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1.  Associations of Candidate Biomarkers of Vascular Disease with the Ankle–Brachial Index and Peripheral Arterial Disease 
American Journal of Hypertension  2013;26(4):495-502.
BACKGROUND
The use of multiple biomarkers representing various etiologic pathways of atherosclerosis may improve the prediction of interindividual variation in the ankle–brachial index (ABI). To this end, we investigated associations of 47 candidate biomarkers with the ABI and presence of peripheral arterial disease (PAD) in African–Americans (AAs) and non-Hispanic whites (NHWs).
METHODS
Study participants included 1,291 AAs (71.1% women, mean age, 63.4±9.3 years) and 1,152 NHWs (57.5% women, mean age 58.5±10.1 years) belonging to hypertensive sibships. Peripheral arterial disease was defined as an ABI ≤ 0.90. Circulating levels of 47 candidate biomarkers were log-transformed before analysis because of skewed distribution. Multivariate regression analyses were used to identify biomarkers associated with ABI or PAD independently of age, sex, conventional risk factors, and medication use.
RESULTS
After adjustment for covariates, higher levels of nine biomarkers were associated with a lower ABI in AAs (all P ≤ 0.005); these biomarkers were C-reactive protein (CRP), interleukin-6, tumor necrosis factor receptor-II (TNF-R II), lipoprotein(a), N-terminal pro-brain natriuretic peptide (NT-proBNP), pro-atrial natriuretic peptide, C-terminal pro-arginine vasopressin, osteoprotegerin, and fibrinogen. Three biomarkers - myeloperoxidase, NT-proBNP, and D-dimer - were associated with ABI in NHWs (all P ≤ 0.01). C-reactive protein, interleukin-6, TNF-R II, lipoprotein(a), NT-proBNP, pro-atrial natriuretic peptide, D-dimer, and fibrinogen were associated with PAD (all P ≤ 0.005) in AAs after adjustment for covariates. None of the biomarkers were independently associated with PAD in NHWs.
CONCLUSION
A multimarker approach improved the prediction of interindividual variation in the ABI in AAs and NHWs, and improved prediction of the presence of PAD in AAs.
doi:10.1093/ajh/hps073
PMCID: PMC3626040  PMID: 23467205
ankle–brachial index; peripheral arterial disease; biomarker; hypertension; blood pressure.
2.  Ethnic differences in Ankle Brachial Index are Present in Middle-Aged Individuals without Peripheral Arterial Disease 
International journal of cardiology  2011;162(3):228-233.
Introduction
To better understand the basis for previously reported ethnic differences in ankle brachial index (ABI), we investigated whether these differences were present in individuals without known peripheral arterial disease (PAD).
Methods
We used data from National Health and Nutrition Examination surveys (NHANES 1999–2004) to determine whether ethnic differences were present in respondents without PAD (1≤ABI≤1.3). We assessed whether ethnicity was an independent predictor of ABI and ankle systolic blood pressure (SBP) in linear regression models that adjusted for conventional and novel cardiovascular risk factors. To minimize effects of atherosclerosis on ABI, we studied adults aged ≤ 60 years, and also repeated our analyses in a subset aged ≤ 50 years that did not have risk factors for PAD.
Results
3348 participants aged ≤ 60 years were included in the study. Mean ABI was 1.11 in non-Hispanic Blacks (NHB) and 1.13 in non-Hispanic Whites (NHW) (P <0.0001). In multivariable linear regression analysis that adjusted for age, gender, ethnicity, smoking, height, diabetes, brachial SBP, dyslipidemia, diabetes, renal function, concurrent cardiovascular disease, and plasma levels of homocysteine, fibrinogen and C-reactive protein, NHB had lower ABI than NHW (β= − 0.03± 0.004, P < 0.00001). Although, NHBs had higher ankle SBP than NHWs (by 5.3 mm Hg), NHBs had a lower mean ankle SBP (β= − 3.663 mm Hg ± 0.500, P <.0001) after adjusting for clinical covariates, including brachial SBP, in multivariable analysis.
Conclusion
Ethnic differences in ABI are present in middle-aged adults at low risk for peripheral atherosclerosis.
doi:10.1016/j.ijcard.2011.05.068
PMCID: PMC3174274  PMID: 21652099
ankle brachial index; ethnicity
3.  Sex Differences in Arterial Stiffness and Ventricular-Arterial Interactions 
Objectives
To assess sex-differences in ventricular-arterial interactions.
Background
Heart failure with preserved ejection fraction (HFpEF) is more prevalent in women than men, but the basis for this difference remains unclear.
Methods
Echocardiography and arterial tonometry were performed to quantify arterial and ventricular stiffening and interaction in 461 participants without heart failure (189 men, age 67±9 years; 272 women, age 65±10 years). Aortic characteristic impedance (Zc), total arterial compliance (TAC, pulsatile load) and systemic vascular resistance index (SVRI, steady load) were compared between men and women, and sex-specific multivariable regression analyses were performed to assess associations of these arterial parameters with diastolic dysfunction and ventricular-arterial coupling (effective arterial elastance/left ventricular end-systolic elastance, Ea/Ees) after adjustment for potential confounders.
