Analysis of stress-only imaging, comparing upright and supine CZT camera acquisition to conventional gamma camera images with and without attenuation correction, with coronary angiography as a reference.

BACKGROUND: Diagnostic performance of stress-only imaging using a Cadmium-Zinc-Telluride (CZT) camera has not been directly compared in the same patients to stress-only attenuation-corrected conventional Anger camera images. METHODS: 112 subjects with correlative coronary angiographic data and 40 subjects with <5% pre-test likelihood of coronary disease completed attenuation-corrected stress-only images on a conventional Anger camera and uncorrected upright and supine stress images on a CZT camera. Two readers provided independent, blinded interpretations of stress-only images. RESULTS: Upright and supine stress-only CZT images and attenuation-corrected Anger camera images provided similar positive (reader 1/reader 2, 50.0%/44.1% vs 46.4%/51.9%) and negative (66.7%/64.0% vs 67.9%/67.7%) predictive values (all P = NS) for obstructive coronary artery disease; however, the sensitivity was higher (81.3% vs 58.3%, P = .05), specificity lower (29.7% vs 50.0%, P = .005), and normalcy rate lower (87.5% vs 100%, P = .025) with attenuation-corrected Anger camera images for the first reader with no significant differences between cameras for the second reader. CONCLUSIONS: Stress-only upright and supine CZT imaging was non-inferior statistically to attenuation-corrected stress-only Anger camera imaging. Nevertheless, stress-only CZT imaging may be associated with reduced diagnostic sensitivity for some readers compared to attenuation-corrected Anger camera images, which may be less acceptable clinically compared to stress plus rest images.

Computer derived transient ischemic dilation ratio for identifying extensive coronary artery disease using a CZT camera and imaging in the upright position.

BACKGROUND: Transient ischemic dilation (TID) of the left ventricle (LV) has not been validated as a marker of extensive coronary artery disease (CAD) for studies using a cadmium-zinc-telluride (CZT) camera with upright imaging. METHODS: TID ratios were obtained from upright stress and rest images on a CZT camera. Separate cut-off values were determined for exercise and for regadenoson stress. The cutoffs were then applied to 28 patients with extensive CAD and 101 patients without extensive CAD. RESULTS: With treadmill exercise, an upright TID ratio ≥1.16 provided a positive predictive value of 50% and a negative predictive value of 85.4% for the identification of extensive CAD. In the regadenoson group, an upright TID ratio of 1.29 provided a positive predictive value of 20% and a negative predictive value of 75.9%. Although not an independent predictor of extensive CAD in all subjects, in subjects with a normal upright LVEF, it provided a predictive value by receiver operating characteristics comparable to the SSS. CONCLUSIONS: Increased upright TID measurements on a CZT camera are associated with extensive CAD. The upright TID measurements can serve in an adjunctive role to SSS, and may be most effective in patients with a normal upright exercise LVEF.

Family history as a risk factor for carotid artery stenosis.

BACKGROUND AND PURPOSE: We investigated whether family history of stroke or coronary heart disease (CHD) is associated with presence of carotid artery stenosis (CAS). METHODS: The study cohort included 864 patients (72±8 years; 68% men) with CAS and 1698 controls (61±11 years; 55% men) referred for noninvasive vascular testing. CAS was defined as ≥70% stenosis in the internal carotid artery on ultrasound or history of carotid revascularization. Controls did not have CAS or history of cerebrovascular disease or CHD. Family history of stroke and CHD was defined as having ≥1 first-degree relative who had stroke or CHD before age 65 years. Logistic regression analysis was used to evaluate whether family history of stroke or CHD was associated with presence of CAS, independent of conventional risk factors. RESULTS: Family history of stroke and CHD was present more often in patients with CAS than in controls, with a resulting odds ratios (95% confidence interval) of 2.02 (1.61-2.53) and 2.01 (1.70-2.37), respectively. The associations remained significant after adjustment for age, sex, body mass index, smoking, diabetes mellitus, hypertension, and dyslipidemia; odds ratios: 1.41 (1.06-1.90) and 1.69 (1.35-2.10), respectively. A greater number of affected relatives with stroke or CHD was associated with higher odds of CAS; adjusted odds ratios: 1.25 (0.91-1.72) and 1.46 (1.14-1.89) versus 2.65 (1.35-5.40) and 2.13 (1.57-2.90) for patients with 1 and ≥2 affected relatives with stroke and CHD, respectively. CONCLUSIONS: Family history of stroke, and of CHD were each associated with CAS, suggesting that shared genetic and environmental factors contribute to the risk of CAS. We show that (1) family history of stroke or CHD is independently associated with presence of CAS; (2) sibling history of stroke or CHD confers greater risk than parental history; and (3) the magnitude of the association is greater in those with greater number of affected relatives, independent of the size of the family [corrected].

