Obstructive sleep apnea is associated with future subclinical carotid artery disease: thirteen-year follow-up from the Wisconsin sleep cohort.

OBJECTIVE: To determine the longitudinal associations between obstructive sleep apnea, carotid artery intima-media thickness (IMT), and plaque. APPROACH AND RESULTS: This is a population-based, prospective cohort study conducted from July, 1989, to November, 2012, on 790 randomly selected Wisconsin residents who completed a mean of 3.5 (range, 1-6) polysomnograms during the study period. Obstructive sleep apnea was characterized by the apnea-hypopnea index (AHI, events/h). Common carotid artery IMT and plaque were assessed by B-mode ultrasound. The mean (SD) time from the first polysomnograms to carotid ultrasound was 13.5 (3.6) years. Multivariable regression models were created to estimate the independent associations of baseline and cumulative obstructive sleep apnea exposure with subsequent carotid IMT and plaque. At baseline, the mean age of participants was 47.6 (7.7) years (55% men, 97% white). AHI was 4.4 (9.0) events/h (range, 0-97); 7% had AHI >15 events/h. Carotid IMT was 0.755 (0.161) mm; 63% had plaque. Adjusting for age, sex, body mass index, systolic blood pressure, smoking, and use of lipid-lowering, antihypertensive, and antidiabetic medications, baseline AHI independently predicted future carotid IMT (ß=0.027 mm/unit log10[AHI+1]; P=0.049), plaque presence (odds ratio, 1.55 [95% confidence intervals, 1.02-2.35]; P=0.041) and plaque score (odds ratio, 1.30 [1.05-1.61]; P=0.018). In cumulative risk factor-adjusted models, AHI independently predicted future carotid plaque presence (P=0.012) and score (P=0.039), but not IMT (P=0.608). CONCLUSIONS: Prevalent obstructive sleep apnea is independently associated with increased carotid IMT and plaque more than a decade later, indicating increased future cardiovascular disease risk.

Effects of an office-based carotid ultrasound screening intervention.

BACKGROUND: Carotid ultrasound screening (CUS) has been recommended for cardiovascular disease risk prediction, but its effectiveness in clinical practice is unknown. The purpose of this study was to prospectively determine the effects of office-based CUS on physician decision making and patient health-related behaviors. METHODS: Physicians from five nonacademic, community practices recruited patients aged ≥40 years with ≥1 cardiovascular disease risk factor. Abnormal results on CUS (AbnlCUS) were defined as carotid intima-media thickness >75th percentile or carotid plaque presence. Subjects completed questionnaires before and immediately after CUS and then 30 days later to determine self-reported behavioral changes. Odds ratios (ORs) for changes in physician management and patient health-related behaviors were determined from multivariate hierarchical logistic regression models. RESULTS: There were 355 subjects (mean age, 53.6 ± 7.9 years; mean number of risk factors, 2.3 ± 0.9; 58% women); 266 (74.9%) had AbnlCUS. The presence of AbnlCUS altered physicians' prescription of aspirin (P < .001) and cholesterol medications (P < .001). Immediately after CUS, subjects reported increased ability to change health-related behaviors (P = .002), regardless of their test results. Subjects with AbnlCUS reported increased cardiovascular disease risk perception (OR, 4.14; P < .001) and intentions to exercise (OR, 2.28; P = .008), make dietary changes (OR, 2.95; P < .001), and quit smoking (OR, 4.98; P = .022). After 30 days, 34% increased exercise frequency and 37% reported weight loss, but these changes were not predicted by the CUS results. AbnlCUS modestly predicted reduced dietary sodium (OR, 1.45; P = .002) and increased fiber (OR, 1.55; P = .022) intake. CONCLUSIONS: Finding abnormal results on CUS had major effects on physician but not patient behaviors.

Effects of smoking and smoking cessation on endothelial function: 1-year outcomes from a randomized clinical trial.

