬎49%); 2) with discrete ranges adjusted for location and 3) the raw maximum stenosis by QCA. Approximately 70% of women underwent one or more noninvasive studies for ischemia.
ACC CURRENT JOURNAL REVIEW Jul/Aug 2001
27
Conclusions: Hormone therapy with estrogens and progestins in postmenopausal women with CHD had no significant effect on the risk for stroke or TIAs. Perspective: The incidence of stroke in HERS was over twice that in white women aged 45– 84 years (4/1000 personyears), a finding likely explained by the association of cerebral and carotid disease with CHD and shared risk factors. The findings are important since if the subset of patients with CHD for whom there is a risk of early thrombotic events can be distinguished, the long-term benefits of HRT on CHD risk reduction should be obtained without an increased risk of neurologic events. MR
creased thrombosis and decreased thrombolysis, an atherogenic lipid profile with small LDL particles and low HDL-C, abnormal endothelial function, carotid and coronary disease, and now silent cerebral lacunar infarcts, a marker of stroke risk (odds ratio ⬃ 10). While somewhat painful and frustrating, diet and exercise, which increase insulin sensitivity, have been recommended since biblical times to promote a long and healthy life. How did they know? MR
Chronic Infections and the Risk of Carotid Atherosclerosis. Prospective Results From a Large Population Study
Hyperinsulinemia and Hemostatic Abnormalities Are Associated With Silent Lacunar Cerebral Infarcts in Elderly Hypertensive Subjects
Kiechel S, Egger G, Mayr M, et al. Circulation 2001;103:1064 – 70. Study Question: This study sought to determine the relationship between chronic infection and carotid atherosclerosis. Methods: A random sample of 919 inhabitants (40 –79 years of age) of Bruneck, Italy underwent screening for coronary risk factors, serum markers of inflammation and infection and clinical evidence of chronic infections. A carotid ultrasound was performed at baseline and after 5 years of followup. Carotid disease was defined as minimal plaque, the average of plaque diameter at eight sites, average intimamedia thickness (IMT) and occurrence or progression to lesions ⬎40%. Results: Average age was 58 years, 25% were smokers, ⬃70% were in the lower socioeconomic tertile and other risk factors comparable to the US. 268 of the 826 subjects with complete data had diagnostic criteria for chronic infection, the most common of which were respiratory and urinary tract. After adjustment for age and sex, several serum markers of inflammation and infection correlated with chronic infection, including CRP (0.17 mg/dL vs. 0.52 mg/dL), endotoxin, soluble heat shock protein-60 and IgA to C. pneumoniae. New carotid plaque developed in 41% of all subjects and 25% of those plaque free at baseline. After adjustment for other variables, the odds ratio (OR) for new plaque attributable to chronic infection was 4.1, which was not influenced by smoking, aspirin or the absence of classic risk factors, but exaggerated in diabetes. New plaque was associated with any chronic infection and IgA to C. pneumoniae ⬎1/16, and most likely (OR ⫽ 5) when the CRP was ⬎60% percentile. There was no association between new plaque and CMV, herpes zoster or chronic active hepatitis B or C. Chronic infection was the strongest variable associated with new plaque, the others being ferritin, hypertension, LDL-C and age. Conclusions: This study provides solid evidence for a role of common chronic infections in human atherogenesis. Induction of systemic inflammation and autoimmunity may be potential pathophysiologic links.
Kario K, Matsuo T, Kobayashi H, Hoshide S, Shimada K. J Am Coll Cardiol 2001;37:871–7. Study Question: Silent lacunar cerebral infarcts (sLCI), which are strong predictors of subsequent strokes, can be detected by magnetic resonance imaging (MRI) in about 40% of normotensive older adults. This study sought to determine the incidence of lacunar infarcts in an elderly hypertensive population and the association with hyperinsulinemia and hemostatic factors. Methods: 123 asymptomatic hypertensive men and women ⬎54 years old (range 55– 88 years) were studied off antihypertensive and lipid lowering medication for at least 2 weeks. Patients with coronary disease, CHF, atrial fibrillation, previous stroke, diabetes, liver and kidney disease were excluded. All underwent a brain MRI with sLCI lesions classified as none, few (1–2), and multiple (⬎2) and location as subcortical or basal ganglia. Other studies included 24-hour ambulatory BP monitoring, ECG, an oral glucose and insulin tolerance test, lipids and hemostatic/thrombolytic factors including von Willebrand factor (vWF). Results: The average age was 68 years, 30% were male, 30% smoked, LVH was present in 20%, and the average blood pressure was 169/97 mm Hg. At least one sLCI was detected in 80 subjects (65%) and multiple in 39%. The presence of one or more sLCI was associated with older age, higher mean 24-hour blood pressures, 2-hour post-glucose insulin levels, prothrombin fragment 1 ⫹ 2, PAI-1 and vWF. Insulin resistance was associated with subcortical infarcts, while hemostatic abnormalities were more often found in those with multiple sLCI, particulary in the basal ganglia. Conclusions: In older asymptomatic hypertensive subjects, hyperinsulinemia is associated with lacunar-type silent cortical infarcts, particularly white matter, while hemostatic abnormalities more often predispose to multiple sLCI in the basal ganglia. Perspective: Insulin resistance has been associated with hypertension, truncal obesity, higher levels of CRP, in-
ACC CURRENT JOURNAL REVIEW Jul/Aug 2001
28