- Email: [email protected]
Intensive diabetes therapy and carotid intima-media thickness in type-1 diabetes mellitus
significant neutropenia or thrombocytopenia attributable to ticlopidine. Conclusions: During a 2-year follow-up, there was no difference between ASA and ticlopidine in the prevention of recurrent stroke, MI or vascular events. However, there was a trend to reduction in fatal and non-fatal strokes with ASA. Perspective: Previous studies showed no advantage of ticlopidine over ASA in total primary end points in post-CVA patients but a slight advantage in recurrent strokes, which are so prevalent in blacks. The subset analysis prompted this study in blacks. The study was terminated by the safety and monitoring board because futility analysis showed ⬍1% likelihood of an advantage for ticlopidine and about a 50% likelihood of ASA for prevention of recurring strokes. There was an advantage of clopidogrel compared to ASA for the composite end points in CAPRIE, which evaluated post-MI, post-CVA and PVOD subjects, but CAPRIE was not powered to assess benefit for stroke alone. The clinician is left to choose from several platelet antagonist options in men and women. The therapeutic implication of the large number of small-vessel strokes, and the high prevalence of hypertension and diabetes in blacks is not clear. MR
(p⫽0.04), and 12 MIs occurred, 11 of which were in the group with CED (p⬍0.05). Conclusions: The presence of coronary endothelial dysfunction in patients without obstructive CAD is independently associated with cerebrovascular events. Perspective: Why would a measure of coronary endothelial function be associated with previous and subsequent strokes? The answer is not simply prevalence of classic risk factors. Arterial endothelial dysfunction is generalized and present in the normal coronary artery branches in persons with coronary obstructive disease. Would a reliable method of characterizing arterial endothelial function and pre-clinical atherosclerosis be more helpful for deciding who would benefit from aggressive preventive strategies than standard risk analysis? The NHLBI funded MESA study evaluating coronary calcification, carotid IMT/plaque volume, brachial reactivity and aortic elastance in healthy volunteers was designed to provide the answer by about 2008. MR
Intensive Diabetes Therapy and Carotid IntimaMedia Thickness in Type-1 Diabetes Mellitus The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. N Engl J Med 2003;348:2294 –303.
Coronary Endothelial Dysfunction Is Associated With an Increased Risk of Cerebrovascular Events
Study Question: In the Diabetes Control and Complications Trial (DCCT) in Type-1 DM, 6 years of intensive diabetic therapy reduced the risk of neuropathy and microvascular complications but not the CV complication rate, probably because of the relatively young age of the cohort. To determine the impact of glycemic control on atherosclerosis, the Epidemiology of Diabetes Interventions and Complications Study (EDIC) sought to determine the impact of therapy on the carotid intima-media thickness (IMT) in an extended observation period? Methods: 1 to 2 years after the completion of DCCT, a baseline IMT was obtained and repeated at 6-year follow-up in 1229 participants, who were also compared to 222 ageand gender-matched controls. Diabetic therapy during the extended 6 years of EDIC was recommended to be intensive and at the discretion of the attending physicians. Results: At 1 year of EDIC, mean age was 35⫾7 years, 20% were smokers, 55% were male and average duration of diabetes was 14 years. Mean BP was 115/75 mm Hg, cholesterol 188 mg/dL, trigs 90 mg/dL, LDL-C 115 mg/dL and HDL-C was 59 mg/dL in women and 49 mg/dL in men. In men during DCCT, the mean glycosylated Hgb was 7.2% on intensive treatment and 9% on standard therapy, and at year 1 of EDIC, 7.8 and 8.3%, respectively, and was similar in women. The common carotid (CCA) IMT in the control population was 0.58⫾0.10 mm, which did not differ from the diabetic cohort at EDIC year 1, but by year 6, the CCA and ICA IMT was greater in the diabetics for men and women after adjusting for smoking. There was significantly less progression of CCA IMT thickness among those who