OBJECTIVES: The purpose of this study was to determine whether smoking cessation improves flow-mediated dilation (FMD) of the brachial artery. BACKGROUND: The long-term effects of continued smoking and smoking cessation on endothelial function have not been described previously. METHODS: This was a 1-year, prospective, double-blind, randomized, placebo-controlled clinical trial of the effects of 5 smoking cessation pharmacotherapies. FMD was measured by B-mode ultrasonography before and 1 year after the target smoking cessation date. Cessation was verified by exhaled carbon monoxide levels. DeltaFMD was compared among study arms and between subjects who successfully quit smoking and those who continued to smoke. Predictors of baseline FMD and DeltaFMD were identified by multivariable regression. RESULTS: The 1,504 current smokers (58% female, 84% white) were 44.7 +/- 11.1 years of age and smoked 21.4 +/- 8.9 cigarettes/day. Baseline FMD was similar in each treatment arm (p = 0.499) and was predicted by BA diameter (p < 0.001), reactive hyperemia blood flow (p < 0.001), high-density lipoprotein cholesterol (p = 0.001), and carbon monoxide (p = 0.012) levels. After 1 year, 36.2% quit smoking. FMD increased by 1% (6.2 +/- 4.4% to 7.2 +/- 4.2%) after 1 year (p = 0.005) in those who quit, but did not change (p = 0.643) in those who continued to smoke. Improved FMD among quitters remained significant (p = 0.010) after controlling for changes in brachial artery diameter, reactive hyperemia, low-density lipoprotein cholesterol, and the presence of a home smoking ban. CONCLUSIONS: Despite weight gain, smoking cessation leads to prolonged improvements in endothelial function, which may mediate part of the reduced cardiovascular disease risk observed after smoking cessation. (Smoking Cessation Medications: Efficacy, Mechanisms and Algorithms; NCT00332644).

Left atrial volume is associated with inflammation and atherosclerosis in patients with kidney disease.

BACKGROUND: Left atrial volume (LAV) is an independent echocardiographic predictor of cardiovascular events in the general population. We evaluated predictors of LAV in patients with advanced chronic kidney disease (CKD). HYPOTHESIS: Increasing LAV identifies increased cardiovascular risk in patients with CKD. METHODS: Transthoracic echocardiography was performed in CKD patients undergoing cardiovascular evaluation prior to listing for renal transplantation. LAV was measured using the biplane area-length formula and indexed for body surface area. Carotid intima-media thickness was assessed by B-mode ultrasound. Lipoproteins were measured by nuclear magnetic resonance spectroscopy. Values are presented as mean (standard deviation). Relationships with LAV were evaluated using univariate and multivariable regression analyses. RESULTS: There were 99 participants (80% white, 68% male). Their mean age was 55.7 (9.3) years. Significant correlates of LAV were systolic blood pressure (r = 0.24), C-reactive protein (r = 0.29), carotid intima-media thickness (r = 0.29), peak transmitral E-wave (r = 0.38), and severity of mitral regurgitation (r = 0.23, P < 0.05 for all). LAV also was higher among individuals with a history of stroke (45 mL/m2 vs 36.3 mL/m2, P = 0.04) and with >75% stenosis on coronary angiography (38.4 mL/m2 vs 31.8 mL/m2, P = 0.03). In regression models, high sensitivity CRP (hs-CRP), the transmitral E-wave velocity, and a history of stroke independently predicted LAV (P < or = 0.05). CONCLUSION: In individuals with advanced CKD, LAV is associated with inflammation, increased early transmitral filling velocities, and atherosclerosis. These findings may indicate increased cardiovascular risk with increasing LAV in patients with CKD.

Mitral annular calcification is associated with reduced left ventricular function and inflammation in patients with chronic kidney disease.

BACKGROUND: Mitral annular calcification (MAC) is prevalent in patients with chronic kidney disease (CKD); however, it is not known whether the increased cardiovascular risk observed in patients with CKD and MAC is related to atherosclerotic burden, because they share common risk factors. METHODS: Transthoracic echocardiography was performed in patients with CKD undergoing pre-kidney transplantation evaluation. Fasting lipids, high-sensitivity C-reactive protein, parathyroid hormone, calcium, and creatinine levels were measured. RESULTS: Of 99 participants, the 31 with MAC had higher carotid intima-media thickness (P = .004), lower left ventricular ejection fraction (P = .016), and higher high-sensitivity C-reactive protein (P = .01). MAC was predicted independently by increasing high-sensitivity C-reactive protein, decreasing left ventricular ejection fraction, and not being on dialysis (likelihood ratio 21.8, P < .001). Models were not affected significantly by the addition of age, carotid intima-media thickness, and other laboratory tests. CONCLUSIONS: In patients with CKD, MAC is associated with inflammation, reduced left ventricular function, and treatment with dialysis, independent of the degree of subclinical atherosclerosis.