Association of soluble cell adhesion molecules with ankle-brachial index in a biethnic cohort of predominantly hypertensive individuals.

BACKGROUND: Higher plasma concentrations of soluble adhesion molecules have been shown to be associated with increased risk of cardiovascular events. We investigated the association of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) with ankle-brachial index (ABI), a measure of peripheral arterial disease (PAD), in a biethnic cohort of adults without known coronary heart disease or stroke. METHODS: Participants included 1102 blacks (mean age, 63 years; 74% women) and 1013 non-Hispanic whites (mean age, 58 years; 59% women) belonging to sibships ascertained on the basis of hypertension. We measured plasma concentrations of sICAM-1 and sVCAM-1 using high-sensitivity immunoassays and ABI using a standard protocol; PAD was defined as ABI <0.9. We used generalized estimating equations to assess whether sICAM-1 and sVCAM-1 were associated with ABI and PAD, independently of conventional risk factors. RESULTS: After adjustment for conventional risk factors, blacks with sICAM-1 and sVCAM-1 concentrations in the highest quartiles had lower ABIs than those in the lowest quartiles (mean ABI 1.02 vs 0.98, P = 0.007, vs 1.02 vs 0.99, P = 0.003, respectively). In multivariable logistic regression analysis, sICAM-1 and sVCAM-1 concentrations in the highest quartiles were each associated with a higher odds ratio of having PAD, compared with the lowest quartiles: odds ratio (95% CI): 5.2 (1.8-15.2) and 2.2 (1.0-4.8), respectively. In contrast, in non-Hispanic whites, sICAM-1 and sVCAM-1 concentrations were not associated with ABI or PAD. CONCLUSIONS: Higher sICAM-1 and sVCAM-1 concentrations were independently associated with lower ABI and PAD in blacks, but not in non-Hispanic whites.

Markers of inflammation are inversely associated with VO2 max in asymptomatic men.

We investigated whether markers of inflammation, including a cytokine (IL-6), acute-phase reactants [C-reactive protein (CRP) and fibrinogen], and white blood cell (WBC) count are associated with maximal O(2) consumption (Vo(2 max)) in men without coronary heart disease (CHD). In asymptomatic men (n = 172, 51 +/- 9.3 yr old), Vo(2 max) was measured during a symptom-limited graded treadmill exercise test. Physical activity level was assessed by a standardized questionnaire. IL-6 and CRP were measured by immunoassays, fibrinogen by the Clauss method, and WBC count with a Coulter counter. IL-6 and CRP were logarithmically transformed to reduce skewness. Multivariable regression was used to assess whether markers of inflammation were associated with Vo(2 max) after adjustment for age, body mass index, CHD risk factors, and lifestyle variables (physical activity level, percent body fat, and alcohol intake). Vo(2 max) was 34.5 ml.kg(-1).min(-1) (SD 6.1). Log IL-6 (r = -0.38, P < 0.001), log CRP (r = -0.40, P < 0.001), fibrinogen (r = -0.42, P < 0.001), and WBC count (r = -0.22, P = 0.004) were each correlated with Vo(2 max). In separate multivariable linear regression models that adjusted for age, body mass index, CHD risk factors, and lifestyle variables, log IL-6 [beta-coeff = -1.66 +/- 0.63 (SE), P = 0.010], log CRP [beta-coeff = -0.99 +/- 0.33 (SE), P = 0.003], fibrinogen [beta-coeff = -1.51 +/- 0.44 (SE), P = 0.001], and WBC count [beta-coeff = -0.52 +/- 0.30 (SE), P = 0.088] were each inversely associated with Vo(2 max). In conclusion, higher circulating levels of IL-6, CRP, and fibrinogen are independently associated with lower Vo(2 max) in asymptomatic men.

