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1.  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
2.  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
3.  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
5.  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
6.  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
7.  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
8.  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
9.  Coronary Microvascular Reactivity to Adenosine Predicts Adverse Outcome in Women Evaluated for Suspected Ischemia: Results from the NHLBI Women's Ischemia Syndrome Evaluation (WISE) 
Objective
We investigated whether coronary microvascular dysfunction predicts major adverse outcomes during follow-up among women with signs and symptoms of ischemia.
Background
Altered coronary reactivity occurs frequently in women evaluated for suspected ischemia and the endothelium-dependent component is linked with adverse outcomes. Possible links between endothelium-independent microvascular coronary reactivity and adverse outcomes remain uncertain.
Methods
As part of the National Heart, Lung and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE), we investigated relationships between major adverse outcomes and baseline coronary flow reserve (CFR) following intracoronary adenosine in 189 women referred to evaluate suspected ischemia.
Results
At 5.4 (mean) years, we observed significant associations between CFR and major adverse outcomes (death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure). An exploratory ROC analysis identified CFR <2.32 as the best discriminating threshold for adverse outcomes (event rate 26.7% and ≥2.32 event rate 12.2%; p = 0.01). Lower CFR was associated with increased risk for major adverse outcomes (HR 1.16, 95% CI 1.04 to 1.30; p = 0.009). This held true among the 152 women without obstructive coronary artery disease (CAD) (HR 1.20, 95% CI 1.05 to 1.38; p = 0.008). CFR significantly improved prediction of adverse outcomes over angiographic CAD severity and other risk conditions.
Conclusions
Among women with suspected ischemia and atherosclerosis risk factors, coronary microvascular reactivity to adenosine significantly improves prediction of major adverse outcomes over angiographic CAD severity and CAD risk factors. These findings suggest coronary microvessels represent novel targets for diagnostic and therapeutic strategies to predict and limit adverse outcomes in women.
doi:10.1016/j.jacc.2010.01.054
PMCID: PMC2898523  PMID: 20579539
women; ischemia; adverse outcomes; microcirculation
10.  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
11.  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
12.  Raising awareness of angina in women 
Heart  2007;93(3):279-280.
“If ischaemic heart disease affects women differently from men, then our diagnostic testing, risk stratification schemes and treatment modalities should be sexist as well”
doi:10.1136/hrt.2006.111955
PMCID: PMC1861458  PMID: 17322502
angina; iscahemic heart disease; women
13.  Multimarker Approach Predicts Adverse Cardiovascular Events in Women Evaluated for Suspected Ischemia: Results from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) 
Clinical cardiology  2009;32(5):244-250.
Summary
Background
Inflammatory marker and hemoglobin levels (e.g. biomarkers) considered separately predict adverse events in selected populations.
Hypothesis
A multiple biomarker approach predicts adverse events in women referred for evaluation of ischemia.
Methods
We investigated associations between biomarkers (high sensitivity C-reactive protein, interleukin-6, serum amyloid-A and hemoglobin levels) with adverse outcomes in women referred for coronary angiography for suspected ischemia in WISE.
Results
Among 595 women (mean age 58 years, ejection fraction 65%, majority without coronary stenosis ≥50%) followed for 3.6±1.8 years (mean±SD), those without abnormal markers had fewer events (11.6%) compared to those with one (18.4%), two (20.9%), or three (37%) abnormal markers (p<0.001 for trend). Women without abnormal markers had fewer deaths (1.6%) than women with one (6.1%), two (9.1%), or three (17%) abnormal markers (p<0.001 for trend). Adding low hemoglobin was associated with higher adverse event and all-cause mortality rates. In multivariate analysis, as number of abnormal biomarkers increased risk increased. Women with three or four abnormal biomarkers were approximately 10–20 times more likely to die (p<0.05). Biomarkers added to predictive information provided by the Framingham Risk Score.
Conclusions
Among women undergoing coronary angiography for suspected ischemia, a multi-biomarker approach predicted adverse events. Biomarkers added prognostic information beyond that obtained from traditional risk factors.
doi:10.1002/clc.20454
PMCID: PMC2811492  PMID: 19452486
Inflammation; Anemia; Cardiovascular Events; Women; Multimarker
14.  Systolic Blood Pressure and Subjective Well-Being in Patients with Coronary Artery Disease 
Clinical cardiology  2009;32(11):627-632.
Background
Limited information exists regarding the association between subjective well-being (SWB) and systolic blood pressure (SBP) among hypertensive patients with coronary artery disease (CAD).
Hypothesis
We tested the hypothesis that there is an association between SBP and SWB.
Methods
We studied 22,576 hypertensive CAD patients ≥50 years old in the INternational VErapamil SRTrandolapril Study (INVEST), a randomized, blinded-endpoint trial of antihypertensive therapy in stable CAD patients. At each study visit, patients rated their SWB in the previous 4 weeks as “excellent,” “good,” “fair,” or “poor” prior to SBP recordings. The outcome measure was SWB of “fair” or “poor.” A longitudinal analysis using generalized estimating equations was performed to assess the association between SBP and odds of reporting fair/poor SWB, controlling for baseline SWB of fair/poor and angina reported during the study.