Results
Zc was higher and TAC was lower in women, whereas SVRI was similar between sexes. In women but not men, higher Zc was associated with E/A ratio (β±SE: −0.17±0.07), diastolic dysfunction (OR 7.8; 95% CI: 2.0, 30.2) and Ea/Ees (β±SE: 0.13±0.0) (P≤0.01 for all). Similarly, TAC was associated with E/A ratio (β± SE: 0.12±0.04), diastolic dysfunction (OR 0.33; 95% CI: 0.12, 0.89) and Ea/Ees (β± SE: −0.09±0.03) in women only (P≤0.03 for all). SVRI was not associated with diastolic dysfunction or Ea/Ees.
Conclusions
Proximal aortic stiffness (Zc) is greater in women than men, and women may be more vulnerable to the deleterious effects of greater pulsatile and early arterial load on diastolic function and ventricular-arterial interaction. This may contribute to the greater risk of HFpEF in women.
doi:10.1016/j.jacc.2012.08.997
PMCID: PMC3773521  PMID: 23122799
aortic stiffness; diastolic dysfunction; echocardiography; sex-specific; ventricular-arterial interaction
4.  Aortic Pulse Wave Velocity Is Associated With Measures of Subclinical Target Organ Damage 
JACC. Cardiovascular imaging  2011;4(7):10.1016/j.jcmg.2011.04.011.
OBJECTIVES
Our goal was to evaluate the associations of central arterial stiffness, measured by aortic pulse wave velocity (aPWV), with subclinical target organ damage in the coronary, peripheral arterial, cerebral, and renal arterial beds.
BACKGROUND
Arterial stiffness is associated with adverse cardiovascular outcomes. We hypothesized that aPWV is associated with subclinical measures of atherosclerosis—coronary artery calcification (CAC) and ankle-brachial index (ABI) and arteriolosclerosis—brain white matter hyperintensity (WMH) and urine albumin-creatinine ratio (UACR).
METHODS
Participants (n = 812; mean age 58 years; 58% women, 71% hypertensive) belonged to hypertensive sibships and had no history of myocardial infarction or stroke. aPWV was measured by applanation tonometry, CAC by electron beam computed tomography, ABI using a standard protocol, WMH volume by brain magnetic resonance, and UACR by standard methods. WMH was log-transformed, whereas CAC and UACR were log-transformed after adding 1 to reduce skewness. The associations of aPWV with CAC, ABI, WMH, and UACR were assessed by multivariable linear regression using generalized estimating equations to account for the presence of sibships. Covariates included in the models were age, sex, body mass index, history of smoking, hypertension and diabetes, total and high-density lipoprotein cholesterol, estimated glomerular filtration rate, use of aspirin and statins, and pulse pressure.
RESULTS
The mean ± SD aPWV was 9.8 ± 2.8 m/s. After adjustment for age, sex, conventional cardiovascular risk factors, and pulse pressure, higher aPWV (1 m/s increase) was significantly associated with higher log (CAC + 1) (β ± SE = 0.14 ± 0.04; p = 0.0003), lower ABI (β ± SE =−0.005 ± 0.002; p = 0.02), and greater log (WMH) (β ± SE = 0.03 ± 0.009; p = 0.002), but not with log (UACR + 1) (p = 0.66).
CONCLUSIONS
Higher aPWV was independently associated with greater burden of subclinical disease in coronary, lower extremity, and cerebral arterial beds, highlighting target organ damage as a potential mechanism underlying the association of arterial stiffness with adverse cardiovascular outcomes. (J Am Coll Cardiol Img 2011;4:754–61)
doi:10.1016/j.jcmg.2011.04.011
PMCID: PMC3862768  PMID: 21757166
arterial stiffness; arteriosclerosis; coronary artery calcification; hypertension; leukoariosis; peripheral arterial disease; pulse wave velocity; target organ damage
5.  Serum N-Terminal Pro-B-Type Natriuretic Peptide Levels Are Associated With Functional Capacity in Patients With Peripheral Arterial Disease 
Angiology  2011;63(6):10.1177/0003319711423095.
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 I, 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.
doi:10.1177/0003319711423095
PMCID: PMC3855435  PMID: 22096207
N-terminal pro-B-type natriuretic peptide; natriuretic peptides; functional capacity; peripheral arterial disease
6.  Association of serum myeloperoxidase with the ankle—brachial index and peripheral arterial disease 
Atherosclerosis  2009;206(2):575-580.
Myeloperoxidase (MPO) is an enzymatic mediator of several inflammatory cascades and higher serum levels have been associated with increased risk of adverse cardiovascular events. We investigated the association of serum MPO with the ankle–brachial index (ABI) and peripheral arterial disease (PAD) in a bi-ethnic cohort of African-Americans and non-Hispanic white individuals. Participants included 1324 African-Americans (mean age 64 years, 71% women) and 1237 non-Hispanic white individuals (mean age 59 years, 57% women) belonging to hypertensive sibships. Serum levels of MPO were measured by solid phase sandwich immunoassay. ABI was measured using a standard protocol and PAD was defined as an ABI < 0.90. Multivariable regression analysis using generalized estimating equations were performed to assess whether serum MPO levels were associated with ABI and the presence of PAD. After adjustment for age and sex, higher MPO levels were significantly associated with lower ABI and the presence of PAD in African-Americans (p = 0.004 and p = 0.005, respectively) and in non-Hispanic white individuals (p = 0.001 and p = 0.016, respectively). After additional adjustment for conventional risk factors (diabetes, smoking status, total and high-density lipoprotein cholesterol, waist circumference, hypertension), prior history of myocardial infarction or stroke, and medication use (statins, aspirin, estrogen), higher MPO levels remained significantly associated with lower ABI and the presence of PAD in both African-Americans (p = 0.008 and p = 0.010, respectively) and non-Hispanic white individuals (p = 0.001 and p = 0.018, respectively). We conclude that higher MPO levels are associated with lower ABI and the presence of PAD in African-Americans and non-Hispanic white individuals.
