- Email: [email protected]
Chronic infections and the risk of carotid atherosclerosis. Prospective results from a large population study
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
Perspectives: This study lends further support to the infection/inflammation story and supports a role for the cardiologist to encourage both patients and primary care physicians to include chronic infection (with or without an increased CRP) as a possible preventable risk factor. MR
Results: 237 index cases were identified and their 5442 family members underwent genetic screening. 945 men and 1094 women had a LDL-receptor gene mutation. The average LDL-C in carriers was 218⫾64 mg/dL and 138⫾43 mg/dL in non-carriers. About 50% of carriers vs. 10% of non-carriers were aware of their cholesterol, and 39% of carriers vs. 5% of non-carriers were on a statin. One year after screening, 93% of those with hypercholesterolemia were being treated. The best available cut-point for total cholesterol to diagnose FH in family members of index cases was the age-gender adjusted 90th percentile, which resulted in 18% false positives and 18% false negatives. The probability of FH was 0.6 for cholesterol above the 90th percentile vs. 0.08 for those below this value. Conclusions: Targeted family screening with DNA analysis was effective in identifying patients with hypercholesterolemia. Most of the identified patients sought treatment. The findings could have wider relevance for the screening of other prevalent genetic disorders. Perspectives: The findings are consistent with other similar studies, but genetic screening is of little relevance in health care systems in which cholesterol screening is standard of care. Selective genetic screening for FH and apo E genotyping can be useful to lipid specialists in the diagnosis and treatment of complex and inheritable lipid disorders and for family counseling. MR
Review of First 5 Years of Screening for Familial Hypercholesterolemia in The Netherlands Umans-Eckenhausen MAW, Defesche JC, Sijbrands EJG, Scheerder RLJM, Kastelein JJP. Lancet 2001;357:165– 8. Study Question: Familial hypercholesterolemia (FH) is characterized by a mutation in the gene responsible for LDL receptors and results in decreased LDL particle clearance, very high levels of total and LDL cholesterol (LDL-C) and premature coronary artery disease (CAD). This study sought to measure the impact of a genetic screening program on patient care and to determine the best cholesterol and LDL-C values for detecting persons with genetically confirmed FH. Methods: Lipid center patients in The Netherlands with markedly elevated LDL-C levels and abnormalities such as tendinous xanthomas were screened for LDL receptor mutations by leukocyte genomic DNA using PCR. Fasting lipid profiles were available in the first 1129 consecutive persons screened and not being treated.
ACC CURRENT JOURNAL REVIEW Jul/Aug 2001
29
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
Perspectives: This study lends further support to the infection/inflammation story and supports a role for the cardiologist to encourage both patients and primary care physicians to include chronic infection (with or without an increased CRP) as a possible preventable risk factor. MR
Results: 237 index cases were identified and their 5442 family members underwent genetic screening. 945 men and 1094 women had a LDL-receptor gene mutation. The average LDL-C in carriers was 218⫾64 mg/dL and 138⫾43 mg/dL in non-carriers. About 50% of carriers vs. 10% of non-carriers were aware of their cholesterol, and 39% of carriers vs. 5% of non-carriers were on a statin. One year after screening, 93% of those with hypercholesterolemia were being treated. The best available cut-point for total cholesterol to diagnose FH in family members of index cases was the age-gender adjusted 90th percentile, which resulted in 18% false positives and 18% false negatives. The probability of FH was 0.6 for cholesterol above the 90th percentile vs. 0.08 for those below this value. Conclusions: Targeted family screening with DNA analysis was effective in identifying patients with hypercholesterolemia. Most of the identified patients sought treatment. The findings could have wider relevance for the screening of other prevalent genetic disorders. Perspectives: The findings are consistent with other similar studies, but genetic screening is of little relevance in health care systems in which cholesterol screening is standard of care. Selective genetic screening for FH and apo E genotyping can be useful to lipid specialists in the diagnosis and treatment of complex and inheritable lipid disorders and for family counseling. MR
Review of First 5 Years of Screening for Familial Hypercholesterolemia in The Netherlands Umans-Eckenhausen MAW, Defesche JC, Sijbrands EJG, Scheerder RLJM, Kastelein JJP. Lancet 2001;357:165– 8. Study Question: Familial hypercholesterolemia (FH) is characterized by a mutation in the gene responsible for LDL receptors and results in decreased LDL particle clearance, very high levels of total and LDL cholesterol (LDL-C) and premature coronary artery disease (CAD). This study sought to measure the impact of a genetic screening program on patient care and to determine the best cholesterol and LDL-C values for detecting persons with genetically confirmed FH. Methods: Lipid center patients in The Netherlands with markedly elevated LDL-C levels and abnormalities such as tendinous xanthomas were screened for LDL receptor mutations by leukocyte genomic DNA using PCR. Fasting lipid profiles were available in the first 1129 consecutive persons screened and not being treated.
ACC CURRENT JOURNAL REVIEW Jul/Aug 2001
29