Targonski PV, Bonetti PO, Pumper GM, Higano ST, Holmes DR, Lerman A. Circulation 2003;107:2805–9. Study Question: Is there a relationship between coronary endothelial dysfunction and cerebrovascular events (CVE)? Methods: 503 patients without obstructive CAD (no lesion ⱖ30% stenosis) underwent coronary endothelial function (CEF) testing with intracoronary acetylcholine (Ach) from 1992 to 2001. Coronary endothelial dysfunction (CED) was defined as ⱕ20% increase in epicardial vessel diameter or ⱕ50% increase in coronary blood flow with peak Ach dose. Medical records were reviewed for ischemic or hemorrhagic strokes or TIA prior to or following Ach testing. Results: The average age was 50, 40% were male, 16% smokers, 33% had hypertension, 40% hypercholesterolemia, 7% diabetes, 13% were taking a statin and 7% an ACEi and 10% had a previous MI. 305 patients (60%) had CED and 198 had normal CEF. Patients with CED were older, had higher BMI and otherwise did not differ from those with normal CEF. Average endothelial independent CFR to adenosine did not differ between those with normal and abnormal CEF. 25 CVEs were documented including 13 ischemic strokes, two hemorrhagic strokes and 10 TIAs. Twenty-two of the CVEs occurred in patients with CED and three with normal CEF (7.2% vs. 1.5%, p⫽0.008). CED was the strongest factor correlating with CVE (OR⫽4.32) when including traditional CVD risk factors. Over a 90month follow-up, seven patients experienced a CVE in those with CED vs. none in those with normal CEF
ACC CURRENT JOURNAL REVIEW Sep/Oct 2003
31
Conclusions: Contrary to earlier reports, hypertension prevalence is increasing in the US. Hypertension control rates, while improving, continue to be low. Programs targeting hypertension prevention and treatment are of utmost importance. Perspective: The relatively poor results occurred despite a major effort to enlighten the public and encourage detection and treatment by physicians with the publication of excellent guidelines. With the evidence from ALLHAT that very inexpensive diuretics can be first-line antihypertensive therapy, the next NHANES reporting period should be considerably better. Hypertension control is becoming more important as the population ages. MR
had been assigned intensive treatment and regression in the ICA such that the combined difference at 6 years was 0.162 mm (95% CI 0.031– 0.293, p⫽0.02). The results were similar by gender and lipid and blood pressure treatments. Other variables affecting change in CCA IMT were age, BMI, smoking, sBP, LDL-C, the log albumin excretion rate and glycosylated Hgb value. Similar variables affected ICA IMT with the exception of treatment group and BMI. Using multivariate analysis, the change in IMT correlated most with baseline IMT and age and not significantly with original DCCT treatment group. Conclusions: Intensive therapy during the DCCT resulted in decreased progression of carotid artery intima-media thickness 6 years after the end of the trial. Perspective: Carotid IMT correlates with coronary risk factors and cardiovascular events, but is not a good surrogate for atherosclerosis. The patients were too young to have measurable plaque volume, which begins at an IMT of 1.3 mm. Better glycemic control was associated with less progression and more frequent regression in IMT 6 years after study end. That there was so little difference in glycemic control between the original assignment groups during the extended follow-up period strengthens the meaning of the conclusion. MR
Genome-Wide Mapping of Human Loci for Essential Hypertension Caulfield M, Munroe P, Pembroke J, et al., for The MRC British Genetics of Hypertension Study. Lancet 2003;361:1118 –23. Study Question: To describe the results of a genome scan for hypertension in a large white European population. Methods: 2010 affected sibling pairs from 1599 severely hypertensive families underwent phenotyping and a 10 centimorgan (every 10 million bases) genome-wide scan. The families were identified to have at least two members with hypertension before age 60, with a blood pressure above the 95th percentile in the UK (⬎150/100 mm Hg in one or 145/95 mm Hg as an average of three readings). Anthropomorphic measures, an ECG, laboratory tests and 24-hour ambulatory BP were obtained on each participant. Patients consuming excessive alcohol (over 21 units per week), diabetes and renal disease were excluded. The genotypic data were analyzed by non-parametric linkage, which tests whether genes are shared in excess among the affected sibling pairs. Lod scores, calculated at regular points along each chromosome, were used to assess the support for linkage. Results: The mean age at the time of diagnosis of hypertension was 48 years and during phenotyping was 64 years. Mean BP was 172/104 mm Hg at the time of diagnosis and 156/94 during phenotyping. Average BMI was 27 kg/m2 (range 25–30) at baseline and waist to hip ratio 0.94 in men and 0.82 in women. At the time of phenotyping, 21% had a BMI ⬎30 kg/m2 most of whom had been “lean hypertensives” at diagnosis. Linkage analysis found a principle locus on chromosome 6q, with a lod score of 3.21 (p⫽0.042). The inclusion of three further loci with lod scores higher than 1.57 (2q, 5q and 9q) also showed genome wide significance (p⫽0.017). Conclusions: The findings imply that human essential hypertension has an oligogenic element (a few genes may be involved in determination of the trait), possibly superimposed on more minor genetic effects, and that several genes may be identified using a positional cloning strategy.
