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2.  Coronary Angiography: Is it Time to Reassess? 
Circulation  2013;127(17):1760-1762.
doi:10.1161/CIRCULATIONAHA.113.002566
PMCID: PMC3746971  PMID: 23630085
angiography; stenosis; cardiovascular disease; diagnosis
3.  IMPACT OF TCF7L2 SINGLE NUCLEOTIDE POLYMORPHISMS ON HYDROCHLOROTHIAZIDE-INDUCED DIABETES 
Pharmacogenetics and genomics  2013;23(12):697-705.
OBJECTIVE
Thiazide diuretics have been associated with increased risk for new onset diabetes (NOD), but pharmacogenetic markers of thiazide-induced NOD are not well studied. Single nucleotide polymorphisms (SNPs) in the Transcription Factor 7-Like 2 gene (TCF7L2) represent the strongest and most reproducible genetic associations with diabetes. We investigated the association of tag SNPs in TCF7L2 with thiazide-induced NOD.
METHODS
We identified cases that developed NOD and age, gender, and race/ethnicity-matched controls from the INternational VErapamil SR Trandolapril STudy (INVEST). INVEST compared cardiovascular outcomes between two antihypertensive treatment strategies in ethnically diverse patients with hypertension and coronary artery disease. We genotyped 101 TCF7L2 tag SNPs and used logistic regression to test for pharmacogenetic (SNP*hydrochlorothiazide treatment) interactions. Permuted interaction p values were corrected with the PACT test and adjusted for diabetes-related variables.
RESULTS
In INVEST whites, we observed three TCF7L2 SNPs with significant SNP*treatment interactions for NOD. The strongest pharmacogenetic interaction was observed for rs7917983 (synergy index 3.37 [95%CI 1.72–6.59], p=5.0×10−4, PACT =0.03), which was associated with increased NOD risk in hydrochlorothiazide-treated patients (OR 1.53 [1.04–2.25], p=0.03) and decreased NOD risk in non hydrochlorothiazide-treated patients (OR 0.48 [0.27–0.86], p=0.02). The TCF7L2 SNP rs4506565, previously associated with diabetes, showed a similar, significant pharmacogenetic association.
CONCLUSIONS
Our results suggest that hydrochlorothiazide treatment is an environmental risk factor that increases diabetes risk beyond that attributed to TCF7L2 variation in white, hypertensive patients. Further study and replication of our results is needed to confirm pharmacogenetic influences of TCF7L2 SNPs on thiazide-induced NOD.
doi:10.1097/FPC.0000000000000012
PMCID: PMC3893755  PMID: 24128935
pharmacogenetics; TCF7L2; diabetes mellitus; hydrochlorothiazide
4.  Implementation of Cardiovascular Cell Therapy Network Trials Challenges, Innovation, and Lessons Learned: Experiences of the CCTRN 
The Cardiovascular Cell Therapy Network (CCTRN) was developed by the National Heart, Lung, and Blood Institute to design and conduct clinical trials to advance the field of cardiovascular (CV) cell-based therapy. The CCTRN successfully completed three clinical trials involving approximately 300 subjects across five centers and six satellites. Although the concept of a network within clinical trials research is not new, the knowledge gained in the implementation of such large-scale trials, particularly in novel therapeutic areas such as cell therapy is not often detailed in the literature. The purpose of this communication is to summarize key factors in achieving Network goals and share the knowledge gained to promote success in future CV disease cell therapy trials and networks.
doi:10.1586/14779072.2013.839943
PMCID: PMC4117343  PMID: 24147517
stem cell therapy; network; cardiovascular disease; acute myocardial infarction; heart failure; TIME; LateTIME; FOCUS; Cardiovascular Cell Therapy Network
5.  Anxiety Associations with Cardiac Symptoms, Angiographic Disease Severity, & Healthcare Utilization: The NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation 
International journal of cardiology  2013;168(3):2335-2340.
Background
Anxiety is common among patients presenting with suspected coronary artery disease (CAD). In a sample of women with signs and symptoms of ischemia, we examined three anxiety markers as predictors of CAD endpoints including: 1) cardiac symptom indicators; 2) angiographic CAD severity; and 3) healthcare utilization (cardiac hospitalizations & 5-year cardiovascular [CVD] healthcare costs).
Methods
Participants completed a baseline protocol including coronary angiogram, cardiac symptoms, psychosocial measures and a median 5.9-year follow-up to track hospitalizations. We calculated CVD costs based on cardiac hospitalizations, treatment visits, and CVD medications. Anxiety measures included anxiolytic medication use, Spielberger Trait Anxiety Inventory (STAI) scores, and anxiety disorder treatment history.
Results
The sample numbered 514 women with anxiety measure data and covariates (mean age=57.5[11.1]). One in five (20.4%) women reported using anxiolytic agents. Anxiety correlated with cardiac symptom indicators (anxiolytic use with nighttime angina & nitroglycerine use; STAI scores & anxiety disorder treatment history with nighttime angina, shortness of breath, & angina frequency). Anxiety disorder treatment history (but not STAI scores or anxiolytics) predicted less severe CAD. Anxiolytic use (but not STAI scores or anxiety disorder treatment history) predicted hospitalizations for chest pain and coronary catheterization (HR’s=2.0, 95% CI’s=1.1–4.7). Anxiety measures predicted higher 5-year CVD costs (+9.0–42.7%) irrespective of CAD severity.