An abbreviated carotid intima-media thickness scanning protocol to facilitate clinical screening for subclinical atherosclerosis.

BACKGROUND: Carotid intima-media thickness (CIMT) testing can assist with cardiovascular risk prediction; however, the requirement for rigorous, time-consuming protocols has limited it use in clinical practice. METHODS: Bilateral images of the common carotid artery (CCA), bulb, and internal carotid artery segments were obtained using a comprehensive scanning protocol. Three abbreviated scanning protocols were evaluated for their ability to identify patients with increased CIMT (> or = 75th percentile). RESULTS: Of 261 subjects, 134 (51.3%) had increased left or right CCA CIMT (CCA protocol), 136 (52.1%) had carotid plaque (plaque protocol), and 190 (72.7%) had plaque or at least one increased CCA CIMT (combination protocol). The area under the receiver-operator characteristic curves for the CCA (0.738) and combination protocols (0.692) were higher than the plaque protocol (0.625, P < .05). The combination protocol was 100% sensitive. CONCLUSIONS: Compared with a comprehensive scanning protocol, plaque screening with measurement of far wall CCA CIMT identifies all patients with increased CIMT.

Coronary flow velocity changes in response to hypercapnia: assessment by transthoracic Doppler echocardiography.

BACKGROUND: The effects of hypercapnia on coronary arteries in human beings are not known. We used transthoracic Doppler echocardiography to evaluate coronary blood flow velocity (CFV) changes in response to hypercapnia in healthy adults. METHODS: Twenty adults underwent transthoracic Doppler echocardiography of the left anterior descending coronary artery while breathing room air, 40% fraction of inspired oxygen, and 40% fraction of inspired oxygen with carbon dioxide supplemented to end-tidal tensions of +5, +7.5, and +10 mm Hg above baseline. RESULTS: Mean (SD) diastolic peak CFV values for these conditions were 23.1 (9.1), 23.0 (9.0), 25.5 (9.3), 27.9 (11.5), and 31.5 (13.0) cm/s, respectively. Significant overall differences between conditions (P < .001) and progressive levels of hypercapnia (P < or = .01) were observed. CFV increases remained significant after adjusting for increases in cardiac output (P = .038). CONCLUSIONS: CFV increases with hypercapnia. This is the first report of human coronary artery flow responses to hypercapnia. Transthoracic Doppler echocardiography methodology is feasible for measuring CFV and the effects of hypercapnia on the coronary circulation.

Is the ankle-brachial index a useful screening test for subclinical atherosclerosis in asymptomatic, middle-aged adults?

BACKGROUND: Measurement of the ankle-brachial index (ABI) is recommended as a screening test for cardiovascular risk prediction in individuals > or = 50 years old; however, there is little data regarding the utility of the ABI as a screening test in individuals for whom physicians actually order non-invasive testing for cardiovascular risk prediction. METHODS: This study included 493 consecutive asymptomatic patients without known atherosclerotic vascular disease who were referred by their physician for measurement of the ABI and ultrasound measurement of carotid intima-media thickness (CIMT). ABI values were classified as "reduced" (<0.9), "normal" (0.9-1.3), and "increased" (>1.3). RESULTS: The mean age of the patients was 55.3 (standard deviation 7.5) years. Only 1 patient had a reduced ABI (0.2%). ABI values tended to be higher in those with increased CIMT (P=0.051); however, CIMT was not significantly different between those with normal and increased ABI values (P=0.802). There were no significant differences in the prevalence of traditional cardiovascular risk factors or carotid plaque presence among the ABI groups. CONCLUSIONS: Despite recommendations, the ABI is not sensitive as a screening tool for detecting subclinical atherosclerosis in asymptomatic middle-aged individuals.

Use of carotid intima-media thickness and vascular age to modify cardiovascular risk prediction.

