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1.  Mild renal dysfunction and long-term adverse outcomes in women with chest pain: results from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) 
American heart journal  2015;169(3):412-418.
Chronic kidney disease (CKD) is associated with accelerated atherosclerosis and adverse cardiovascular outcomes, but mechanisms are unclear. We hypothesized that mild CKD independently predicts adverse outcomes in women with symptoms and signs of ischemia.
We categorized 876 women from the Women’s Ischemia Syndrome Evaluation (WISE) cohort according to estimated glomerular filtration rate (eGFR) [eGFR ≥90, normal; 60–89, mild; ≤59, severe CKD). Time to death from all-cause and cardiovascular causes and major adverse outcomes were assessed by multivariate regression adjusted for baseline covariates.
Obstructive coronary artery disease (CAD) was present only in a minority of patients (39%). Even after adjusting for CAD severity, renal function remained a strong, independent predictor of all-cause and cardiac mortality (p<0.001). Every 10 unit decrease in eGFR was associated with a 14% increased risk of all-cause mortality [adjusted hazard ratio (AHR) 1.14 (1.08–1.20); p<0.0001], 16% increased risk of cardiovascular mortality [AHR 1.16 (1.09–1.23); p<0.0001], and 9% increased risk of adverse cardiovascular events [AHR 1.09 (1.03–1.15); p=0.002].
Even mild CKD is a strong independent predictor of all-cause and cardiac mortality in women with symptoms/signs of ischemia, regardless of underlying obstructive CAD severity, underscoring the need to better understand the interactions between ischemic heart disease and CKD.
PMCID: PMC4347936  PMID: 25728732
Chronic kidney disease; Ischemic heart disease; Mortality; Adverse outcomes
2.  Microvascular Coronary Dysfunction and Ischemic Heart Disease – Where Are We in 2014? 
Many patients with angina and signs of myocardial ischemia on stress testing have no significant obstructive epicardial coronary disease. There are many potential coronary and non-coronary mechanisms for ischemia without obstructive epicardial coronary disease, and prominent among these is coronary microvascular and/or endothelial dysfunction. Patients with coronary microvascular and/or endothelial dysfunction are often at increased risk of adverse cardiovascular events, including ischemic events and heart failure despite preserved ventricular systolic function. In this article, we will review the diagnosis and treatment of coronary microvascular and endothelial dysfunction, discuss their potential contribution to heart failure with preserved ejection fraction, and highlight recent advances in the evaluation of atherosclerotic morphology in these patients, many of whom have non-obstructive epicardial disease.
PMCID: PMC4336803  PMID: 25454903
3.  Relationships between components of metabolic syndrome and coronary intravascular ultrasound atherosclerosis measures in women without obstructive coronary artery disease: the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation Study 
Cardiovascular endocrinology  2015;4(2):45-52.
In women, metabolic syndrome (MetS) is associated with higher risk of ischemic heart disease-related adverse outcomes versus individual components. We examined the relationship of MetS to subclinical coronary atherosclerosis.
Women (n = 100) undergoing coronary angiography for suspected ischemia but without obstructive coronary artery disease (CAD) underwent intravascular ultrasound (IVUS) of a segment of the left coronary artery. A core lab, masked to other findings, assessed IVUS measures and normalized volume measures to pull-back length. MetS [defined using ATPIII criteria (fasting glucose ≥ 100 mg/dl per revised NCEP guideline)] and its components were entered into multiple regression models to assess associations with IVUS measures.
Detailed IVUS measurements were available in 87 women. Mean age was 54 ± 10 years, 36% had MetS, and 78% had atheroma. Comparing women with MetS versus without MetS, significant differences were observed for seven IVUS atherosclerosis measures, but were not significant after adjusting for the MetS components. Systolic blood pressure and waist circumference components remained independently positively associated with the IVUS measures after adjusting for age, diabetes, CAD family history, dyslipidemia, smoking, and hormone replacement.
In women with signs and symptoms of ischemia and no obstructive CAD, MetS is associated with coronary atherosclerosis presence and severity. However, these associations appear largely driven by components of waist circumference and systolic blood pressure versus MetS cluster. This supports the concept that MetS is a convenient clustering of risk factors rather than an independent risk predictor, and emphasizes that the critical factors for coronary atherosclerosis are potentially modifiable.