Conclusions
Among women with signs and symptoms of myocardial ischemia, anxiety measures predict cardiac endpoints ranging from cardiac symptom severity to healthcare utilization. Based on these findings, anxiety may warrant greater consideration among women with suspected CAD.
doi:10.1016/j.ijcard.2013.01.036
PMCID: PMC3683077  PMID: 23410495
cardiovascular disease; women; prospective; anxiety; depression
6.  Diminazene aceturate enhances ACE2 activity and attenuates ischemia-induced cardiac pathophysiology 
Hypertension  2013;62(4):10.1161/HYPERTENSIONAHA.113.01337.
Angiotensin-converting enzyme 2 (ACE2) plays a critical role against myocardial infarction (MI). We hypothesized that activation of intrinsic ACE2 would be protective against ischemia-induced cardiac pathophysiology. Diminazine aceturate (DIZE), a small molecule ACE2 activator has been used to evaluate this hypothesis. DIZE (15 mg/kg/day, s.c.) was injected two days prior to MI surgery and continued throughout the study-period. MI rats showed a 62% decrease in fractional shortening (FS,%) [control (Con): 51.1 ± 3.2; DIZE alone (D) : 52.1 ± 3.2; MI (M): 19.1± 3.0], a 55% decrease in contractility (dP/dtmax mmHg/s) (Con: 9480 ± 425.3; D: 9585 ± 597.4; M: 4251 ± 657.7), and a 27% increase in ventricular hypertrophy [VH, mg/mm (Con: 26.5 ± 1.5; D: 26.9 ± 1.4; M: 33.4± 1.1)]. DIZE attenuated the MI-induced decrease in FS by 89%, improved dP/dtmax by 92%, and reversed VH by 18%. MI also significantly increased ACE and angiotensin type 1 receptor levels while decreased ACE2 activity by 40% (Con: 246.2 ± 25.1; D: 254.2 ± 20.6; M: 148.9 ± 29.2, RFU/min), which was reversed by DIZE treatment. Thus, DIZE treatment decreased the infarct area, attenuated LV remodeling post-MI and restored normal balance of the cardiac renin angiotensin system. Additionally, DIZE treatment increased circulating endothelial progenitor cells, increased engraftment of cardiac progenitor cells and decreased inflammatory cells in peri-infarct cardiac regions. All of the beneficial effects associated with DIZE treatment were abolished by C-16, an ACE2 inhibitor. Collectively, DIZE and DIZE-like small molecules may represent promising new therapeutic agents for MI.
doi:10.1161/HYPERTENSIONAHA.113.01337
PMCID: PMC3881360  PMID: 23959549
angiotensin converting enzyme 2; myocardial infarction; Diminazene; Macrophages; stem cell
7.  Clinical implications of the Women’s Ischemia Syndrome Evaluation : interrelationships between symptoms, psychosocial factors and cardiovascular outcomes 
Women's health (London, England)  2013;9(5):479-490.
Cardiovascular disease (CVD) remains the leading cause of death in the US and is associated with several modifiable (hypertension, diabetes, high cholesterol, tobacco use, physical inactivity, obesity and unhealthy diet) and nonmodifiable (age, gender, family history) risk factors. The role of psychosocial risk factors in the development of CVD has a growing body of literature, and differences in men and women have been identified. The Women’s Ischemia Syndrome Evaluation (WISE) provides insight into psychosocial risk factors in a cohort of women presenting with chest pain who had a comprehensive battery of psychosocial assessments and who had long-term follow up. This review focuses on symptom presentation for chest pain, and its relationship to CVD morbidity and mortality, quality of life, healthcare costs, and psychosocial predictor variables including anxiety, depression, hostility, and social networks. In WISE, persistent chest pain was associated with increased rate of adverse events and relatively high rates of depression and anxiety with reduced functional capacity and impaired QOL over a median of 6 years follow-up. More research is needed to better understand these relationships between symptoms and negative emotions and determine if psychological (pharmacologic and/or cognitive) interventions might impact both psychological and cardiovascular outcomes.
doi:10.2217/whe.13.50
PMCID: PMC4136496  PMID: 24007253
Women; chest pain; nonobstructive disease; depression; anxiety; coronary artery disease
8.  Loci influencing blood pressure identified using a cardiovascular gene-centric array 
Ganesh, Santhi K. | Tragante, Vinicius | Guo, Wei | Guo, Yiran | Lanktree, Matthew B. | Smith, Erin N. | Johnson, Toby | Castillo, Berta Almoguera | Barnard, John | Baumert, Jens | Chang, Yen-Pei Christy | Elbers, Clara C. | Farrall, Martin | Fischer, Mary E. | Franceschini, Nora | Gaunt, Tom R. | Gho, Johannes M.I.H. | Gieger, Christian | Gong, Yan | Isaacs, Aaron | Kleber, Marcus E. | Leach, Irene Mateo | McDonough, Caitrin W. | Meijs, Matthijs F.L. | Mellander, Olle | Molony, Cliona M. | Nolte, Ilja M. | Padmanabhan, Sandosh | Price, Tom S. | Rajagopalan, Ramakrishnan | Shaffer, Jonathan | Shah, Sonia | Shen, Haiqing | Soranzo, Nicole | van der Most, Peter J. | Van Iperen, Erik P.A. | Van Setten, Jessica | Vonk, Judith M. | Zhang, Li | Beitelshees, Amber L. | Berenson, Gerald S. | Bhatt, Deepak L. | Boer, Jolanda M.A. | Boerwinkle, Eric | Burkley, Ben | Burt, Amber | Chakravarti, Aravinda | Chen, Wei | Cooper-DeHoff, Rhonda M. | Curtis, Sean P. | Dreisbach, Albert | Duggan, David | Ehret, Georg B. | Fabsitz, Richard R. | Fornage, Myriam | Fox, Ervin | Furlong, Clement E. | Gansevoort, Ron T. | Hofker, Marten H. | Hovingh, G. Kees | Kirkland, Susan A. | Kottke-Marchant, Kandice | Kutlar, Abdullah | LaCroix, Andrea Z. | Langaee, Taimour Y. | Li, Yun R. | Lin, Honghuang | Liu, Kiang | Maiwald, Steffi | Malik, Rainer | Murugesan, Gurunathan | Newton-Cheh, Christopher | O'Connell, Jeffery R. | Onland-Moret, N. Charlotte | Ouwehand, Willem H. | Palmas, Walter | Penninx, Brenda W. | Pepine, Carl J. | Pettinger, Mary | Polak, Joseph F. | Ramachandran, Vasan S. | Ranchalis, Jane | Redline, Susan | Ridker, Paul M. | Rose, Lynda M. | Scharnag, Hubert | Schork, Nicholas J. | Shimbo, Daichi | Shuldiner, Alan R. | Srinivasan, Sathanur R. | Stolk, Ronald P. | Taylor, Herman A. | Thorand, Barbara | Trip, Mieke D. | van Duijn, Cornelia M. | Verschuren, W. Monique | Wijmenga, Cisca | Winkelmann, Bernhard R. | Wyatt, Sharon | Young, J. Hunter | Boehm, Bernhard O. | Caulfield, Mark J. | Chasman, Daniel I. | Davidson, Karina W. | Doevendans, Pieter A. | FitzGerald, Garret A. | Gums, John G. | Hakonarson, Hakon | Hillege, Hans L. | Illig, Thomas | Jarvik, Gail P. | Johnson, Julie A. | Kastelein, John J.P. | Koenig, Wolfgang | März, Winfried | Mitchell, Braxton D. | Murray, Sarah S. | Oldehinkel, Albertine J. | Rader, Daniel J. | Reilly, Muredach P. | Reiner, Alex P. | Schadt, Eric E. | Silverstein, Roy L. | Snieder, Harold | Stanton, Alice V. | Uitterlinden, André G. | van der Harst, Pim | van der Schouw, Yvonne T. | Samani, Nilesh J. | Johnson, Andrew D. | Munroe, Patricia B. | de Bakker, Paul I.W. | Zhu, Xiaofeng | Levy, Daniel | Keating, Brendan J. | Asselbergs, Folkert W.
Human Molecular Genetics  2013;22(16):3394-3395.
doi:10.1093/hmg/ddt177
PMCID: PMC3888295
9.  A Critical Analysis of Clinical Outcomes Reported in Stem Cell Trials for Acute Myocardial Infarction: Some Thoughts for Design of Future Trials 
The purpose of stem cell therapy for myocardial infarction (MI) is to improve clinical outcomes, and detailed information on clinical outcomes is critical to appropriate planning of phase III trials. We examined data from select phase II trials using autologous bone marrow-derived stem cells (BMCs) in patients with acute MI. We extracted available definitions and outcome data, and generated standardized estimates of events to permit summary comparisons. Nine trials (1040 patients) with results for 6 months to 5 years were evaluated. Adverse outcomes varied widely, and there was a general lack of details in the definitions of these outcomes. Heart failure related hospitalizations occurred in only 16 (1.5%) and death in only 43 (4.1%) of all patients. Ischemia-related outcomes outnumbered heart failure outcomes more than 10-fold. Uniform criteria need to be developed to better define clinical outcomes of interest. Furthermore, a refocus from heart failure to ischemia-related outcomes seems appropriate.
doi:10.1007/s11883-013-0341-9
PMCID: PMC3800160  PMID: 23793731
stem cells; acute myocardial infarction; clinical outcomes; secondary outcomes; phase II trials
10.  Mortality implications of angina and blood pressure in hypertensive patients with coronary artery disease: new data from extended follow-up of the INternational VErapamil/Trandolapril STudy (INVEST) 
Clinical cardiology  2013;36(8):442-447.
Background
Angina and hypertension are common in patients with coronary artery disease (CAD), however the effect on mortality is unclear. We conducted this prespecified analysis of the INternational VErapamil/Trandolapril STudy (INVEST) to assess relationships between angina, blood pressure (BP), and mortality among elderly, hypertensive CAD patients.
Hypothesis
Angina and elevated BP will be associated with higher mortality.
Methods and Results
Extended follow-up was performed using the National Death Index for INVEST patients in the United States (n=16,951). Based on angina history at enrollment and during follow-up visits, patients were divided into groups: persistent (n=7184), new onset (n=899), resolved (n=4070), or never (n=4798). BP was evaluated at baseline, during drug titration and during follow-up on-treatment. On-treatment systolic BP was classified as tightly controlled (<130 mmHg), controlled (130–139 mmHg), or uncontrolled (≥140 mmHg). A Cox proportional hazards model was created adjusting for age, heart failure, diabetes, renal impairment, myocardial infarction, stroke, and smoking. The angina groups and BP control groups were compared using the never angina group as the reference. Only in the persistent angina group was a significant association with mortality observed, with an apparent protective effect (HR 0.82, 95% CI 0.75 to 0.89, P <0.0001). Uncontrolled BP was associated with increased mortality risk (HR 1.29, 95% CI 1.20 to 1.40, P <0.0001), as were several other known cardiovascular risk factors.