doi:10.1016/j.atherosclerosis.2009.03.032
PMCID: PMC3773523  PMID: 19423112
ankle–brachial index; inflammation; myeloperoxidase; peripheral arterial disease
7.  Biomarkers Associated With Pulse Pressure in African-Americans and Non-Hispanic Whites 
American journal of hypertension  2011;25(2):145-151.
BACKGROUND
Pulse pressure (an indirect measure of arterial stiffness) is a robust predictor of cardiovascular events, but its pathophysiology remains poorly understood. To gain insight into the pathophysiology of arterial stiffness we conducted an exploratory investigation of the associations of 47 circulating biomarkers in etiologic pathways of arteriosclerosis with brachial artery pulse pressure.
METHODS
Participants included 1,193 African-Americans and 1,145 non-Hispanic whites belonging to hypertensive sibships. Blood pressure (BP) was measured with a random-zero sphygmomanometer. Multivariable linear regression was employed to assess the associations of biomarkers with pulse pressure after adjustment for age, sex, conventional risk factors, mean arterial pressure, heart rate, and use of aspirin, statins, estrogens, and antihypertensives. Statistical significance was set at P ≤ 0.001 (Bonferroni correction for multiple testing).
RESULTS
Log N-terminal probrain natriuretic peptide (NT-proBNP) (African-Americans: β = 2.11 ± 0.52, non-Hispanic whites: β = 2.65 ± 0.55), log midregional proatrial natriuretic peptide (African-Americans: β = 4.83 ± 0.70, non-Hispanic whites: β = 3.70 ± 0.67), and log osteoprotegerin (African-Americans: β = 4.64 ± 1.02, non-Hispanic whites: β = 4.19 ±0.99) were independently associated with pulse pressure (P < 0.001 for all) in both ethnicities. Log C-reactive protein (CRP) (β = 1.56 ± 0.35), log midregional proadrenomedullin (MR-proADM) (β = 5.53 ± 1.19) and log matrix metalloproteinase-2 (β = 3.89 ± 1.06) were associated with greater pulse pressure in African-Americans only (P ≤ 0.001 for all), whereas higher fibrinogen was associated with pulse pressure in non-Hispanic whites only (β = 0.02 ± 0.004. P < 0.001).
CONCLUSIONS
Our results suggest that hemodynamic stress, vascular inflammation and calcification, and matrix remodeling may have a role in the pathogenesis and/or adverse consequences of increased pulse pressure.
doi:10.1038/ajh.2011.193
PMCID: PMC3707798  PMID: 22012208
adrenomedullin; arterial stiffness; atrial natriuretic peptide; biomarkers; blood pressure; brain natriuretic peptide; fibrinogen; hypertension; matrix metalloproteinase-2; osteoprotegerin; pulse pressure
8.  BIOMARKERS OF LEFT VENTRICULAR HYPERTROPHY AND REMODELING IN BLACKS 
Hypertension  2011;58(5):920-925.
Left ventricular hypertrophy, a marker for adverse cardiovascular events, is more common in blacks than non-Hispanic whites. Mechanisms leading to left ventricular hypertrophy and mediating its clinical sequelae in blacks are not fully understood. We investigated the associations of 39 candidate biomarkers in distinct biological pathways with left ventricular mass and geometry in blacks. Participants included 1193 blacks (63 ± 9 years, 72% women, 78% hypertensive) belonging to hypertensive sibships. Left ventricular mass was measured by transthoracic echocardiography and indexed to height2.7. Left ventricular geometry was categorized as: normal, concentric remodeling, concentric hypertrophy and eccentric hypertrophy. Generalized estimating equations were employed to assess associations of the 39 biomarkers with left ventricular mass index after adjustment for age, sex, and conventional risk factors. After adjustment for potential confounders, log-transformed levels of the following biomarkers were independently associated with left ventricular mass index: N-terminal pro-brain natriuretic peptide (β±SE= 0.07±0.01 pg/mL, P< 0.0001), mid-regional pro-atrial natriuretic peptide (β±SE= 0.08±0.02 pmol/L, P< 0.0001), mid-regional pro-adrenomedullin (β±SE= 0.09±0.03 nmol/L, P= 0.0006), C-terminal pro-endothelin (β±SE= 0.05±0.02 pmol/L, P=0.0009) and osteoprotegerin (β±SE=0.07±0.02 pg/mL, P=0.0005). The associations of these biomarkers with left ventricular mass index were mainly due to their association with eccentric hypertrophy. Higher circulating levels of natriuretic peptides, adrenomedullin, endothelin and osteoprotegerin were associated with increased left ventricular mass index, providing insights into the pathophysiology of left ventricular hypertrophy in blacks.
doi:10.1161/HYPERTENSIONAHA.111.178095
PMCID: PMC3249445  PMID: 21986506
left ventricular hypertrophy; biomarkers; brain natriuretic peptide; atrial natriuretic peptide; adrenomedullin; endothelin; osteoprotegerin
9.  Usefulness of Red Cell Distribution Width to Predict Mortality in Patients with Peripheral Artery Disease 
The American journal of cardiology  2011;107(8):1241-1245.