PMCID: PMC4671302  PMID: 26665010
adverse outcomes; coronary angiography; coronary artery disease; coronary atherosclerosis; intravascular ultrasound; ischemic heart disease; metabolic syndrome; risk assessment; women
4.  Multiple Causes for Ischemia Without Obstructive CAD: Not a Short List 
Circulation  2015;131(12):1044-1046.
PMCID: PMC4664445  PMID: 25712204
5.  2014 Hypertension Recommendations From the Eighth Joint National Committee Panel Members Raise Concerns for Elderly Black and Female Populations 
A report from panel members appointed to the Eighth Joint National Committee titled "2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults" has garnered much attention due to its major change in recommendations for hypertension treatment for patients ≥60 years of age and for their treatment goal. In response, certain groups have opposed the decision to initiate pharmacologic treatment to lower blood pressure (BP) at systolic BP ≥150 mm Hg and treat to a goal systolic BP of <150 mm Hg in the general population age ≥60 years. This paper contains 3 sections–an introduction followed by the opinions of 2 writing groups–outlining objections to or support of maintaining this proposed strategy in certain at-risk populations, namely African Americans, women, and the elderly. Several authors argue for maintaining current targets, as opposed to adopting the new recommendations, to allow for optimal treatment for older women and African Americans, helping to close sex and race/ethnicity gaps in cardiovascular disease morbidity and mortality.
PMCID: PMC4242519  PMID: 25060376
hypertension and prevention/hypertension; quality of care and outcomes assessment/quality of care; quality of care and outcomes assessment/appropriateness
6.  The Prevalence of Microvascular Dysfunction, Its Role among Men, and Links with Adverse Outcomes: Non-Invasive Imaging Reveals the Tip of the Iceberg 
Circulation  2014;129(24):2497-2499.
PMCID: PMC4124593  PMID: 24787470
Editorial; coronary microvascular function; coronary flow reserve; corrected TIMI frame count; ischemic heart disease
7.  Cardiac Magnetic Resonance Myocardial Perfusion Reserve Index Is Reduced in Women With Coronary Microvascular Dysfunction: A National Heart, Lung and Blood Institute-Sponsored Study From the Women's Ischemia Syndrome Evaluation (WISE) 
Circulation. Cardiovascular imaging  2015;8(4):10.1161/CIRCIMAGING.114.002481 e002481.
Women with signs and symptoms of ischemia and no obstructive coronary artery disease often have coronary microvascular dysfunction (CMD), diagnosed by invasive coronary reactivity testing (CRT). While traditional noninvasive stress imaging is often normal in CMD, cardiac magnetic resonance imaging (CMRI) may be able to detect CMD in this population.
Methods and Results
Vasodilator stress CMRI was performed in 118 women with suspected CMD who had undergone CRT and 21 asymptomatic reference subjects. Semi quantitative evaluation of the first-pass perfusion images was completed to determine myocardial perfusion reserve index (MPRI). The relationship between CRT findings and MPRI was examined by Pearson correlations, logistic regression and sensitivity/specificity. Symptomatic women had lower mean pharmacologic stress MPRI compared to reference subjects (1.71±0.43 vs. 2.23±0.37, p<0.0001). Lower MPRI was predictive of one or more abnormal CRT variables (OR = 0.78 [0.70, 0.88], p<0.0001, c-statistic 0.78 [0.68, 0.88]). An MPRI threshold of 1.84 predicted CRT abnormality with sensitivity 73% and specificity 74%.
Noninvasive CMRI MPRI can detect CMD defined by invasive CRT. Further work is aimed to optimize the non-invasive identification and management of CMD patients.