Conclusions
In hypertensive CAD patients, persistent angina was associated with lower mortality. The observed effect was small compared with other cardiovascular risk factors, such as BP, which were associated with increased mortality.
doi:10.1002/clc.22145
PMCID: PMC3775918  PMID: 23720247
Angina; Hypertension; Coronary disease; Prognosis; Myocardial infarction
11.  PHARMACOGENOMIC ASSOCIATION OF NON-SYNONYMOUS SNPS IN SIGLEC12, A1BG AND THE SELECTIN REGION AND CARDIOVASCULAR OUTCOMES 
Hypertension  2013;62(1):48-54.
We sought to identify novel pharmacogenetic markers associated with cardiovascular outcomes in patients with hypertension on antihypertensive therapy. We genotyped a 1:4 case:control cohort (n=1345) on the Illumina HumanCVD Beadchip from the International Verapamil SR-Trandolapril Study, where participants were randomized to a β blocker strategy or a calcium channel blocker strategy. Genome-spanning SNP × treatment interaction analyses of non-synonymous SNPs were conducted in white and Hispanic race/ethnic groups. Top hits from whites were tested in Hispanics for consistency. A genetic risk score was constructed from the top three signals and tested in the Nordic Diltiazem study. SIGLEC12 rs16982743 and A1BG rs893184 had a significant interaction with treatment strategy for adverse cardiovascular outcomes (International Verapamil SR-Trandolapril Study whites and Hispanics combined interaction P=0.0038, and 0.0036, respectively). A genetic risk score including rs16982743, rs893184 and rs4525 in F5, was significantly associated with treatment-related adverse cardiovascular outcomes in whites and Hispanics from the International Verapamil SR-Trandolapril Study and in the Nordic Diltiazem study (meta-analysis interaction P=2.39×10−5). In patients with a genetic risk score of zero or 1, calcium channel blocker treatment was associated with lower risk (OR (95% CI) = 0.60 (0.42-0.86)), and in those with a genetic risk score of 2-3, calcium channel blocker treatment was associated with higher risk, OR (95% CI) = 1.31 (1.08-1.59)). These results suggest cardiovascular outcomes may differ based on SIGLEC12, A1BG, F5 genotypes and antihypertensive treatment strategy. These specific genetic associations and our risk score provide insight into a potential approach to personalized antihypertensive treatment selection.
doi:10.1161/HYPERTENSIONAHA.111.00823
PMCID: PMC3686553  PMID: 23690342
Pharmacogenomics; Hypertension; antihypertensive agents; cardiovascular outcomes; genetic variation; beta-blockers, calcium channel blockers
12.  Adverse Outcomes Among Women Presenting with Signs and Symptoms of Ischemia and No Obstructive Coronary Artery Disease: Findings from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) Angiographic Core Laboratory 
American heart journal  2013;166(1):134-141.
Background
Women presenting with signs and symptoms of myocardial ischemia frequently have no or non-obstructive coronary artery disease (CAD).
Objective
To investigate associations between angiographic measures and longer-term clinical outcomes among women with signs and symptoms of ischemia referred for coronary angiography.
Methods
Prospective cohort analysis of women referred for coronary angiography and enrolled in the National Heart, Lung, and Blood Institute-sponsored Women’s Ischemia Syndrome Evaluation (WISE). An angiographic severity score was prospectively developed, assigning points for any stenosis weighted by stenosis severity, location and collaterals, and then tested for prediction for adverse outcome in 917 women over a median 9.3 years.
Setting
Referral centers.
Patients
Women, with signs and/or symptoms of myocardial ischemia, referred for coronary angiography were consecutively consented and enrolled in a prospective study.
Main Outcome Measures
First occurrence of cardiovascular death or non-fatal myocardial infarction. Hospitalization for angina was a secondary outcome.
Results
Cardiovascular death or myocardial infarction at 10 years occurred in 6.7%, 12.8% and 25.9% of women with no, non-obstructive, and obstructive CAD (p<0.0001), respectively. Cumulative 10-year cardiovascular death or MI rates showed progressive, near linear, increases for each WISE CAD severity score range of 5, 5.1–10, 10.1–20, 20.1–50, and >50. The optimal threshold in the WISE severity score classifications for predicting cardiovascular mortality was >10 (e.g. 5.0–10 vs. 10.1–89), with both a sensitivity and specificity of 0.64 and an area under the curve of 0.64 (p=0.02, 95% CI = 0.59, 0.68).
Conclusions
Among women with signs and symptoms of ischemia, non-obstructive CAD is common, and associated with adverse outcomes over the longer-term. The new WISE angiographic score appears to be useful for risk prediction in this population.
doi:10.1016/j.ahj.2013.04.002
PMCID: PMC3703586  PMID: 23816032
angiography score; coronary disease; prognosis; women
13.  TIMI Frame Count and Adverse Events in Women with No Obstructive Coronary Disease: A Pilot Study from the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) 
PLoS ONE  2014;9(5):e96630.
Background
TIMI frame count (TFC) predicts outcomes in patients with obstructive coronary artery disease (CAD); it remains unclear whether TFC predicts outcomes in patients without obstructive CAD.
Methods
TFC was determined in a sample of women with no obstructive CAD enrolled in the Women's Ischemia Syndrome Evaluation (WISE) study. Because TFC is known to be higher in the left anterior descending artery (LAD), TFC determined in the LAD was divided by 1.7 to provide a corrected TFC (cTFC).
Results
A total of 298 women, with angiograms suitable for TFC analysis and long-term (6–10 year) follow up data, were included in this sub-study. Their age was 55±11 years, most were white (86%), half had a history of smoking, and half had a history of hypertension. Higher resting cTFC was associated with a higher rate of hospitalization for angina (34% in women with a cTFC >35, 15% in women with a cTFC ≤35, P<0.001). cTFC provided independent prediction of hospitalization for angina after adjusting for many baseline characteristics. In this cohort, resting cTFC was not predictive of major events (myocardial infarction, heart failure, stroke, or all-cause death), cardiovascular events, all-cause mortality, or cardiovascular mortality.