BACKGROUND: This study identified predictors of patients for whom carotid artery intima-media thickness (CIMT) measurement and determination of vascular age could change cardiovascular disease (CVD) risk assessment. METHODS: We studied consecutive patients who were asymptomatic and nondiabetic, referred for ultrasound measurement of CIMT. Individuals with CIMT 75th percentile or greater for age, sex, and race were defined as having advanced subclinical atherosclerosis. CIMT values were converted to vascular age estimates and were used to modify Framingham 10-year CVD risk estimates. RESULTS: Of 506 patients, 261 (51.6%) were not taking lipid-lowering therapy. Advanced subclinical atherosclerosis was present in 77 (30%). There were 62 patients (23.8%) with a change in CVD risk of 5% or more. Predictors of 5% or more change in CVD risk were systolic blood pressure (P < .001), total/high-density lipoprotein cholesterol ratio (P < .001), and male sex (P < .001). Of the 97 patients at moderate or moderately high risk, 56.7% changed risk classification. CONCLUSIONS: Measurement of CIMT and determination of vascular age can identify individuals with advanced subclinical atherosclerosis, resulting in clinically meaningful alterations in CVD risk estimates.

Use of hand-held ultrasound by a nonsonographer clinician to measure carotid intima-media thickness.

OBJECTIVE: We sought to evaluate the accuracy of carotid intima-media thickness (CIMT) measurements by a nonsonographer clinician using hand-held ultrasound (HHU). BACKGROUND: Use of a HHU for point-of-care CIMT measurement has not been tested previously. METHODS: Participants underwent reference ultrasound and HHU studies. HHU validity was tested by an expert sonographer. Nonsonographer clinician accuracy using the HHU was tested against the expert sonographer. CIMT bioequivalence was tested with .5 pixel limits. RESULTS: The 75 participants were (mean [SD]) 55 [7] years old. CIMT values were bioequivalent (0.714 [0.029] vs 0.685 [0.029] mm, phase I; 0.697 [0.015] vs 0.687 [0.015] mm, phase II; P(two 1-sided t test) < .05). Agreement was 80% for CIMT classifications (intraclass correlation coefficient = 0.451, P < .001) and 90% for plaque presence (intraclass correlation coefficient = 0.797, P < .001). CONCLUSIONS: CIMT measured by HHU was bioequivalent to a reference ultrasound system, when used by an expert sonographer or nonsonographer clinician. Clinical classifications by CIMT quartile and plaque presence were similar. HHU may be suitable for office-based atherosclerosis screening.

Validation of a carotid intima-media thickness border detection program for use in an office setting.

BACKGROUND: A unique semiautomated border detection program (BDP) designed for use on a personal computer was evaluated to determine whether: (1) carotid intima-media thickness (CIMT) measurements were bioequivalent to a reference laboratory; and (2) it would allow a novice (NOV) reader with no medical training to accurately and reproducibly measure CIMT. METHODS: Far-wall CIMT was measured blindly and in duplicate by an experienced and NOV reader using BDP and by a reference laboratory. RESULTS: Mean CIMT using BDP was bioequivalent to the reference laboratory (two 1-sided T-test, P < .05) with small absolute differences (experienced 0.011 +/- 0.004 mm, NOV 0.022 +/- 0.004 mm). Reproducibility was high, with small coefficients of variation when used by either the experienced (3.1%) or NOV (7.8%) reader. CONCLUSION: CIMT measurements using BDP were accurate and reproducible. It was mastered easily by a NOV reader and appeared suitable for use in an office setting.

Skin cholesterol content identifies increased carotid intima-media thickness in asymptomatic adults.