PMCID: PMC4375783  PMID: 25801710
coronary microvascular dysfunction; cardiac magnetic resonance imaging; myocardial perfusion; women
8.  Adverse Pregnancy Conditions, Infertility, and Future Cardiovascular Risk: Implications for Mother and Child 
Adverse pregnancy conditions in women are common and have been associated with adverse cardiovascular and metabolic outcomes such as myocardial infarction and stroke. As risk stratification in women is often suboptimal, recognition of non-traditional risk factors such as hypertensive disorders of pregnancy and premature delivery has become increasingly important. Additionally, such conditions may also increase the risk of cardiovascular disease in the children of afflicted women. In this review, we aim to highlight these conditions, along with infertility, and the association between such conditions and various cardiovascular outcomes and related maternal risk along with potential translation of risk to offspring. We will also discuss proposed mechanisms driving these associations as well as potential opportunities for screening and risk modification.
PMCID: PMC4758514  PMID: 26037616
Pregnancy; Preterm birth; Hypertension; Stroke; Myocardial infarction
9.  Bone Marrow Characteristics Associated with Changes in Infarct Size after STEMI: A Biorepository Evaluation from the CCTRN TIME Trial 
Circulation research  2014;116(1):99-107.
Despite significant interest in bone marrow mononuclear cell (BMC) therapy for ischemic heart disease, current techniques have resulted in only modest benefits. However, select patients have shown improvements after autologous BMC therapy, but the contributing factors are unclear.
The purpose of this study was to identify BMC characteristics associated with a reduction in infarct size following STEMI.
Methods and Results
This prospective study comprised patients consecutively enrolled in the CCTRN TIME trial who agreed to have their BMCs stored and analyzed at the CCTRN Biorepository. Change in infarct size between baseline (3 days after percutaneous coronary intervention) and 6-month follow-up was measured by cardiac magnetic resonance imaging (cMRI). Infarct-size measurements and BMC phenotype and function data were obtained for 101 patients (mean age, 56.5 years; mean screening ejection fraction, 37%; mean baseline cMRI ejection fraction, 45%). At 6 months, 75 patients (74.3%) showed a reduction in infarct size (mean change, -21.0%±17.6%). Multiple regression analysis indicated that infarct size reduction was greater in patients who had a larger percentage of CD31+ BMCs (P=0.046) and in those with faster BMC growth rates in CFU-Hill and ECFC functional assays (P=0.033 and P=0.032, respectively).
This study identified BMC characteristics associated with a better clinical outcome in patients with STEMI and highlighted the importance of endothelial precursor activity in regenerating infarcted myocardium. Furthermore, it suggests that for these STEMI patients, myocardial repair was more dependent on baseline BMC characteristics than on whether the patient underwent intracoronary BMC transplantation.
Trial Registration Identifier: NCT00684021
PMCID: PMC4282599  PMID: 25406300
Acute myocardial infarction; coronary circulation; cardiac regeneration; cellular therapy – experimental
10.  Assessing cardiovascular risk in women: Looking beyond traditional risk factors 
Trends in cardiovascular medicine  2014;25(2):152-153.
PMCID: PMC4664450  PMID: 25468290
11.  Harmful Effects of NSAIDs among Patients with Hypertension and Coronary Artery Disease 
The American journal of medicine  2011;124(7):614-620.
There is limited information about the safety of chronic nonsteroidal anti-inflammatory drugs (NSAIDs) in hypertensive patients with coronary artery disease.
This was a post hoc analysis from the INternational VErapamil Trandolapril STudy (INVEST), which enrolled patients with hypertension and coronary artery disease. At each visit, patients were asked by the local site investigator if they were currently taking NSAIDs. Patients who reported NSAID use at every visit were defined as chronic NSAID users, while all others (occasional or never users) were defined as nonchronic NSAID users. The primary composite outcome was all-cause death, nonfatal myocardial infarction, or nonfatal stroke. Cox regression was used to construct a multivariate analysis for the primary outcome.
There were 882 chronic NSAID users and 21,694 nonchronic NSAID users (n = 14,408 for never users and n = 7286 for intermittent users). At a mean follow-up of 2.7 years, the primary outcome occurred at a rate of 4.4 events per 100 patient-years in the chronic NSAID group, versus 3.7 events per 100 patient-years in the nonchronic NSAID group (adjusted hazard ratio [HR] 1.47; 95% confidence interval [CI], 1.19–1.82; P = .0003). This was due to an increase in cardiovascular mortality (adjusted HR 2.26; 95% CI, 1.70–3.01; P = .0001).