Family history as a risk factor for peripheral arterial disease.

The association of a family history of peripheral arterial disease (PAD) with the presence of PAD is largely unknown. We conducted a case-control study of 2,296 patients with PAD (69 ± 10 years, 64% men) and 4,390 controls (66 ± 11 years, 62% men) identified from noninvasive vascular and stress testing laboratories at Mayo Clinic, Rochester, Minnesota, from October 2006 through June 2012. PAD was defined as an ankle brachial index of ≤ 0.9 at rest and/or after exercise, a history of lower extremity revascularization, or having poorly compressible leg arteries. Controls were patients with normal ankle brachial index or without a history of PAD. Family history of PAD was defined as having at least 1 first-degree relative who had undergone revascularization or stent placement for PAD before the age of 65 years. Logistic regression analyses were used to evaluate whether a family history of PAD was associated with the presence of PAD, independent of conventional risk factors. A family history of PAD was present more often in patients with PAD than in controls, with a resulting odds ratio (OR) of 2.20 (95% confidence interval [CI] 1.82 to 2.67). The association remained significant after adjustment for conventional risk factors (OR 1.97, 95% CI 1.60 to 2.42). The association was stronger in younger subjects (age <68 years; adjusted OR 2.46, 95% CI 1.79 to 3.38) than in older subjects (adjusted OR 1.61, 95% CI 1.22 to 2.12). A greater number of affected relatives with PAD was also associated with greater odds of presence of PAD (adjusted OR 1.86, 95% CI 1.48 to 2.33 and adjusted OR 2.56, 95% CI 1.60 to 4.11 for patients with 1 and ≥ 2 affected relatives with PAD, respectively). In conclusion, individuals with a family history of PAD have nearly double the odds of having PAD relative to those without such a history.

Serum N-terminal pro-B-type natriuretic peptide levels are associated with functional capacity in patients with peripheral arterial disease.

We hypothesized that higher serum levels of N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) are associated with lower functional capacity in patients with peripheral arterial disease ([PAD] n = 481, mean age 67, 68% men). Functional capacity was quantified as distance walked on a treadmill for 5 minutes. Patients were divided into 3 groups according to the distance walked: >144 yards (group 1, n = 254); 60 to 144 yards (group 2, n = 80); <60 yards or did not walk (group 3, n = 147). The association between NT-pro-BNP levels and the ordinal 3-level walking distance was assessed using multivariable ordinal logistic regression analyses that adjusted for several possible confounding variables. Higher levels of NT-pro-BNP were associated with a lower ordinal walking category independent of possible confounders (odds ratio [OR] 1.51, 95% confidence interval [CI] 1.28-1.77; P < .001). In conclusion, higher levels of NT-pro-BNP are independently associated with lower functional capacity in patients with PAD and may be a marker of hemodynamic stress in these patients.

Plasma C-terminal pro-endothelin-1 is associated with target-organ damage in African Americans with hypertension.

BACKGROUND: Endothelin-1 (ET-1) is a vasoactive peptide with vasoconstrictor and mitogenic properties. We investigated whether plasma levels of C-terminal pro-ET-1 (CT-proET-1), a newly described stable fragment of the ET-1 precursor, are associated with target-organ damage in hypertension. METHODS: Participants included 981 African Americans (65 ± 9 years, 71% women) and 812 non-Hispanic whites (61 ± 9 years, 54% women) ascertained from sibships with hypertension. We measured plasma CT-proET-1 by an immunoluminometric assay. Measures of target-organ damage included the ankle-brachial index (ABI) and urinary albumin:creatinine ratio (UACR). Multivariable regressions analyses were employed to assess whether plasma CT-proET-1 levels were independently associated with ABI and UACR. RESULTS: In hypertensive African Americans, higher plasma levels of CT-proET-1 were significantly associated with lower ABI (P < 0.01) and higher UACR (P < 0.01). After adjustment for age, sex, body mass index, systolic blood pressure (SBP) and diastolic blood pressure (BP), diabetes, serum glucose, insulin use, estimated glomerular filtration rate (eGFR), history of smoking, total and high-density lipoprotein cholesterol, medication use, and previous history of myocardial infarction (MI) or stroke, higher plasma levels of CT-proET-1 remained significantly associated with lower ABI (P < 0.01) and higher UACR (P = 0.02). In non-Hispanic white hypertensives, higher plasma levels of CT-proET-1 were weakly associated with higher UACR (P = 0.02) and with lower ABI (P = 0.07). After adjustment for the relevant covariates, no statistically significant associations between CT-proET-1 and ABI or UACR were present in whites. CONCLUSIONS: Plasma levels of CT-proET-1 were independently associated with lower ABI and greater UACR in African American but not non-Hispanic white adults with hypertension.