Trends in Prevalence, Awareness, Treatment and Control of Hypertension in the United States, 1988 –2000 Hajjar I, Kotchen TA. JAMA 2003;290:199 –206. Study Question: To describe trends in the prevalence, awareness, treatment and control of hypertension (Htn) in the United States. Methods: Compare trends in persons 18 years and older using the NHANES data survey in 1999 –2000 (n⫽5448), 1988 –1991 (n⫽9901) and 1991–1994 (n⫽9717). Htn was defined as a BP ⬎139/89 mm Hg or reported use of antihypertensive drugs. Control was defined as BP ⬍140/90 mm Hg. Results: In each of the three periods, about 75% were non-Hispanic white, 50% women, the mean age was about 44 and 40% were under 40 and 35% over 60 years old. In 1999 –2000, 7% were diabetic, a significant increase from the 5% in the two earlier periods. Mean BP in each period was 122/72 mm Hg. In 1999 –2000, 29% of participants had Htn, an increase of 3.7% (95% CI, 0%– 8.3%) from 1988 –1991. Htn prevalence was highest in non-Hispanic blacks (33.5%), increased with age (65% among those ⬎59 years) and was higher in women. Independent variables associated with Htn include race, age and increasing BMI. In 1999 –2000, nearly 70% were aware of their Htn, 58% were treated (a significant 6% increase) and BP was controlled in 31%, an increase of 6.4% (95% CI, 1.6 –11.2%). Women, Mexican-Americans and those ⬎59 years had significantly lower rates of control.
ACC CURRENT JOURNAL REVIEW Sep/Oct 2003
32
(p⫽0.04), and 12 MIs occurred, 11 of which were in the group with CED (p⬍0.05). Conclusions: The presence of coronary endothelial dysfunction in patients without obstructive CAD is independently associated with cerebrovascular events. Perspective: Why would a measure of coronary endothelial function be associated with previous and subsequent strokes? The answer is not simply prevalence of classic risk factors. Arterial endothelial dysfunction is generalized and present in the normal coronary artery branches in persons with coronary obstructive disease. Would a reliable method of characterizing arterial endothelial function and pre-clinical atherosclerosis be more helpful for deciding who would benefit from aggressive preventive strategies than standard risk analysis? The NHLBI funded MESA study evaluating coronary calcification, carotid IMT/plaque volume, brachial reactivity and aortic elastance in healthy volunteers was designed to provide the answer by about 2008. MR
Intensive Diabetes Therapy and Carotid IntimaMedia Thickness in Type-1 Diabetes Mellitus The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. N Engl J Med 2003;348:2294 –303.