Among hypertensive patients with coronary artery disease, chronic self-reported use of NSAIDs was associated with an increased risk of adverse events during long-term follow-up.
PMCID: PMC4664475  PMID: 21596367
Coronary artery disease; Hypertension; Myocardial infarction; Nonsteroidal anti-inflammatory drugs; NSAIDs
12.  Coronary Angiography: Is it Time to Reassess? 
Circulation  2013;127(17):1760-1762.
PMCID: PMC3746971  PMID: 23630085
angiography; stenosis; cardiovascular disease; diagnosis
13.  A Detailed Analysis of Bone Marrow from Patients with Ischemic Heart Disease and Left Ventricular Dysfunction: BM CD34, CD11b and Clonogenic Capacity as Biomarkers for Clinical Outcomes 
Circulation research  2014;115(10):867-874.
Bone marrow (BM) cell therapy for ischemic heart disease (IHD) has shown mixed results. Before the full potency of BM cell therapy can be realized, it is essential to understand the BM niche following acute myocardial infarction (AMI).
To study the BM composition in patients with IHD and severe left ventricular dysfunction (LVD).
Methods & Results
BM from 280 patients with IHD and LVD were analyzed for cell subsets by flow cytometry and colony assays. BM CD34+ cell percentage was decreased 7 days after AMI (mean of 1.9% vs. 2.3-2.7% in other cohorts; p< 0.05). BM-derived endothelial colonies were significantly decreased (p< 0.05). Increased BM CD11b+ cells associated with worse left ventricular ejection fraction (LVEF) after AMI (p< 0.05). While increased BM CD34+ percentage associated with greater improvement in LVEF (+9.9% vs. +2.3%, p=0.03, for AMI patients; and +6.6% vs. -0.02%, p=0.021 for chronic IHD patients), decreased BM CD34+ percentage in chronic IHD patients correlated with decrement in LVEF after cell therapy (-2.9% vs. +0.7%, p=0.0355).
In this study we show a heterogeneous mixture of BM cell subsets, decreased endothelial colony capacity, a CD34+ cell nadir seven days after AMI, a negative correlation between CD11b percentage and post-infarct LVEF, and positive correlation of CD34 percentage with change in LVEF after cell therapy. These results serve as a possible basis for the small clinical improvement seen in autologous BM cell therapy trials and support selection of potent cell subsets and/or reversal of co-morbid BM impairment.
PMCID: PMC4358751  PMID: 25136078
Myocardial infarction; blood cells; angiogenesis; bone marrow; stem and progenitor cells
14.  A training program in cardiovascular cell-based therapy: from the NHLBI Cardiovascular Cell Therapy Research Network 
Regenerative medicine  2014;9(6):793-797.
Stem/progenitor cell-based therapies offer novel treatment for many prevalent diseases. However, most physicians are not trained or introduced to cell therapy. We describe a model of a training program aimed at empowering physician–scientists with the knowledge and skills necessary for advancing the field of cardiovascular cell therapy. To date, five full-time scholars have completed this training program, obtained a full-time academic appointment in Cardiovascular Disease, and continue to actively contribute to the advancement of cell therapy applications. Another has returned to his parent institution to complete his PhD and several part-time scholars have continued in scholarly activities in other academic programs.
PMCID: PMC4270075  PMID: 25431915
cardiovascular; fellowship training; physician training; regenerative medicine; stem cell
15.  Depression, dietary habits, and cardiovascular events among women with suspected myocardial ischemia 
The American journal of medicine  2014;127(9):840-847.
Dietary habits and depression are each associated with cardiovascular disease risk. Patient with depression often report poor eating habits and dietary factors may help explain commonly observed associations between depression and cardiovascular disease.
From 1996–2000, 936 women were enrolled in the Women's Ischemia Syndrome Evaluation (WISE) at four US academic medical centers at the time of clinically indicated coronary angiography and then assessed (median follow-up, 5.9 years) for adverse outcomes (cardiovascular disease death, heart failure, myocardial infarction, stroke). Participants completed a protocol including coronary angiography (coronary artery disease severity), depression assessments (Beck Depression Inventory [BDI] scores, antidepressant use, & depression treatment history). A subset of 201 women (mean age= 58.5(SD=11.4) further completed the Food Frequency Questionnaire for Adults (FFQ; 1998 Block). We extracted daily fiber intake and daily servings of fruit and vegetables as measures of dietary habits.