Plasma carboxy-terminal provasopressin (copeptin): a novel marker of insulin resistance and metabolic syndrome.

CONTEXT: Stress-mediated hypothalamic-pituitary-adrenal axis activation, regulated by arginine vasopressin (AVP), may have a role in the pathophysiology of metabolic syndrome (MetSyn). OBJECTIVE: The objective of the study was to investigate whether plasma C-terminal provasopressin fragment (copeptin), a surrogate for circulating AVP, was associated with measures of insulin resistance and presence of MetSyn. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter, community-based study, investigating novel biomarkers for vascular disease. Participants included 1293 African-Americans (AA) (64 +/- 9 yr) and 1197 non-Hispanic whites (NHW) (59 +/- 10 yr) belonging to hypertensive sibships. MAIN OUTCOME MEASURES: Plasma copeptin levels were measured by an immunoluminometric assay. MetSyn was defined per Adult Treatment Panel III criteria. Generalized estimating equations were used to assess whether plasma copeptin was associated with measures of insulin resistance and MetSyn. RESULTS: The prevalence of MetSyn was 50% in AA and 49% in NHW. In each group, after adjustment for age and sex, plasma copeptin levels significantly correlated with body mass index, fasting plasma glucose and insulin, homeostasis model assessment of insulin resistance, triglycerides, and (inversely) high-density lipoprotein cholesterol (P < 0.05 for each variable). In multivariable logistic regression models that adjusted for age, sex, smoking, statin use, serum creatinine, education, physical activity, and diuretic use, plasma copeptin levels in the highest quartile were associated with an increased odds ratio of having MetSyn compared with bottom quartile: odds ratio (95% confidence interval) in AA, 2.07 (1.45-2.95); in NHW, 1.74 (1.21-2.5). CONCLUSIONS: Our findings indicate a novel cross-sectional association between plasma copeptin and measures of insulin resistance and MetSyn.

White blood cell count predicts all-cause mortality in patients with suspected peripheral arterial disease.

OBJECTIVE: We investigated whether markers of inflammation-white blood cell (WBC) count, C-reactive protein (CRP), and lipoprotein-associated phospholipase A2-are associated with mortality in patients referred for noninvasive lower-extremity arterial evaluation. METHODS: Participants (n = 242, mean age 68 years, 54% men) were followed for a median of 71 months. Ankle-brachial index (ABI), WBC count, plasma CRP, and lipoprotein-associated phospholipase A2 were measured at the start of the study. Factors associated with all-cause mortality were identified using Cox proportional hazards. RESULTS: During the follow-up period, 56 patients (25%) died. Factors associated with higher mortality were greater age, history of coronary artery disease/cerebrovascular disease, lower ABI, higher serum creatinine, and higher WBC count/plasma CRP. In stepwise multivariable regression analysis, ABI, serum creatinine, WBC count, and CRP were associated significantly with mortality. Patients in the top tertile of WBC count and CRP level had a relative risk of mortality of 3.37 (confidence interval [CI], 1.56-7.27) and 2.12 (CI, 0.97-4.62), respectively. However, only the WBC count contributed incrementally to prediction of mortality. Inferences were similar when analyses were limited to patients with peripheral arterial disease (ABI<0.9, n = 114). CONCLUSION: WBC count, but not plasma CRP level, provides incremental information about the risk of death in patients referred for lower-extremity arterial evaluation and in the subset of these patients with peripheral arterial disease.