Conclusions
In women with signs and symptoms of ischemia but no obstructive CAD, resting cTFC provides independent prediction of hospitalization for angina. Larger studies are required to determine if resting TFC is predictive of major events in patients without obstructive coronary artery disease.
doi:10.1371/journal.pone.0096630
PMCID: PMC4011756  PMID: 24800739
14.  Phase II Clinical Research Design in Cardiology 
Circulation  2013;127(15):1630-1635.
doi:10.1161/CIRCULATIONAHA.112.000779
PMCID: PMC3967793  PMID: 23588961
clinical trials; phase II; research design; stem cell; therapy
15.  Loci influencing blood pressure identified using a cardiovascular gene-centric array 
Ganesh, Santhi K. | Tragante, Vinicius | Guo, Wei | Guo, Yiran | Lanktree, Matthew B. | Smith, Erin N. | Johnson, Toby | Castillo, Berta Almoguera | Barnard, John | Baumert, Jens | Chang, Yen-Pei Christy | Elbers, Clara C. | Farrall, Martin | Fischer, Mary E. | Franceschini, Nora | Gaunt, Tom R. | Gho, Johannes M.I.H. | Gieger, Christian | Gong, Yan | Isaacs, Aaron | Kleber, Marcus E. | Leach, Irene Mateo | McDonough, Caitrin W. | Meijs, Matthijs F.L. | Mellander, Olle | Molony, Cliona M. | Nolte, Ilja M. | Padmanabhan, Sandosh | Price, Tom S. | Rajagopalan, Ramakrishnan | Shaffer, Jonathan | Shah, Sonia | Shen, Haiqing | Soranzo, Nicole | van der Most, Peter J. | Van Iperen, Erik P.A. | Van Setten, Jessic A. | Vonk, Judith M. | Zhang, Li | Beitelshees, Amber L. | Berenson, Gerald S. | Bhatt, Deepak L. | Boer, Jolanda M.A. | Boerwinkle, Eric | Burkley, Ben | Burt, Amber | Chakravarti, Aravinda | Chen, Wei | Cooper-DeHoff, Rhonda M. | Curtis, Sean P. | Dreisbach, Albert | Duggan, David | Ehret, Georg B. | Fabsitz, Richard R. | Fornage, Myriam | Fox, Ervin | Furlong, Clement E. | Gansevoort, Ron T. | Hofker, Marten H. | Hovingh, G. Kees | Kirkland, Susan A. | Kottke-Marchant, Kandice | Kutlar, Abdullah | LaCroix, Andrea Z. | Langaee, Taimour Y. | Li, Yun R. | Lin, Honghuang | Liu, Kiang | Maiwald, Steffi | Malik, Rainer | Murugesan, Gurunathan | Newton-Cheh, Christopher | O'Connell, Jeffery R. | Onland-Moret, N. Charlotte | Ouwehand, Willem H. | Palmas, Walter | Penninx, Brenda W. | Pepine, Carl J. | Pettinger, Mary | Polak, Joseph F. | Ramachandran, Vasan S. | Ranchalis, Jane | Redline, Susan | Ridker, Paul M. | Rose, Lynda M. | Scharnag, Hubert | Schork, Nicholas J. | Shimbo, Daichi | Shuldiner, Alan R. | Srinivasan, Sathanur R. | Stolk, Ronald P. | Taylor, Herman A. | Thorand, Barbara | Trip, Mieke D. | van Duijn, Cornelia M. | Verschuren, W. Monique | Wijmenga, Cisca | Winkelmann, Bernhard R. | Wyatt, Sharon | Young, J. Hunter | Boehm, Bernhard O. | Caulfield, Mark J. | Chasman, Daniel I. | Davidson, Karina W. | Doevendans, Pieter A. | FitzGerald, Garret A. | Gums, John G. | Hakonarson, Hakon | Hillege, Hans L. | Illig, Thomas | Jarvik, Gail P. | Johnson, Julie A. | Kastelein, John J.P. | Koenig, Wolfgang | März, Winfried | Mitchell, Braxton D. | Murray, Sarah S. | Oldehinkel, Albertine J. | Rader, Daniel J. | Reilly, Muredach P. | Reiner, Alex P. | Schadt, Eric E. | Silverstein, Roy L. | Snieder, Harold | Stanton, Alice V. | Uitterlinden, André G. | van der Harst, Pim | van der Schouw, Yvonne T. | Samani, Nilesh J. | Johnson, Andrew D. | Munroe, Patricia B. | de Bakker, Paul I.W. | Zhu, Xiaofeng | Levy, Daniel | Keating, Brendan J. | Asselbergs, Folkert W.
Human Molecular Genetics  2013;22(8):1663-1678.
Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ∼50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ∼2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10−6). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.
doi:10.1093/hmg/dds555
PMCID: PMC3657476  PMID: 23303523
16.  In Women with Symptoms of Cardiac Ischemia, Non-Obstructive Coronary Arteries, and Microvascular Dysfunction, ACE Inhibition is Associated with Improved Microvascular Function: A Double-blind Randomized Study from the NHLBI Women’s Ischemia Syndrome Evaluation (WISE) 
American heart journal  2011;162(4):678-684.
Background
We investigated the role of the renin-angiotensin system in women with signs and symptoms of ischemia without obstructive coronary artery disease (CAD). Although microvascular dysfunction has been suggested to explain this syndrome and recently was found to predict adverse outcomes, the mechanisms and treatments remain unclear.