In separate Cox regression models adjusted for age, smoking, and coronary artery disease severity, Beck Depression Inventory scores (HR=1.05, 95% CI=1.01–1.10), antidepressant use (HR=2.4, 95% CI=1.01–5.9) and a history of treatment for depression (HR=2.4, 95%CI=1.1–5.3) were each adversely associated with time to cardiovascular disease outcomes. Fiber intake (HR=.87, 95% CI=.78–.97) and fruit and vegetable consumption (HR=.36, 95% CI=.19–.70) was associated with a decreased time to cardiovascular disease event risk. In models including dietary habits and depression, fiber intake and fruit and vegetable consumption remained associated with time to cardiovascular disease outcomes, whereas depression relationships were reduced by 10–20% and non-significant.
Among women with suspected myocardial ischemia, we observed consistent relationships between depression, dietary habits, and time to cardiovascular disease events. Dietary habits partly explained these relationships. These results suggest that dietary habits be included in future efforts to identify mechanisms linking depression to cardiovascular disease.
PMCID: PMC4161621  PMID: 24769297
cardiovascular disease; women; prospective; depression; diet
16.  2014 Eighth Joint National Committee Panel Recommendation for Blood Pressure Targets Revisited 
The 2014 Eighth Joint National Committee panel recommendations for management of high blood pressure (BP) recommend a systolic BP threshold for initiation of drug therapy and a therapeutic target of <150 mm Hg in those ≥60 years of age, a departure from prior recommendations of <140 mm Hg. However, it is not known whether this is an optimal choice, especially for the large population with coronary artery disease (CAD).
This study sought to evaluate optimal BP in patients ≥60 years of age.
Patients 60 years of age or older with CAD and baseline systolic BP >150 mm Hg randomized to a treatment strategy on the basis of either atenolol/hydrochlorothiazide or verapamil-SR (sustained release)/trandolapril in INVEST (INternational VErapamil SR Trandolapril STudy) were categorized into 3 groups on the basis of achieved on-treatment systolic BP: group 1, <140 mm Hg; group 2, 140 to <150 mm Hg; and group 3, ≥150 mm Hg. Primary outcome was first occurrence of all-cause death, nonfatal myocardial infarction (MI), or nonfatal stroke. Secondary outcomes were all-cause mortality, cardiovascular mortality, total MI, nonfatal MI, total stroke, nonfatal stroke, heart failure, or revascularization, tabulated separately. Outcomes for each group were compared in unadjusted and multiple propensity score–adjusted models.
Among 8,354 patients included in this analysis with an accumulated 22,308 patient-years of follow-up, 4,787 (57%) achieved systolic BP of <140 mm Hg (group 1), 1,747 (21%) achieved systolic BP of 140 to <150 mm Hg (group 2), and 1,820 (22%) achieved systolic BP of ≥150 mm Hg (group 3). In unadjusted models, group 1 had the lowest rates of the primary outcome (9.36% vs. 12.71% vs. 21.32%; p < 0.0001), all-cause mortality (7.92% vs. 10.07% vs. 16.81%; p < 0.0001), cardiovascular mortality (3.26% vs. 4.58% vs. 7.80%; p < 0.0001), MI (1.07% vs. 1.03% vs. 2.91%; p < 0.0001), total stroke (1.19% vs. 2.63% vs. 3.85%; p <0.0001), and nonfatal stroke (0.86% vs 1.89% vs 2.86%; p<0.0001) compared with groups 2 and 3, respectively. In multiple propensity score–adjusted models, compared with the reference group of <140 mm Hg (group 1), the risk of cardiovascular mortality (adjusted hazard ratio [HR]: 1.34; 95% confidence interval [CI]: 1.01 to 1.77; p = 0.04), total stroke (adjusted HR: 1.89; 95% CI: 1.26 to 2.82; p = 0.002) and nonfatal stroke (adjusted HR: 1.70; 95% CI: 1.06 to 2.72; p = 0.03) was increased in the group with BP of 140 to <150 mm Hg, whereas the risk of primary outcome, all-cause mortality, cardiovascular mortality, total MI, nonfatal MI, total stroke, and nonfatal stroke was increased in the group with BP ≥150 mm Hg.