Increased red cell distribution width (RDW), a marker of anisocytosis, has been associated with adverse outcomes in multiple settings. Whether RDW is predictive of mortality in patients with peripheral artery disease (PAD) is unknown. We studied 13,039 consecutive outpatients (age 69.5 ±12.0 years, 60.9% men, 97.6% white) with PAD identified by non-invasive lower-extremity arterial testing at Mayo Clinic from 1/97 to 12/07, with follow-up through 9/09. We defined PAD as low (≤0.9) or high (≥1.4) ankle-brachial index (ABI). Cardiovascular risk factors and comorbidities were ascertained using electronic medical record (EMR)-based algorithms. RDW was obtained from the complete blood count drawn around the time of arterial evaluation. Mortality was ascertained using the Mayo EMR and Accurint® database. The association of RDW with all-cause mortality was analyzed by multivariable Cox proportional hazards regression. During a median follow-up of 5.5 years, 4039 (31.0 %) deaths occurred (28.7% in low and 38.9% in high ABI subsets). After adjustment for age, sex, cardiovascular risk factors and comorbidities, patients in the highest quartile of RDW (>14.5%) had 66% greater risk of mortality compared to the lowest quartile (<12.8%) (P<0.0001); a 1% increment in RDW was associated with 10% greater risk of all-cause mortality (hazard ratio, 1.10, 95% confidence interval [CI], 1.08 to 1.12, P<0.0001). The adjusted hazard ratio was similar in the low (1.10, 1.08-1.12) and high (1.09, 1.06-1.12) ABI subsets. In conclusion, RDW, a routinely available measure, is an independent prognostic marker in patients with PAD.
doi:10.1016/j.amjcard.2010.12.023
PMCID: PMC3209662  PMID: 21296321
10.  Return of results in the genomic medicine projects of the eMERGE network 
The electronic Medical Records and Genomics (eMERGE) (Phase I) network was established in 2007 to further genomic discovery using biorepositories linked to the electronic health record (EHR). In Phase II, which began in 2011, genomic discovery efforts continue and in addition the network is investigating best practices for implementing genomic medicine, in particular, the return of genomic results in the EHR for use by physicians at point-of-care. To develop strategies for addressing the challenges of implementing genomic medicine in the clinical setting, the eMERGE network is conducting studies that return clinically-relevant genomic results to research participants and their health care providers. These genomic medicine pilot studies include returning individual genetic variants associated with disease susceptibility or drug response, as well as genetic risk scores for common “complex” disorders. Additionally, as part of a network-wide pharmacogenomics-related project, targeted resequencing of 84 pharmacogenes is being performed and select genotypes of pharmacogenetic relevance are being placed in the EHR to guide individualized drug therapy. Individual sites within the eMERGE network are exploring mechanisms to address incidental findings generated by resequencing of the 84 pharmacogenes. In this paper, we describe studies being conducted within the eMERGE network to develop best practices for integrating genomic findings into the EHR, and the challenges associated with such work.
doi:10.3389/fgene.2014.00050
PMCID: PMC3972474  PMID: 24723935
genomics; electronic health records; incidental findings; implementation; genetic counseling; next generation sequencing; pharmacogenetics
11.  Aortic Augmentation Index is Associated with the Ankle Brachial Index; A Community Based Study 
Atherosclerosis  2007;195(2):248-253.
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 (± SD) 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.
doi:10.1016/j.atherosclerosis.2006.12.017
PMCID: PMC3249443  PMID: 17254587
arterial stiffness; ankle-brachial index; arteries
12.  Serum Osteocalcin Is Associated With Measures of Insulin Resistance, Adipokine Levels, and the Presence of Metabolic Syndrome 
Objective
Osteocalcin has been reported to influence insulin secretion in experimental animals. We investigated whether serum osteocalcin was associated with measures of insulin resistance, circulating adipokine levels, and the presence of metabolic syndrome (MetSyn).
Methods and Results
Serum osteocalcin was measured by solid-phase sandwich immunoassay in 1284 blacks (64±9 years; 71% women) and 1209 non-Hispanic whites (59±10 years; 57% women) belonging to hypertensive sibships. MetSyn was defined per Adult Treatment Panel III criteria. The prevalence of MetSyn was 50% in blacks and 49% in non-Hispanic whites. In each ethnic group, after adjustment for age and gender, osteocalcin levels were inversely correlated with body mass index, fasting glucose and insulin, homeostasis model assessment of insulin resistance, triglycerides, and leptin, and positively correlated with adiponectin (P<0.001 for each variable). In multivariable regression analyses that adjusted for age, gender, smoking, serum creatinine, and statin and estrogen use, osteocalcin levels in the highest quartile (compared with the lowest quartile) were associated with a lower odds ratio (OR) of having MetSyn: OR (95% CI) in blacks, 0.33 (0.23 to 0.46); OR in non-Hispanic whites, 0.43 (0.31 to 0.63).