Methods
In a substudy within the Women’s Ischemia Syndrome Evaluation, 78 women with microvascular dysfunction (coronary flow reserve [CFR] <3.0 following adenosine) and no obstructive CAD were randomly assigned to either an angiotensin-converting enzyme inhibition (ACE-I) with quinapril or a placebo treatment group. The primary efficacy parameter was CFR at 16 weeks adjusted for baseline characteristics and clinical site. The secondary response variable was freedom from angina symptoms assessed using the Seattle Angina Questionnaire.
Results
A total of 61 women completed the 16-week treatment period with repeat CFR measurements, and treatment was well tolerated. For the primary outcome, at 16 weeks CFR improved more with ACE-I than placebo (p<0.02). For the secondary outcome of symptom improvement, ACE-I treatment (p=0.037) and CFR increase (p=0.008) both contributed.
Conclusions
Microvascular function improves with ACE-I therapy in women with signs and symptoms of ischemia without obstructive CAD. This improvement is associated with reduction in angina. The beneficial response of the coronary microvasculature was limited to women with lower baseline CFR values, suggesting that the renin-angiotensin system may be more involved among women with more severe microvascular defects.
doi:10.1016/j.ahj.2011.07.011
PMCID: PMC3191889  PMID: 21982660
17.  Genetic Variation in PEAR1 is Associated with Platelet Aggregation and Cardiovascular Outcomes 
Background
Aspirin or dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is standard therapy for patients at increased risk for cardiovascular events. However, the genetic determinants of variable response to aspirin (alone and in combination with clopidogrel) are not known.
Methods and Results
We measured ex-vivo platelet aggregation before and after DAPT in individuals (n=565) from the Pharmacogenomics of Antiplatelet Intervention (PAPI) Study and conducted a genome-wide association study (GWAS) of drug response. Significant findings were extended by examining genotype and cardiovascular outcomes in two independent aspirin-treated cohorts: 227 percutaneous coronary intervention (PCI) patients, and 1,000 patients of the International VErapamil SR/trandolapril Study (INVEST) GENEtic Substudy (INVEST-GENES). GWAS revealed a strong association between single nucleotide polymorphisms on chromosome 1q23 and post-DAPT platelet aggregation. Further genotyping revealed rs12041331 in the platelet endothelial aggregation receptor-1 (PEAR1) gene to be most strongly associated with DAPT response (P=7.66×10−9). In Caucasian and African American patients undergoing PCI, A-allele carriers of rs12041331 were more likely to experience a cardiovascular event or death compared to GG homozygotes (hazard ratio = 2.62, 95%CI 0.96-7.10, P=0.059 and hazard ratio = 3.97, 95%CI 1.10-14.31, P=0.035 respectively). In aspirin-treated INVEST-GENES patients, rs12041331 A-allele carriers had significantly increased risk of myocardial infarction compared to GG homozygotes (OR=2.03, 95%CI 1.01-4.09, P=0.048).
Conclusions
Common genetic variation in PEAR1 may be a determinant of platelet response and cardiovascular events in patients on aspirin, alone and in combination with clopidogrel.
Clinical Trial Registration Information
clinicaltrials.gov; Identifiers: NCT00799396 and NCT00370045
doi:10.1161/CIRCGENETICS.111.964627
PMCID: PMC3715320  PMID: 23392654
pharmacogenomics; platelets; percutaneous coronary intervention; PEAR1; CYP2C19
18.  Association of variants in NEDD4L with blood pressure response and adverse cardiovascular outcomes in hypertensive patients treated with thiazide diuretics 
Journal of hypertension  2013;31(4):698-704.
Objective
Single-nucleotide polymorphisms (SNPs) in NEDD4L may influence the ability of the NEDD4L protein to reduce epithelial sodium channel expression. A variant in NEDD4L, rs4149601, was associated with antihypertensive response and cardiovascular outcomes during treatment with thiazide diuretics and β-blockers in a Swedish population. We sought to further evaluate associations between NEDD4L polymorphisms, blood pressure response and cardiovascular outcomes with thiazide diuretics and β-blockers.
Methods
Four SNPs, rs4149601, rs292449, rs1008899 and rs75982813, were genotyped in 767 patients from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) clinical trial and association was assessed with blood pressure response to hydrochlorothiazide and atenolol. One SNP, rs4149601, was also genotyped in 1345 patients from the International Verapmil SR Trandolapril Study (INVEST), and association was examined with adverse cardiovascular outcomes relative to hydrochlorothiazide treatment.
Results
Significant associations or trends were found between rs4149601, rs292449, rs75982813 and rs1008899 and decreases in blood pressure in whites on hydrochlorothiazide, and a significant association was observed with increasing copies of the GC rs4149601-rs292449 haplotype and greater blood pressure response to hydrochlorothiazide in whites (P = 0.0006 and 0.006, SBP and DBP, respectively). Significant associations were also seen with rs4149601 and an increased risk for adverse cardiovascular outcomes in whites not treated with hydrochlorothiazide [P = 0.022, odds ratio (95% confidence interval) = 10.65 (1.18–96.25)].
Conclusion
NEDD4L rs4149601, rs292449 and rs75982813 may be predictors for blood pressure response to hydrochlorothiazide in whites, and NEDD4L rs4149601 may be a predictor for adverse cardiovascular outcomes in whites not treated with hydrochlorothiazide.
doi:10.1097/HJH.0b013e32835e2a71
PMCID: PMC3756535  PMID: 23353631
epithelial sodium channel; hypertension; International Verapamil SR Trandolapril Study; neural precursor cell expressed developmentally down-regulated 4 like; Pharmacogenomic Evaluation of Antihypertensive Responses; pharmacogenetics
19.  Effect of Phosphodiesterase Type 5 Inhibition on Microvascular Coronary Dysfunction in Women: A Women’s Ischemia Syndrome Evaluation (WISE) Ancillary Study 
Clinical cardiology  2011;34(8):483-487.
