Mahyar Khaleghi

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.

Haemostatic markers are associated with measures of vascular disease in adults with hypertension.

Haemostatic markers have been implicated in the development and progression of vascular disease. We investigated the associations of several haemostatic markers (fibrinogen, D-dimer, FV, FVII, FVIII, von Willebrand factor (vWF) and antithrombin III) with two quantitative measures of vascular disease in adults with hypertension. Participants included 1051 African Americans (65±9 years, 72% women) and 894 non-Hispanic whites (61±9 years, 55% women) belonging to hypertensive sibships. Phenotypes of vascular disease included the ankle–brachial index (ABI), a measure of peripheral arterial disease, and urinary albumin/creatinine ratio (UACR), a surrogate of glomerular endothelial function. Generalized estimating equations were used to assess whether plasma levels of haemostatic markers were associated with measures of arteriosclerosis, after adjustment for conventional risk factors and medication (statin, aspirin and oestrogen) use. Higher fibrinogen and D-dimer were significantly associated with lower ABI in African Americans (P<0.001 and 0.004 respectively) and in non-Hispanic whites (P<0.001 and 0.010 respectively). Higher fibrinogen (P<0.001), D-dimer (P=0.003), FVIII (P<0.001) and vWF (P<0.001) were significantly associated with higher UACR in African Americans, whereas, in non-Hispanic whites, higher fibrinogen (P=0.020) and FVII (P=0.006) were significantly associated with higher UACR. Our findings indicate that in adults with essential hypertension, several markers in the haemostatic pathway are independently associated with ABI and UACR, two measures of vascular 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.

African‐American ethnicity is associated with higher plasma levels of D‐dimer in adults with hypertension

Summary.  Background: African Americans with hypertension have higher cardiovascular morbidity and mortality than hypertensives from other ethnic groups. Plasma D‐dimer, a fragment generated from fibrin during lysis of mature clot in vivo, is a predictor of adverse cardiovascular events. Objective: We investigated whether plasma levels of D‐dimer differ between African American (AA) and non‐Hispanic white (NHW) adults with hypertension. Methods: Participants included 933 AA (65 ± 9 years, 72% women) and 821 NHW (61 ± 9 years, 56% women) from the community. D‐dimer was measured using an immunoturbidimetric assay. Multivariable regression analyses, stratified by gender, were performed to assess whether AA ethnicity was associated with D‐dimer levels after adjustment for age, body mass index (BMI), total and high‐density lipoprotein (HDL) cholesterol, systolic blood pressure, diabetes, history of smoking, medication (statin and aspirin) use, lifestyle variables (physical activity, alcohol intake, and education), estimated glomerular filtration rate (eGFR), and a marker of inflammation, C‐reactive protein (CRP). Results: D‐dimer levels were higher in AA men and women than in their NHW counterparts (mean ± SD; men 256 ± 199 vs. 190 ± 183 ng mL−1, P < 0.001; women, 290 ± 233 vs. 225 ± 195 ng mL−1, P < 0.001). In both sexes, after adjustment for age, conventional risk factors, medication use, and lifestyle variables, AA ethnicity remained associated with higher D‐dimer levels (P = 0.002 in men, P = 0.006 in women). These associations remained significant after additional adjustment for eGFR and plasma CRP (P = 0.003 in men, P < 0.0001 in women). Conclusions: Among adults with hypertension, AA ethnicity was independently associated with higher plasma levels of D‐dimer.

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.

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.

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.

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.

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.