Conclusion
Serum osteocalcin is associated with measures of insulin resistance, adipokine levels, and the presence of MetSyn, suggesting a novel cross-talk between bone and adipose tissue.
doi:10.1161/ATVBAHA.110.204859
PMCID: PMC2939910  PMID: 20395593
adiponectin; insulin resistance; leptin; metabolic syndrome; osteocalcin
13.  Increased Serum N-Terminal Pro–B-Type Natriuretic Peptide Levels in Patients With Medial Arterial Calcification and Poorly Compressible Leg Arteries 
Objective
To determine whether serum levels of N-terminal (NT) pro–B-type natriuretic peptide (pro-BNP) are higher in patients with poorly compressible arteries (PCA) than in patients with peripheral artery disease (PAD) and control subjects without PCA or PAD.
Methods and Results
Medial arterial calcification in the lower extremities results in PCA and may be associated with increased arterial stiffness and hemodynamic/myocardial stress. PCA was defined as having an ankle-brachial index >1.4 or an ankle blood pressure >255 mm Hg, whereas PAD was defined as having an ankle-brachial index ≤0.9. Study participants with PCA (n=100; aged 71±10 years; 70% men) and age- and sex-matched patients with PAD (n=300) were recruited from the noninvasive vascular laboratory. Age- and sex-matched controls (n=300) were identified from a community-based cohort and had no history of PAD. NT pro-BNP levels were approximately 2.5-fold higher in patients with PCA than in patients with PAD and approximately 4-fold higher than in age- and sex-matched controls. In multivariable regression analyses that adjusted for age, sex, smoking, hypertension, history of coronary heart disease/stroke, systolic blood pressure, and serum creatinine, NT pro-BNP levels remained significantly higher in patients with PCA than in patients with PAD and controls (P<0.001).
Conclusion
Patients with medial arterial calcification and PCA have higher serum levels of NT pro-BNP than patients with PAD and controls, which is suggestive of an adverse hemodynamic milieu and increased risk for adverse cardiovascular outcomes.
doi:10.1161/ATVBAHA.110.216770
PMCID: PMC3115928  PMID: 20947817
medial arterial calcification; poorly compressible arteries; peripheral artery disease; NT pro-BNP; arterial stiffness; natriuretic peptides; risk factors
14.  Ethical, legal, and social implications of incorporating genomic information into electronic health records 
The inclusion of genomic data in the electronic health record raises important ethical, legal, and social issues. In this article, we highlight these challenges and discuss potential solutions. We provide a brief background on the current state of electronic health records in the context of genomic medicine, discuss the importance of equitable access to genome-enabled electronic health records, and consider the potential use of electronic health records for improving genomic literacy in patients and providers. We highlight the importance of privacy, access, and security, and of determining which genomic information is included in the electronic health record. Finally, we discuss the challenges of reporting incidental findings, storing and reinterpreting genomic data, and nondocumentation and duty to warn family members at potential genetic risk.
doi:10.1038/gim.2013.117
PMCID: PMC3926430  PMID: 24030434
clinical decision support, electronic health records; ethical, legal, and social implications; genomics; personalized medicine
15.  Association of Serum Osteoprotegerin With Left Ventricular Mass in African-American Adults With Hypertension 
American journal of hypertension  2010;23(7):767-774.
BACKGROUND
African-Americans with hypertension are susceptible to left ventricular hypertrophy (LVH). Serum osteoprotegerin level has been reported to be associated with LVH. We investigated the association of osteoprotegerin with LV mass (LVM) in 898 African-Americans with hypertension (mean age 65 years, 71% women).
METHODS
Osteoprotegerin levels were measured in serum by an immunoassay and log-transformed for analyses. LVM index (LVMi; LVM/height2.7) was estimated using M-mode echocardiography. Linear regression analyses using generalized estimating equations were used to assess the association of osteoprotegerin with LVMi.
RESULTS
Serum osteoprotegerin was correlated with LVMi (r = 0.21; P < 0.0001), an estimated increase in LVMi of 5.05 (95% confidence interval 2.93, 7.17) g/m2.7 in the highest compared to the lowest osteoprotegerin quartile. This association remained statistically significant after adjustment for conventional cardiovascular risk factors (age, sex, body mass index (BMI), history of smoking, diabetes, systolic blood pressure (BP), total and high-density lipoprotein cholesterol), estimated renal function, history of myocardial infarction and stroke, lifestyle factors (physical activity score, years of education, amount of alcohol consumption), medications (aspirin, antihypertensives, statins, estrogens), and C-reactive protein (CRP) (P = 0.02). Additionally, osteoprotegerin was correlated with early/atrial (E/A) ratio (r = −0.16; P < 0.0001), LV mean wall thickness (r = 0.17; P < 0.0001) and relative wall thickness (r = 0.14; P < 0.0001) but not ejection fraction (r = 0.04; P = 0.24) or internal end-diastolic dimension (r = 0.02; P = 0.60).