Plasma midregional pro-atrial natriuretic peptide is associated with blood pressure indices and hypertension severity in adults with hypertension.

BACKGROUND: Midregional pro-atrial natriuretic peptide (MR-proANP) is a newly described stable fragment of the N-terminal part of pro-atrial natriuretic peptide. We tested the hypothesis that in adults with essential hypertension, plasma levels of MR-proANP would be associated with systolic blood pressure (SBP), pulse pressure, and hypertension severity. METHODS: Participants included 1,034 African Americans (65 +/- 9 years, 72% women) and 880 non-Hispanic whites (61 +/- 9 years, 55% women) belonging to sibships ascertained on the basis of hypertension. MR-proANP was measured by an immunoluminometric assay. Hypertension severity was based on number of hypertension medication classes used and multiples of SBP and diastolic blood pressure (DBP) deviations from 120/70 mm Hg. Generalized estimating equations were used to assess whether plasma levels of MR-proANP were associated with SBP, pulse pressure, and hypertension severity independent of potential confounding variables. RESULTS: In African Americans, after adjustment for age, sex, body mass index, estimated glomerular filtration rate (eGFR), smoking history, diabetes, total cholesterol, high-density lipoprotein cholesterol, medication (beta-blocker, statin, and aspirin) use, and previous history of myocardial infarction or stroke, higher MR-proANP levels were significantly associated with greater SBP (P < 0.0001), pulse pressure (P < 0.0001), and hypertension severity (P = 0.0013). The associations were replicated in non-Hispanic whites; after adjustment for the above variables, higher MR-proANP levels were significantly associated with greater SBP (P = 0.013), pulse pressure (P = 0.0006), and hypertension severity (P = 0.028). CONCLUSION: Plasma MR-proANP may be a marker of arterial stiffness and severity of hypertension in adults with hypertension.

Mid-regional pro-adrenomedullin is associated with pulse pressure, left ventricular mass, and albuminuria in African Americans with hypertension.

BACKGROUND: African Americans with hypertension are prone to target-organ damage and adverse cardiovascular events. Biomarkers for early detection of target-organ damage in this ethnic group are needed. Adrenomedullin (ADM) is a circulating vasoactive peptide with vasodilatory and antiproliferative effects that has been reported to be elevated in adults with hypertension. METHODS: We investigated the associations of plasma levels of mid-regional pro-ADM (MR-proADM) with pulse pressure, left ventricular mass (LVM), and albuminuria in 1,034 African-American adults (65 +/- 9 years, 72% women) with hypertension. MR-proADM was measured by an immunoluminometric assay, LVM was assessed by 2-dimensional echocardiography, and albuminuria was assessed by urine albumin:creatinine ratio (UACR). Multivariable regression analyses were used to assess whether plasma MR-proADM was independently associated with pulse pressure, LVM indexed by height to the power 2.7 (LVMi), and UACR. RESULTS: Plasma MR-proADM was significantly correlated (P < 0.001) with pulse pressure, LVMi, and UACR. In separate multivariable linear regression models that adjusted for age and sex, log MR-proADM was associated with greater pulse pressure (P = 0.007), log LVMi (P = 0.001), and log (UACR+1) (P < 0.0001). After additional adjustment for body mass index (BMI), total and high-density lipoprotein (HDL) cholesterol, smoking history, diabetes, estimated glomerular filtration rate (eGFR), history of myocardial infarction (MI) or stroke, and medication use, log MR-proADM remained significantly associated with greater pulse pressure (P = 0.001), log LVMi (P = 0.029), and log (UACR+1) (P = 0.002). CONCLUSIONS: In African-American adults with hypertension, plasma MR-proADM is independently associated with pulse pressure, LVMi, and albuminuria and is a potential biomarker for target organ damage.

Relation of plasma midregional proatrial natriuretic peptide to target organ damage in adults with systemic hypertension.