SUMMARY
Background
Microvascular coronary dysfunction (MCD) is associated with symptoms, signs of ischemia, and adverse outcomes in women without macrovascular obstructive coronary artery disease (M-CAD). Although, MCD can be quantified using coronary flow reserve (CFR), treatment is poorly defined.
Hypothesis
Phosphodiesterase type 5 (PDE-5) inhibition acutely improves MCD in these women.
Methods
The subjects were 23 symptomatic women (age 54±11 years) participating in an ancillary study of the Women’s Ischemia Syndrome Evaluation (WISE) with baseline CFR ≤3.0 (Doppler flow wire and intracoronary adenosine) and without M-CAD. CFR was re-measured 45 minutes after PDE-5 inhibition (100 mg oral sildenafil). The primary measure of interest was change in CFR adjusted for baseline variables.
Results
The relationship between log2 transformed CFR post–PDE-5 inhibition (adjusted) and baseline was different from the line of identity (slope: 0.55 vs. 1.0, P=0.008; intercept: 0.73 vs. 0.0, P=0.01), indicating that PDE-5 inhibition improves CFR and the lower the baseline CFR, the greater the response. Among women with baseline CFR ≤2.5 (N=11), CFR increased from 2.1±0.2 to 2.7±0.6 (P=0.006). For women with baseline CFR >2.5 (N=12), CFR did not change (3.1±0.3 to 3.0±0.6; P=0.70).
Conclusions
For women with symptoms and signs of ischemia and no M-CAD, PDE-5 inhibition is associated with acute improvement in CFR and the effect concentrates among those with CFR ≤2.5. If these acute effects are sustained, then PDE-5 inhibition would provide a rational strategy for management of MCD in symptomatic women without M-CAD. The longer-term effects warrant study in a randomized trial using a sustained acting PDE-5 inhibitor.
doi:10.1002/clc.20935
PMCID: PMC3151010  PMID: 21780138
Women; Microvascular coronary dysfunction; Coronary flow reserve; Phosphodiesterase type 5 inhibition
20.  Cardiovascular and Mortality Risk of Apparent Resistant Hypertension in Women With Suspected Myocardial Ischemia: A Report From the NHLBI‐Sponsored WISE Study 
Background
Women are more likely than men to develop resistant hypertension, which is associated with excess risk of major adverse outcomes; however, the impact of resistant hypertension in women with ischemia has not been explicitly studied. In this Women's Ischemia Syndrome Evaluation (WISE) analysis, we assessed long‐term adverse outcomes associated with apparent treatment‐resistant hypertension (aTRH) among women with suspected myocardial ischemia referred for coronary angiography.
Methods and Results
Women (n=927) were grouped according to baseline blood pressure (BP): normotensive (no hypertension history, BP <140/90 mm Hg, no antihypertensive drugs); controlled (BP <140/90 mm Hg and a hypertension diagnosis or on 1 to 3 drugs); uncontrolled (BP ≥140/90 mm Hg on ≤2 drugs); or aTRH (BP ≥140/90 mm Hg on 3 drugs or anyone on ≥4 drugs). Adverse outcomes (first occurrence of death [any cause], nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure or angina) were collected over 10 years of follow‐up. Apparent treatment‐resistant hypertension prevalence was 10.4% among those with hypertension. Women with aTRH had a greater incidence of adverse outcomes, compared with normotensive women (adjusted hazard ratio [HR], 3.25; 95% confidence interval [CI], 1.94 to 5.43), and women with controlled (HR, 1.77; 95% CI, 1.26 to 2.49) and uncontrolled (HR, 1.62; 95% CI, 1.15 to 2.27) hypertension; outcome differences were evident early in follow‐up. Risk of all‐cause death was greater in the aTRH group, compared to the normotensive women and women with controlled and uncontrolled hypertension.
Conclusions
In this cohort of women with evidence of ischemia, aTRH was associated with a profoundly increased long‐term risk of major adverse events, including death, that emerged early during follow‐up.
doi:10.1161/JAHA.113.000660
PMCID: PMC3959684  PMID: 24584740
hypertension; resistant hypertension; WISE; women
22.  Number and Function of Bone-Marrow Derived Angiogenic Cells and Coronary Flow Reserve in Women without Obstructive Coronary Artery Disease: A Substudy of the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) 
PLoS ONE  2013;8(12):e81595.
Background
In women with ischemia and no obstructive coronary artery disease, the Women's Ischemic Syndrome Evaluation (WISE) observed that microvascular coronary dysfunction (MCD) is the best independent predictor of adverse cardiovascular events. Since coronary microvascular tone is regulated in part by endothelium, we hypothesized that circulating endothelial cells (CEC), which reflect endothelial injury, and the number and function of bone-marrow derived angiogenic cells (BMDAC), which could help repair damaged endothelium, may serve as biomarkers for decreased coronary flow reserve (CFR) and MCD.
Methods
We studied 32 women from the WISE cohort. CFR measurements in response to intracoronary adenosine were taken as an index of MCD. We enumerated BMDAC colonies and CEC in peripheral blood samples. BMDAC function was assessed by assay of migration of CD34+ cells toward SDF-1 and measurement of bioavailable nitric oxide (NO). These findings were compared with a healthy reference group and also entered into a multivariable model with CFR as the dependent variable.