Coronary Endothelial Dysfunction Is Associated With an Increased Risk of Cerebrovascular Events
Study Question: In the Diabetes Control and Complications Trial (DCCT) in Type-1 DM, 6 years of intensive diabetic therapy reduced the risk of neuropathy and microvascular complications but not the CV complication rate, probably because of the relatively young age of the cohort. To determine the impact of glycemic control on atherosclerosis, the Epidemiology of Diabetes Interventions and Complications Study (EDIC) sought to determine the impact of therapy on the carotid intima-media thickness (IMT) in an extended observation period? Methods: 1 to 2 years after the completion of DCCT, a baseline IMT was obtained and repeated at 6-year follow-up in 1229 participants, who were also compared to 222 ageand gender-matched controls. Diabetic therapy during the extended 6 years of EDIC was recommended to be intensive and at the discretion of the attending physicians. Results: At 1 year of EDIC, mean age was 35⫾7 years, 20% were smokers, 55% were male and average duration of diabetes was 14 years. Mean BP was 115/75 mm Hg, cholesterol 188 mg/dL, trigs 90 mg/dL, LDL-C 115 mg/dL and HDL-C was 59 mg/dL in women and 49 mg/dL in men. In men during DCCT, the mean glycosylated Hgb was 7.2% on intensive treatment and 9% on standard therapy, and at year 1 of EDIC, 7.8 and 8.3%, respectively, and was similar in women. The common carotid (CCA) IMT in the control population was 0.58⫾0.10 mm, which did not differ from the diabetic cohort at EDIC year 1, but by year 6, the CCA and ICA IMT was greater in the diabetics for men and women after adjusting for smoking. There was significantly less progression of CCA IMT thickness among those who
Targonski PV, Bonetti PO, Pumper GM, Higano ST, Holmes DR, Lerman A. Circulation 2003;107:2805–9. Study Question: Is there a relationship between coronary endothelial dysfunction and cerebrovascular events (CVE)? Methods: 503 patients without obstructive CAD (no lesion ⱖ30% stenosis) underwent coronary endothelial function (CEF) testing with intracoronary acetylcholine (Ach) from 1992 to 2001. Coronary endothelial dysfunction (CED) was defined as ⱕ20% increase in epicardial vessel diameter or ⱕ50% increase in coronary blood flow with peak Ach dose. Medical records were reviewed for ischemic or hemorrhagic strokes or TIA prior to or following Ach testing. Results: The average age was 50, 40% were male, 16% smokers, 33% had hypertension, 40% hypercholesterolemia, 7% diabetes, 13% were taking a statin and 7% an ACEi and 10% had a previous MI. 305 patients (60%) had CED and 198 had normal CEF. Patients with CED were older, had higher BMI and otherwise did not differ from those with normal CEF. Average endothelial independent CFR to adenosine did not differ between those with normal and abnormal CEF. 25 CVEs were documented including 13 ischemic strokes, two hemorrhagic strokes and 10 TIAs. Twenty-two of the CVEs occurred in patients with CED and three with normal CEF (7.2% vs. 1.5%, p⫽0.008). CED was the strongest factor correlating with CVE (OR⫽4.32) when including traditional CVD risk factors. Over a 90month follow-up, seven patients experienced a CVE in those with CED vs. none in those with normal CEF
ACC CURRENT JOURNAL REVIEW Sep/Oct 2003
31
Conclusions: Contrary to earlier reports, hypertension prevalence is increasing in the US. Hypertension control rates, while improving, continue to be low. Programs targeting hypertension prevention and treatment are of utmost importance. Perspective: The relatively poor results occurred despite a major effort to enlighten the public and encourage detection and treatment by physicians with the publication of excellent guidelines. With the evidence from ALLHAT that very inexpensive diuretics can be first-line antihypertensive therapy, the next NHANES reporting period should be considerably better. Hypertension control is becoming more important as the population ages. MR