CONCLUSION
In African-Americans with hypertension, a higher serum osteoprotegerin level is weakly but independently associated with a higher LVM.
doi:10.1038/ajh.2010.59
PMCID: PMC2901868  PMID: 20339356
African-American; biomarker; blood pressure; cardiology; echocardiography; epidemiology; hypertension; hypertrophy; osteoprotegerin
16.  Novel markers of peripheral arterial disease 
Peripheral arterial disease (PAD), a relatively common manifestation of atherosclerotic vascular disease, is associated with significant morbidity and mortality. Although conventional risk factors contribute to the onset and progression of PAD, the role of ‘novel’ biomarkers in pathways of inflammation, thrombosis, lipoprotein metabolism, and oxidative stress in determining susceptibility to PAD is being increasingly recognized. Validation of novel risk factors for PAD may allow earlier detection, an improved understanding of disease etiology and progression, and the development of new therapies. In this review, we discuss available evidence for associations between novel circulating markers and several aspects of PAD including disease susceptibility, progression, functional limitation, and adverse outcomes.
doi:10.1177/1358863X09106869
PMCID: PMC2901866  PMID: 19808725
inflammation; peripheral arterial disease; risk factors
17.  Formin Homology 2 Domain Containing 3 (FHOD3) Variants Associated with Hypertrophic Cardiomyopathy 
Background
Incomplete penetrance and variable expression of Hypertrophic Cardiomyopathy (HCM) is well appreciated. Common genetic polymorphisms variants that may affect HCM penetrance and expression have been predicted but are not well established.
Methods and Results
We performed a case-control genome wide association (GWA) study to identify common HCM-associated genetic polymorphisms and then asked whether such common variants were more represented in HCM or could explain the heterogeneity of HCM phenotypes. We identified an intronic FHOD3 variant (rs516514) associated with HCM (OR = 2.45 (95% CI 1.76–3.41), p=1.25 × 10−7) and validated this finding in an independent cohort. Next, we tested FHOD3-V1151I (rs2303510), a non-synonymous variant in partial linkage disequilibrium (LD) with rs516514, and we detected an even stronger association with HCM (p=1.76 × 10−9). While HCM patients were more likely to carry these FHOD3 alleles subjects homozygous for FHOD3-1151I had similar HCM phenotypes as carriers of the V1151 allele. FHOD3 expression is increased in the setting of HCM and both alleles of FHOD3-V1151I were detected in HCM myectomy tissue. Previously FHOD3 was found to be required for formation of the sarcomere and here we demonstrate that its fly homolog fhos is required for normal adult heart systolic contraction.
Conclusions
Here we demonstrate the association of a common non-synonymous FHOD3 genetic variant with HCM. This discovery further strengthens the potential role of gene mutations and polymorphisms that alter the amino acid sequence of sarcomere proteins and HCM.
doi:10.1161/CIRCGENETICS.112.965277
PMCID: PMC3578062  PMID: 23255317
contractility; genome-wide analysis; hypertrophic cardiomyopathy
18.  Forearm Vascular Reactivity and Arterial Stiffness in Asymptomatic Subjects from the Community 
Hypertension  2008;51(6):1512-1518.
Vascular reactivity may affect the stiffness characteristics of the arterial wall. We investigated the association between forearm microcirculatory and conduit artery function and measures of arterial stiffness in 527 asymptomatic non-Hispanic white adults without known cardiovascular disease. High-resolution ultrasonography of the brachial artery (ba) was performed to assess forearm microcirculatory function (ba blood flow velocity, local shear stress, and forearm vascular resistance at rest and during reactive hyperemia) and conduit artery function (ba flow-mediated dilatation baFMD and ba nitroglycerin-mediated dilatation baNMD). Arterial stiffness was assessed by cuff-derived brachial pulse pressure and aortic pulse wave velocity (aPWV) measured by applanation tonometry. In regression analyses that adjusted for heart rate, mean arterial pressure, height, cardiovascular risk factors, and hypertension medication and statin use, higher baseline ba systolic velocity and systolic shear stress were associated with greater pulse pressure (P=0.0002 and P=0.006, respectively) and higher aPWV (each P<0.0001). During hyperemia, lower ba mean velocity and lower mean shear stress were associated with higher pulse pressure (P=0.045 and P=0.036, respectively) while both systolic and mean velocity (P<0.0001 and P=0.002, respectively) and systolic and mean shear stress (P<0.0001 and P=0.003, respectively) were inversely associated with aPWV. baFMD was not associated with pulse pressure but was inversely associated with aPWV (P=0.011). baNMD was inversely associated with pulse pressure (P=0.0002) and aPWV (P=0.008). Our findings demonstrate that impaired forearm microvascular function (in the form of elevated resting blood flow velocity and impaired flow reserve) and impaired brachial artery reactivity are associated with increased arterial stiffness.
doi:10.1161/HYPERTENSIONAHA.107.106088
PMCID: PMC2869626  PMID: 18426995
microvascular function; flow-mediated dilatation; nitroglycerin-mediated dilatation; arterial stiffness; pulse pressure; pulse wave velocity
19.  Molecular population genetics of PCSK9: a signature of recent positive selection 
Pharmacogenetics and genomics  2008;18(3):169-179.
Objective
Proprotein convertase subtilisin-like kexin type 9 (PCSK9) is a newly discovered serine protease that plays a key role in regulating plasma low-density lipoprotein (LDL) cholesterol levels. Both rare mutations and common variants in the coding regions of PCSK9 affect LDL cholesterol levels and coronary heart disease risk, as well as response to lipid-lowering therapy.