BACKGROUND: A noninvasive assay to measure skin Tc recently has become available for use in the outpatient setting as a cardiovascular (CV) risk prediction tool. The purpose of this study was to determine whether skin tissue cholesterol content (skin Tc) levels are associated with increased carotid intima-media thickness (CIMT) after adjusting for known CV risk factors and Framingham CV risk. METHODS: Consecutive patients without known vascular disease who were referred for determination of CIMT underwent B-mode ultrasonography of the carotid arteries and measurement of skin Tc using a noninvasive assay. Use of medications, cardiac risk factors, and Framingham 10-year CV risk were determined prospectively. Multivariable regression was used to determine predictors of increased CIMT. RESULTS: Among 81 subjects, the mean (SD) age was 55.6 (7.7) years and the mean skin Tc was 95.9 (18.3) U. Carotid intima-media thickness was significantly higher among individuals in the highest quartile of skin Tc (0.87 vs 0.76 mm, P = .011). In multivariable analyses, skin Tc was associated with increased CIMT even after adjusting for age, sex, glucose, systolic blood pressure, total/high-density lipoprotein cholesterol ratio, and use of lipid-lowering therapy (odds ratio [OR] per 10-unit increase = 1.590, 95% CI 1.525-1.658, P = .031). Skin Tc also was associated with increased CIMT after adjustment for Framingham risk (OR = 1.341, 95% CI 1.302-1.380, P = .048). CONCLUSIONS: Skin Tc is an easy-to-measure, noninvasive marker that can help identify subclinical atherosclerosis in asymptomatic middle-aged adults, even after controlling for risk factors and CV risk predicted by the Framingham model.

Ultrasound-detected carotid plaque as a screening tool for advanced subclinical atherosclerosis.

BACKGROUND: There is great need for a simple, noninvasive tool that can be used in an office setting to screen for subclinical atherosclerosis. In patients referred for cardiovascular (CV) risk assessment, we evaluated the ability of ultrasound screening for carotid plaque to identify patients with advanced subclinical atherosclerosis. METHODS: Consecutive asymptomatic patients without vascular disease referred by their physician for measurement of the ankle-brachial pressure index and carotid intima-media thickness (CIMT) were included. Carotid intima-media thickness was measured using the standardized ultrasound protocol from the Atherosclerosis Risk in Communities (ARIC) study. Advanced atherosclerosis was defined as CIMT > or = 75th percentile for age, sex, and race in ARIC. RESULTS: The mean age of the 327 subjects was 55.4 years (SD 7.7 years). The 10-year Framingham CV risk was 5.1% (4.8%). In a multiple logistic regression model that included Framingham CV risk, ankle-brachial pressure index, and use of lipid-lowering medications, plaque presence significantly predicted advanced atherosclerosis (odds ratio 3.08, 95% CI 1.91-4.96, P < .001). In stepwise regression models that included age, body mass index, current tobacco use, family history of premature CV disease, fasting glucose, sex, systolic blood pressure, total/high-density lipoprotein cholesterol ratio, and use of antihypertensive and lipid-lowering medications, plaque presence independently predicted advanced atherosclerosis (P < .001). CONCLUSION: Ultrasound detection of carotid plaque helped identify asymptomatic patients with advanced subclinical atherosclerosis. Screening for carotid plaque is easier than determination of CIMT and may help detect asymptomatic patients at increased CV risk.

Effects of multivitamins and low-dose folic acid supplements on flow-mediated vasodilation and plasma homocysteine levels in older adults.

BACKGROUND: Hyperhomocysteinemia is associated with aging, endothelial dysfunction, and increased risk of coronary heart disease in older adults; however, the effects of homocysteine-lowering therapy on vascular reactivity in older persons are unknown. The objective of this study was to determine the effects of multivitamins (MV) and folic acid (FA) supplements on flow-mediated vasodilation (FMD) in older adults. METHODS: Individuals > or =70 years old with homocysteine levels > or =10 micromol/L were recruited for this 40-week, prospective, single-blinded study. All subjects were treated sequentially, with each of the following daily therapies for 10 weeks: (1) placebo, (2) MV (400 microg FA, 6 mg vitamin B6, 25 microg vitamin B12), (3) placebo, then (4) MV + FA (total FA, 1400 microg). FMD, folate intake, and laboratory values were measured at each visit. Investigators were blinded to subject treatment phase when measuring vessel diameters and calculating FMD. RESULTS: Twenty subjects (mean +/- SEM age, 78.0 +/- 1.2 [range, 70 to 88] years, 9 women) completed the MV and 17 completed the MV + FA interventions. FMD was impaired at baseline (2.0% +/- 1.2%). During the 40-week study, homocysteine levels decreased by 1.4 +/- 0.9 micromol/L (p(trend) = 0.034) from a baseline of 12.8 +/- 0.6 micromol/L; however, FMD did not change significantly (p(trend) = 0.874). FMD did not improve after therapy with MV alone (3.0% +/- 0.9% [week 10] vs 2.4% +/- 1.1% [week 20], P =.716) or with MV + FA (2.6% +/- 0.9% [week 30] vs 1.9% +/- 0.7% [week 40], P =.484). CONCLUSIONS: At doses commonly prescribed in clinical practice, MV and FA supplements did not improve FMD in older adults with hyperhomocysteinemia.