We tested the hypothesis that, in adults with essential hypertension, plasma levels of midregional proatrial natriuretic peptide (MR-proANP) are associated with target organ damage. MR-proANP is a newly described stable fragment of N-terminal proatrial natriuretic peptide. Participants included 1,919 adults with hypertension identified from the community (1,037 African-Americans, 65 +/- 9 years of age, 72% women; 882 non-Hispanic whites, 61 +/- 9 years of age, 55% women). We measured MR-proANP by an immunoluminometric assay. Measurements of target organ damage included the ankle-brachial index (ABI), urinary albumin-creatinine ratio (UACR), and left ventricular (LV) mass (available only in African-Americans). Generalized estimating equations were used to assess whether plasma MR-proANP was associated with measurements of target organ damage, independent of potential confounding variables. In African-Americans, higher MR-proANP was significantly associated with lower ABI (p <0.0001), higher UACR (p <0.0001), and greater LV mass (indexed to height to the power of 2.7, p <0.0001). After adjustment for age, gender, body mass index, systolic blood pressure, estimated glomerular filtration rate, smoking history, diabetes mellitus, total and high-density lipoprotein cholesterols, medication (blood pressure lowering, statin, and aspirin) use, and previous myocardial infarction or stroke, higher MR-proANP levels remained significantly associated with lower ABI (p = 0.01), higher UACR (p = 0.0007), and greater LV mass index (p <0.0001). In non-Hispanic whites, higher MR-proANP levels were significantly associated with lower ABI (p = 0.002) and greater UACR (p = 0.001), but not after adjustment for the covariates listed earlier. In conclusion, plasma MR-proANP may be a marker of target organ damage in the setting of hypertension, especially in African-Americans.

Aortic augmentation index is associated with the ankle-brachial index: a community-based study.

BACKGROUND: Increased arterial stiffness has been associated with greater risk of cardiovascular events. We investigated whether aortic augmentation index (AIx), a measure of arterial stiffness and wave reflection, was associated with the ankle-brachial index (ABI), a measure of peripheral arterial disease (PAD). METHOD: AIx and ABI were measured in a community-based sample of 475 adults without prior history of heart attack or stroke (mean age 59.3 years, 46.5% men). Radial artery pulse waveforms were obtained by applanation tonometry and an ascending aortic pressure waveform derived by a transfer function. AIx is the difference between the first and second systolic peak of the ascending aortic pressure waveform indexed to the central pulse pressure. ABI was measured using a standard protocol, and subjects with non-compressible vessels (ABI >1.5) were excluded from the analyses. Multivariable linear and logistic generalized estimating equations (GEE) analyses were used to assess whether AIx was associated with ABI and ABI <1.00, respectively, independent of conventional risk factors. RESULTS: Mean (+/-S.D.) values were: AIx, 29.3+/-11.6%; ABI, 1.12+/-0.13; 59 (12.4%) participants had an ABI <1.00. Variables associated with a lower ABI (and ABI <1.00) included older age, shorter height, female sex, higher total cholesterol, hypertension medication use, history of smoking, and higher AIx. After adjustment for mean arterial pressure and the above variables, higher AIx remained associated with a lower ABI (P=0.015) and ABI <1.00 (P=0.002). A significant interaction (P=0.007) was present between AIx and age in the prediction of ABI; the (inverse) association of AIx with ABI was stronger in older subjects (>65 years). CONCLUSION: AIx, a measure of arterial stiffness and wave reflection, was independently associated with a lower ABI in asymptomatic subjects from the community, and this association was modified by age.

Genetic markers of vascular aging.

Age is a powerful determinant of cardiovascular risk, being associated with a number of deleterious changes in the cardiovascular system. Increased arterial stiffness is an almost ubiquitous accompaniment of aging. However, there is significant variability in age-related arterial changes between individuals likely due, in part, to genetic factors. Measures of arterial stiffness such as pulse pressure and aortic pulse wave velocity have been shown to be heritable, indicating that genetic factors play a role in the interindividual variation of these phenotypes. Linkage analyses in related individuals have identified several genomic regions that may influence measures of arterial stiffness, and numerous association studies have investigated whether polymorphisms in candidate genes are related to this phenotype. Genome-wide association studies using 500,000 single nucleotide polymorphisms or more are now feasible and will accelerate the discovery of specific genetic polymorphisms that influence vascular aging/stiffness. Such findings will facilitate the development of novel therapies to retard vascular aging.