Methods
We characterized the patterns of variation at the PCSK9 locus in African-Americans and European-Americans using resequenced data from the SeattleSNPs database (pga.gs.washington.edu). We performed a test of population differentiation and the long range haplotype (LRH) test to detect signatures of recent position selection on PCSK9.
Results
A significantly high FST (a measure of population differentiation) between African-Americans and European-Americans was noted for SNP rs505151 (FST = 0.309). The LRH test was suggestive of non-neutral evolution of two single nucleotide polymorphisms (SNPs) (rs505151 and rs562556) in PCSK9 that are associated with elevated LDL cholesterol levels (‘gain-of-function’ mutations), with differential modes of selection in African-Americans and European-Americans. We observed signals of recent positive selection on the ancestral allele of nonsynonymous SNP rs505151 (E670G, P = 0.0227 and P = 0.0001 in theoretical and empirical distribution, respectively) and the derived allele of nonsynonymous SNP rs562556 (I474V, P = 0.0227 and 0.0001) in African-Americans, whereas in European-Americans the ancestral allele of SNP rs562556 (P = 0.1320 and 0.0370) appeared to be under positive selection.
Conclusions
Our findings suggest that evolutionary dynamics may underlie the gain-of-function mutations in PCSK9 that influence inter-individual variation in LDL cholesterol levels.
doi:10.1097/FPC.0b013e3282f44d99
PMCID: PMC2842919  PMID: 18300938
PCSK9; low-density lipoprotein cholesterol; natural selection
20.  Association of Serum Myeloperoxidase with Peripheral Arterial Disease 
Myeloperoxidase (MPO) is an enzymatic mediator of several inflammatory cascades and higher serum levels have been associated with increased risk of adverse cardiovascular events. We investigated the association of serum MPO with the ankle-brachial index (ABI) and peripheral arterial disease (PAD), in a bi-ethnic cohort of African-Americans and non-Hispanic whites. Participants included 1324 African-Americans (64 y, 71% women) and 1237 non- Hispanic whites (59 y, 57% women) belonging to hypertensive sibships. Plasma levels of MPO were measured by solid phase sandwich immunoassay. ABI was measured using a standard protocol and PAD defined as ABI <0.90. Multivariable regression analysis using generalized estimating equations (GEE) were performed to assess whether serum MPO levels were associated with ABI and the presence of PAD. After adjustment for age and sex, higher MPO levels were significantly associated with lower ABI and presence of PAD in African-Americans (P=0.004 and P=0.005, respectively) and in non-Hispanic whites (P=0.001and P=0.021, respectively). After additional adjustment for conventional risk factors (diabetes, smoking status, total and HDL cholesterol, waist circumference, hypertension), prior history of myocardial infarction or stroke, and medication use (statins, aspirin, estrogen), higher MPO levels remained significantly associated with lower ABI and presence of PAD in both African- Americans (P=0.008 and P=0.012, respectively) and non-Hispanic whites (P=0.001and P=0.029, respectively). We conclude that higher MPO levels are associated with lower ABI and the presence of PAD in African-Americans and non-Hispanic whites.
doi:10.1177/1358863X08101999
PMCID: PMC2752685  PMID: 19651670
peripheral arterial disease; inflammation; ankle-brachial index; myeloperoxidase
21.  Association of Soluble Cell Adhesion Molecules with Ankle-Brachial Index in a Bi-Ethnic Cohort of Predominantly Hypertensive Individuals 
Clinical chemistry  2008;54(11):1788-1795.
Background
Higher plasma concentrations of soluble adhesion molecules have been shown to be associated with increased risk of cardiovascular events. We investigated the associations of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) with the ankle-brachial index (ABI), a measure of peripheral arterial disease (PAD), in a bi-ethnic cohort of adults without known coronary heart disease or stroke.
Methods
Participants included 1102 blacks (63 y, 74% women) and 1013 non-Hispanic whites (58 y, 59% women) belonging to hypertensive sibships. Plasma concentrations of sICAM-1 and sVCAM-1 were measured using high-sensitivity immunoassays. ABI was measured using a standard protocol and PAD was defined as ABI <0.9. Generalized estimating equations (GEE) were used to assess whether sICAM-1 and sVCAM-1 were associated with ABI and with PAD, independent 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 ABI than those in the lowest quartiles (mean ABI: 1.02 vs. 0.98, P=0.007 and 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 with PAD.
Conclusion
Higher sICAM-1 and sVCAM-1 concentrations were independently associated with a lower ABI and with PAD in blacks, but not in non-Hispanic whites.
doi:10.1373/clinchem.2008.107003
PMCID: PMC2752683  PMID: 18787016
ethnicity; sICAM-1; sVCAM-1; ankle-brachial index; peripheral arterial disease; hypertension
22.  Genome-wide Association Studies for Atherosclerotic Vascular Disease and Its Risk Factors 
doi:10.1161/CIRCGENETICS.108.816751
PMCID: PMC2740629  PMID: 19750184
atherosclerosis; genetics; risk factors; genome-wide association study
23.  Ethnic Differences in Low-Density Lipoprotein Particle Size in Hypertensive Adults 
Journal of clinical lipidology  2007;1(3):218-224.