Vascular age: integrating carotid intima-media thickness measurements with global coronary risk assessment.

BACKGROUND: An imaging test that quantifies atherosclerotic burden and that can be integrated with existing risk stratification paradigms would be a very useful clinical tool. HYPOTHESIS: Measurement of carotid intima-media thickness (CIMT) is feasible in a clinical setting. Such measurements can be integrated into coronary risk assessment models. METHODS: Carotid intima-media thickness was measured by B-mode ultrasound in 82 consecutive patients without manifest atherosclerotic vascular disease. The values were used to determine "vascular age" (VA) based on nomograms from the Atherosclerosis Risk in Communities study. Vascular age was substituted for chronological age and standard and vascular age-adjusted 10-year coronary heart disease (CHD) risk estimates were compared. RESULTS: The mean chronological age was 55.8 +/- 9.0 years. The mean VA using CIMT was 65.5 +/- 18.9 years (p < 0.001). The Framingham 10-year hard CHD risk estimate was 6.5 +/- 4.9%. Substituting CIMT-derived VA for chronological age increased the 10-year CHD risk estimate to 8.0 +/- 6.8% (p < 0.001). Of 14 subjects initially at intermediate risk, 5 (35.7%) were reclassified as higher risk and 2 (14.3%) were reclassified as lower risk. Significant predictors of reclassification were tobacco use, high-density lipoprotein cholesterol, systolic blood pressure, and low-density lipoprotein cholesterol. CONCLUSIONS: Measurement of CIMT, a noninvasive estimate of current atherosclerotic burden, is feasible in a clinical setting and can be integrated into CHD risk assessment models. Determining VA using CIMT values may help individualize the age component of population-based CHD risk estimates. This strategy should be tested in a large trial with hard clinical endpoints.

Effects of pravastatin on lipoproteins and endothelial function in patients receiving human immunodeficiency virus protease inhibitors.

BACKGROUND: Although recommended as initial therapy for patients with dyslipidemia who are taking human immunodeficiency virus protease inhibitors (HIV PIs), the effects of pravastatin on lipoproteins and arterial reactivity have not been elucidated. The purpose of this study was to determine the effects of pravastatin on lipoprotein subfractions and endothelial function in patients with dyslipidemia who are receiving HIV PIs. METHODS: This was a placebo-controlled, double-blind, crossover study comparing pravastatin (40 mg) to placebo in 20 patients who were taking HIV PIs. Lipoprotein subfractions were measured with nuclear magnetic resonance spectroscopic analysis. Flow-mediated vasodilation (FMD) of the brachial artery was evaluated with high-resolution ultrasound scanning. RESULTS: At baseline, subjects had an increased concentration of low-density lipoprotein (LDL) particles (1756 +/- 180 nmol/L), which tended to be small (19.9 +/- 0.2 nm), a low concentration of large high-density lipoproteins (HDL; 0.94 +/- 0.07 mmol/L), and an increased concentration of large very low-density lipoproteins (VLDL; 1.90 +/- 0.58 mmol/L). FMD was impaired (4.5% +/- 1.1%). Compared with placebo, pravastatin resulted in a 20.8% reduction in LDL particles (P =.030), a 26.7% reduction in small LDL (P =.100), and a 44.9% reduction in small VLDL (P =.023). Total and non-HDL cholesterol levels decreased by 18.3% (P <.001) and 21.7% (P <.001), respectively. FMD tended to increase in patients receiving pravastatin (0.7% +/- 0.6%); however, the difference between treatment phases was not statistically significant (P =.080). CONCLUSIONS: This is the first double-blind, placebo-controlled study of the effects of statin therapy on lipids, lipoprotein subfractions, and endothelial function in patients taking HIV PIs. Pravastatin reduced concentrations of atherogenic lipoproteins, particularly those most associated with future coronary events.