Results
Compared with a healthy reference group, women with MCD had lower numbers of BMDAC colonies [16 (0, 81) vs. 24 (14, 88); P = 0.01] and NO [936 (156, 1875) vs. 1168 (668, 1823); P = 0.02]. Multivariable regression analysis showed strong correlation of CFR to the combination of BMDAC colony count and CD34+ cell function (migration and NO) (R2 = 0.45; P<0.05).
Conclusions
The BMDAC function and numbers of BMDAC colonies are decreased in symptomatic women with MCD and are independently associated with CFR. These circulating cells may provide mechanistic insights into MCD in women with ischemia.
doi:10.1371/journal.pone.0081595
PMCID: PMC3846855  PMID: 24312563
23.  Improved diagnosis and prognosis using Decisions Informed by Combining Entities (DICE): results from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) 
Objectives
To introduce an algorithmic approach to improve the interpretation of myocardial perfusion images in women with suspected myocardial ischemia.
Background
Gated single photon emission computed tomography (SPECT) and magnetic resonance (MR) myocardial perfusion imaging (MPI) approaches have relatively poor diagnostic and prognostic value in women with suspected myocardial ischemia. Here we introduce an approach: Decisions Informed by Combining Entities (DICE) that forms a mathematical model utilizing MPI and cardiac dimensions generated by one modality to predict the perfusion status of another modality. The effect of the model is to systematically incorporate cardiac metrics that influence the interpretation of perfusion images, leading to greater consistency in designation of myocardial perfusion status between studies.
Methods
Women (n=213), with suspected myocardial ischemia, underwent MPI assessment for regional perfusion defects using two modalities: gated SPECT (n=207) and MR imaging (n=203). To determine perfusion status, MR data were evaluated qualitatively and semi-quantitatively while SPECT data were evaluated using conventional clinical criteria. These perfusion status readings were designated “Original”. Four regression models were generated to model perfusion status obtained with one modality [e.g., semi-quantitative magnetic resonance imaging (MRI)] against another modality (e.g., SPECT) and a threshold applied (DICE modeling) to designate perfusion status as normal or low. The DICE models included perfusion status, left ventricular (LV) chamber volumes and myocardial wall thickness. Women were followed for 40±16 months for the development of first major adverse cardiovascular event (MACE: CV death, nonfatal myocardial infarction (MI) or hospitalization for congestive heart failure). Original and DICE perfusion status were compared in their ability to detect high-grade coronary artery disease (CAD) and for prediction of MACE.
Results
Adverse events occurred in 25 (12%) women and CAD was present in 34 (16%). In receiver-operator characteristic (ROC) analysis for CAD detection, the average area under the curve (AUC) for DICE vs. Original status was 0.77±0.03 vs. 0.70±0.03, P<0.01. Similarly, in Kaplan-Meier survival analysis the average log-rank statistic was higher for DICE vs. the Original readings (10.6±5.2 vs. 3.0±0.6, P<0.05).
Conclusions
While two data sets are required to generate the DICE models no knowledge of follow-up results is needed. DICE modeling improved diagnostic and prognostic value vs. the Original interpretation of the myocardial perfusion status.
doi:10.3978/j.issn.2223-3652.2013.10.07
PMCID: PMC3878119  PMID: 24400205
Modeling; prognosis; diagnosis; perfusion; imaging; women
24.  Ankle Brachial Index Values, Leg Symptoms, and Functional Performance Among Community‐Dwelling Older Men and Women in the Lifestyle Interventions and Independence for Elders Study 
Background
The prevalence and significance of low normal and abnormal ankle brachial index (ABI) values in a community‐dwelling population of sedentary, older individuals is unknown. We describe the prevalence of categories of definite peripheral artery disease (PAD), borderline ABI, low normal ABI, and no PAD and their association with lower‐extremity functional performance in the LIFE Study population.
Methods and Results
Participants age 70 to 89 in the LIFE Study underwent baseline measurement of the ABI, 400‐m walk, and 4‐m walking velocity. Participants were classified as follows: definite PAD (ABI <0.90), borderline PAD (ABI 0.90 to 0.99), low normal ABI (ABI 1.00 to 1.09), and no PAD (ABI 1.10 to 1.40). Of 1566 participants, 220 (14%) had definite PAD, 250 (16%) had borderline PAD, 509 (33%) had low normal ABI, and 587 (37%) had no PAD. Among those with definite PAD, 65% were asymptomatic. Adjusting for age, sex, race, body mass index, smoking, and comorbidities, lower ABI was associated with longer mean 400‐m walk time: (definite PAD=533 seconds; borderline PAD=514 seconds; low normal ABI=503 seconds; and no PAD=498 seconds [P<0.001]). Among asymptomatic participants with and without PAD, lower ABI values were also associated with longer 400‐m walk time (P<0.001) and slower walking velocity (P=0.042).
Conclusion
Among older community‐dwelling men and women, 14% had PAD and 49% had borderline or low normal ABI values. Lower ABI values were associated with greater functional impairment, suggesting that lower extremity atherosclerosis may be a common preventable cause of functional limitations in older people.
Clinical Trial Registration
URL: http://clinicaltrials.gov/ Unique identifier: NCT01072500.
doi:10.1161/JAHA.113.000257
PMCID: PMC3886743  PMID: 24222666
aging; exercise; peripheral vascular disease
25.  Treatment of Hypertension: Lower Is Better, Or Is It? 
Hypertension  2012;60(2):10.1161/HYPERTENSIONAHA.112.197632.
doi:10.1161/HYPERTENSIONAHA.112.197632
PMCID: PMC3832986  PMID: 22753207

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