Results
Patients with higher SBP had higher odds of reporting fair/poor SWB. Specifically, compared with patients with SBP of ≤120, patients with SBP 140–150 >150–≤160 and >160 had about 90% and 2.5 times greater odds of feeling fair/poor, respectively (adjusted odds ratio [OR]: 1.5990, 95% confidence interval [CI]: 1.81–2.00 and adjusted OR: 2.53, 95% CI: 2.41–2.66). Those who reported angina in the 4 wks prior to a protocol visit had 2.2 times greater odds of reporting fair/poor SWB (adjusted OR: 2.2, 95% CI: 2.13–2.27). Female gender, black race, history of smoking, diabetes, myocardial infarction, stroke, and cancer also increased the odds of reporting fair/poor SWB.
Conclusions
Among hypertensive CAD patients, higher on-treatment SBP is associated with greater odds of fair/poor SWB during follow-up.
doi:10.1002/clc.20501
PMCID: PMC2810952  PMID: 19711440
15.  Predicting Stroke Risk in Hypertensive Patients With Coronary Artery Disease 
Background and Purpose
Our understanding of factors influencing stroke risk among patients with coronary artery disease is incomplete. Accordingly, factors predicting stroke risk in hypertensive, clinically stable coronary artery disease patients were determined with data from the INternational VErapamil SR-trandolapril STudy (INVEST).
Methods
The effect of baseline characteristics and on-treatment blood pressure (BP) were analyzed to determine the risk of stroke (fatal or nonfatal) among the 22 576 patients enrolled. Cox proportional-hazards models (unadjusted, adjusted, and time dependent) were used to identify predictors of stroke among subgroups with these characteristics present at entry and on-treatment BP.
Results
Excellent BP control (at 24 months, >70% <140/90 mm Hg) was achieved during 61 835 patient-years of follow-up, as 377 patients had a stroke (6.1 strokes/1000 patient-years) and 28% of those patients had a fatal stroke. Increased age, black race, US residency, and history of prior myocardial infarction, smoking, stroke/transient ischemic attack, arrhythmia, diabetes, and coronary bypass surgery were associated with an increased risk of stroke. Achieving a systolic BP <140 mm Hg and a diastolic BP <90 mm Hg was associated with a decreased risk of stroke. There was no statistically significant difference in stroke risk comparing the verapamil SR–based with the atenolol-based treatment strategy (adjusted hazard ratio=0.87; 95% CI, 0.71 to 1.06; P=0.17).
Conclusions
Among hypertensive patients with chronic coronary artery disease, stroke was an important complication associated with significant mortality. Black race, US residency, and conditions associated with increased vascular disease severity and arrhythmia predicted increased stroke risk, whereas achieving a BP <140/90 mm Hg on treatment predicted a reduced stroke risk.
doi:10.1161/STROKEAHA.107.495465
PMCID: PMC2805179  PMID: 18162623
atenolol; coronary artery disease; hydrochlorothiazide; hypertension; stroke; trandolapril; verapamil SR
16.  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
17.  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
18.  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
19.  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
20.  Pulse Pressure and Adverse Outcomes in Women: A Report From the Women’s Ischemia Syndrome Evaluation (WISE) 
American journal of hypertension  2008;21(11):1224-1230.
Background
Recent data suggest that brachial pulse pressure (PP) may be a better predictor of outcome than systolic or diastolic blood pressure (SBP/DBP). We sought to investigate the relative contributions of these indices to risk for adverse outcomes in women with suspected coronary artery disease (CAD) and myocardial ischemia.
Methods
Among 857 women referred for angiography for suspected myocardial ischemia, baseline evaluations were performed, and the women were followed for clinical outcome. Relationships between baseline characteristics, blood pressure components, and outcomes were evaluated. Separate multivariate stepwise Cox regression models for PP and SBP (expressed in 10 mm Hg increments) were constructed and included covariates significantly associated with adverse outcomes.
Results
After 5.2 years (mean), univariate testing identified higher PP associated with higher risk for cardiovascular (CV) mortality and adverse CV outcomes than SBP, DBP, or mean arterial pressure (MAP). Multivariate modeling identified both PP and SBP associated with adverse CV outcomes, but only PP was significantly associated with higher CV mortality. When both PP and SBP were included in the model, only PP remained an independent predictor of adverse outcomes for CV events.
Conclusions
In women with suspected CAD and myocardial ischemia, PP is a stronger predictor of adverse outcomes than SBP, DBP, or MAP with an 18% excess mortality risk for every 10 mm Hg increase in PP. Further investigations into pathophysiologic mechanisms and specific pharmacologic approaches to modifying this novel target are warranted.
doi:10.1038/ajh.2008.268
PMCID: PMC2586110  PMID: 18802432
21.  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
22.  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
23.  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
24.  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
25.  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

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