had been assigned intensive treatment and regression in the ICA such that the combined difference at 6 years was 0.162 mm (95% CI 0.031– 0.293, p⫽0.02). The results were similar by gender and lipid and blood pressure treatments. Other variables affecting change in CCA IMT were age, BMI, smoking, sBP, LDL-C, the log albumin excretion rate and glycosylated Hgb value. Similar variables affected ICA IMT with the exception of treatment group and BMI. Using multivariate analysis, the change in IMT correlated most with baseline IMT and age and not significantly with original DCCT treatment group. Conclusions: Intensive therapy during the DCCT resulted in decreased progression of carotid artery intima-media thickness 6 years after the end of the trial. Perspective: Carotid IMT correlates with coronary risk factors and cardiovascular events, but is not a good surrogate for atherosclerosis. The patients were too young to have measurable plaque volume, which begins at an IMT of 1.3 mm. Better glycemic control was associated with less progression and more frequent regression in IMT 6 years after study end. That there was so little difference in glycemic control between the original assignment groups during the extended follow-up period strengthens the meaning of the conclusion. MR
Genome-Wide Mapping of Human Loci for Essential Hypertension Caulfield M, Munroe P, Pembroke J, et al., for The MRC British Genetics of Hypertension Study. Lancet 2003;361:1118 –23. Study Question: To describe the results of a genome scan for hypertension in a large white European population. Methods: 2010 affected sibling pairs from 1599 severely hypertensive families underwent phenotyping and a 10 centimorgan (every 10 million bases) genome-wide scan. The families were identified to have at least two members with hypertension before age 60, with a blood pressure above the 95th percentile in the UK (⬎150/100 mm Hg in one or 145/95 mm Hg as an average of three readings). Anthropomorphic measures, an ECG, laboratory tests and 24-hour ambulatory BP were obtained on each participant. Patients consuming excessive alcohol (over 21 units per week), diabetes and renal disease were excluded. The genotypic data were analyzed by non-parametric linkage, which tests whether genes are shared in excess among the affected sibling pairs. Lod scores, calculated at regular points along each chromosome, were used to assess the support for linkage. Results: The mean age at the time of diagnosis of hypertension was 48 years and during phenotyping was 64 years. Mean BP was 172/104 mm Hg at the time of diagnosis and 156/94 during phenotyping. Average BMI was 27 kg/m2 (range 25–30) at baseline and waist to hip ratio 0.94 in men and 0.82 in women. At the time of phenotyping, 21% had a BMI ⬎30 kg/m2 most of whom had been “lean hypertensives” at diagnosis. Linkage analysis found a principle locus on chromosome 6q, with a lod score of 3.21 (p⫽0.042). The inclusion of three further loci with lod scores higher than 1.57 (2q, 5q and 9q) also showed genome wide significance (p⫽0.017). Conclusions: The findings imply that human essential hypertension has an oligogenic element (a few genes may be involved in determination of the trait), possibly superimposed on more minor genetic effects, and that several genes may be identified using a positional cloning strategy.
Trends in Prevalence, Awareness, Treatment and Control of Hypertension in the United States, 1988 –2000 Hajjar I, Kotchen TA. JAMA 2003;290:199 –206. Study Question: To describe trends in the prevalence, awareness, treatment and control of hypertension (Htn) in the United States. Methods: Compare trends in persons 18 years and older using the NHANES data survey in 1999 –2000 (n⫽5448), 1988 –1991 (n⫽9901) and 1991–1994 (n⫽9717). Htn was defined as a BP ⬎139/89 mm Hg or reported use of antihypertensive drugs. Control was defined as BP ⬍140/90 mm Hg. Results: In each of the three periods, about 75% were non-Hispanic white, 50% women, the mean age was about 44 and 40% were under 40 and 35% over 60 years old. In 1999 –2000, 7% were diabetic, a significant increase from the 5% in the two earlier periods. Mean BP in each period was 122/72 mm Hg. In 1999 –2000, 29% of participants had Htn, an increase of 3.7% (95% CI, 0%– 8.3%) from 1988 –1991. Htn prevalence was highest in non-Hispanic blacks (33.5%), increased with age (65% among those ⬎59 years) and was higher in women. Independent variables associated with Htn include race, age and increasing BMI. In 1999 –2000, nearly 70% were aware of their Htn, 58% were treated (a significant 6% increase) and BP was controlled in 31%, an increase of 6.4% (95% CI, 1.6 –11.2%). Women, Mexican-Americans and those ⬎59 years had significantly lower rates of control.
ACC CURRENT JOURNAL REVIEW Sep/Oct 2003
32