Background
Hypertensive African Americans have higher rates of coronary heart disease (CHD) than their non-Hispanic white counterparts despite having higher HDL cholesterol (HDL-C) levels and lower triglyceride levels.
Objective
The goal of the present study was to assess whether low-density lipoprotein (LDL) particle size, a correlate of the above lipid traits and a risk factor for CHD, differs between hypertensive African Americans and whites.
Methods
Participants included 1177 hypertensive African Americans from Jackson MS (60±7 years, 72.4% women) and 860 hypertensive whites from Rochester MN (58±7 years, 56.7% women). LDL particle size was measured by polyacrylamide gradient gel electrophoresis. Within each sex, we assessed whether ethnicity was significantly associated with differences in LDL particle size after adjustment for CHD risk factors (age, total cholesterol, HDL-C, triglycerides, systolic BP, diabetes, history of smoking, body mass index), statin use, and estrogen use (in women), and “lifestyle” variables (physical activity and alcohol intake).
Results
Although HDL-C levels were higher and triglyceride levels lower in African Americans, LDL particle size (adjusted for CHD risk factors) was lower (P < 0.0001) in African American men and women than in their white counterparts (mean ± SD; men, 267.6±5.2 Å vs. 270.2±4.8 Å; women 268.7±5.1 Å vs. 271.3±5.1 Å). In both sexes, African American ethnicity was associated with lower LDL particle size after adjustment for CHD risk factors, statin use and estrogen use (in women), as well as physical activity and alcohol intake.
Conclusion
Hypertensive African American men and women have lower LDL particle size than their white counterparts despite having higher HDL-C and lower triglycerides.
doi:10.1016/j.jacl.2007.05.001
PMCID: PMC2130773  PMID: 18074002
low-density lipoprotein; LDL particle size; risk factors; ethnicity; hypertension
24.  An electronic medical record-linked biorepository to identify novel biomarkers for atherosclerotic cardiovascular disease 
Background: Atherosclerotic vascular disease (AVD), a leading cause of morbidity and mortality, is increasing in prevalence in the developing world. We describe an approach to establish a biorepository linked to medical records with the eventual goal of facilitating discovery of biomarkers for AVD. Methods: The Vascular Disease Biorepository at Mayo Clinic was established to archive DNA, plasma, and serum from patients with suspected AVD. AVD phenotypes, relevant risk factors and comorbid conditions were ascertained by electronic medical record (EMR)-based electronic algorithms that included diagnosis and procedure codes, laboratory data and text searches to ascertain medication use. Results: Up to December 2012, 8800 patients referred for vascular ultrasound examination and non-invasive lower extremity arterial evaluation were approached, of whom 5268 consented. The mean age of the initial 2182 patients recruited was 70.4 ± 11.2 years, 62.6% were men and 97.6% were whites. The prevalences of AVD phenotypes were: carotid artery stenosis 48%, abdominal aortic aneurysm 21% and peripheral arterial disease 38%. Positive predictive values for electronic phenotyping algorithms were>0.90 for cases (and>0.95 for controls) for each AVD phenotype, using manual review of the EMR as the gold standard. The prevalences of risk factors and comorbidities were as follows: hypertension 78%, diabetes 29%, dyslipidemia 73%, smoking 70%, coronary heart disease 37%, heart failure 12%, cerebrovascular disease 20% and chronic kidney disease 19%. Conclusions: Our study demonstrates the feasibility of establishing a biorepository of plasma, serum and DNA, with relatively rapid annotation of clinical variables using EMR-based algorithms.
doi:10.5339/gcsp.2013.10
PMCID: PMC3963733
atherosclerotic vascular disease; biorepository; electronic medical records; electronic phenotyping
25.  Billing code algorithms to identify cases of peripheral artery disease from administrative data 
Objective
To construct and validate billing code algorithms for identifying patients with peripheral arterial disease (PAD).
Methods
We extracted all encounters and line item details including PAD-related billing codes at Mayo Clinic Rochester, Minnesota, between July 1, 1997 and June 30, 2008; 22 712 patients evaluated in the vascular laboratory were divided into training and validation sets. Multiple logistic regression analysis was used to create an integer code score from the training dataset, and this was tested in the validation set. We applied a model-based code algorithm to patients evaluated in the vascular laboratory and compared this with a simpler algorithm (presence of at least one of the ICD-9 PAD codes 440.20–440.29). We also applied both algorithms to a community-based sample (n=4420), followed by a manual review.
Results
The logistic regression model performed well in both training and validation datasets (c statistic=0.91). In patients evaluated in the vascular laboratory, the model-based code algorithm provided better negative predictive value. The simpler algorithm was reasonably accurate for identification of PAD status, with lesser sensitivity and greater specificity. In the community-based sample, the sensitivity (38.7% vs 68.0%) of the simpler algorithm was much lower, whereas the specificity (92.0% vs 87.6%) was higher than the model-based algorithm.
Conclusions
A model-based billing code algorithm had reasonable accuracy in identifying PAD cases from the community, and in patients referred to the non-invasive vascular laboratory. The simpler algorithm had reasonable accuracy for identification of PAD in patients referred to the vascular laboratory but was significantly less sensitive in a community-based sample.
doi:10.1136/amiajnl-2013-001827
PMCID: PMC3861931  PMID: 24166724
peripheral artery disease; billing codes; electronic medical record; informatics

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