In hypertensive patients with CAD who are ≥60 years of age, achieving a BP target of 140 to <150 mm Hg as recommended by the JNC-8 panel was associated with less benefit than the previously recommended target of <140 mm Hg.
PMCID: PMC4193384  PMID: 25145522
blood pressure; coronary artery disease; elderly; systolic; target
17.  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.
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.
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.
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.
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.
PMCID: PMC3191889  PMID: 21982660
18.  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.
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.
Phosphodiesterase type 5 (PDE-5) inhibition acutely improves MCD in these women.
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.
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).
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.
PMCID: PMC3151010  PMID: 21780138
Women; Microvascular coronary dysfunction; Coronary flow reserve; Phosphodiesterase type 5 inhibition
19.  Aldosterone inhibition and coronary endothelial function in women without obstructive coronary artery disease: An ancillary study of the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) 
American heart journal  2014;167(6):826-832.
Endothelial dysfunction is highly prevalent and associated with adverse outcomes among patients without obstructive coronary artery disease (CAD). Angiotensin II inhibition may improve endothelial function, but with continued treatment “aldosterone escape” may occur. Thus it is unknown if adding aldosterone blockade further improves endothelial function.
In a double-blind, parallel-group, repeated measures study, women with symptoms and signs of ischemia, no significant CAD, and coronary endothelial dysfunction receiving an angiotensin converting enzyme-inhibitor (ACE-I) or receptor blocker were randomized to aldosterone blockade or placebo. The primary outcome at 16 weeks was percent change in coronary diameter to ACh and secondary outcomes coronary flow reserve to adenosine, both adjusted for baseline reactivity.
Forty-one women completed the treatment period with repeat coronary reactivity testing. Their mean age was 54±10 years, body mass index 30±7.4 kg/m2, 12% had diabetes, and 15% had metabolic syndrome. There were no significant differences between treatment groups. At baseline, the percent change in reference vessel coronary diameter to ACh was −5.0% in the aldosterone blockade group and −3.4% in the placebo group, and at 16 weeks, −7.2% in the aldosterone blockade group versus −14.3% in the placebo group (p=0.15). At 16 weeks, the change in coronary flow reserve to intracoronary adenosine was −0.13 in the aldosterone blockade group versus −0.25 in the placebo group (p=0.66).
Adding aldosterone receptor blockade to angiotensin II inhibition did not improve coronary endothelial or microvascular function among women with signs and symptoms of ischemia in the setting of non-obstructive CAD.
PMCID: PMC4049218  PMID: 24890531
Women; Microcirculation; Ischemia; Adenosine; Acetylcholine; Endothelial dysfunction
21.  Renal Function and Coronary Microvascular Dysfunction in Women with Symptoms/Signs of Ischemia 
PLoS ONE  2015;10(5):e0125374.
Chronic kidney disease (CKD) is more prevalent among women and is associated with adverse cardiovascular events. Among women with symptoms and signs of ischemia enrolled in the Women’s Ischemia Syndrome Evaluation (WISE), a relatively high mortality rate was observed in those with no obstructive coronary artery disease. Coronary microvascular dysfunction or reduced coronary flow reserve (CFR) was a strong and independent predictor of adverse outcomes. The objective of this analysis was to determine if renal function was associated with coronary microvascular dysfunction in women with signs and symptoms of ischemia.
The WISE was a multicenter, prospective, cohort study of women undergoing coronary angiography for suspected ischemia. Among 198 women with additional measurements of CFR, we determined the estimated glomerular filtration rate (eGFR) with the CKD-EPI equation. We tested the association between eGFR and CFR with regression analysis.
The median eGFR was 89 ml/min. The eGFR correlated with CFR (r = 0.22; P = 0.002). This association persisted even after covariate adjustment. Each 10-unit decrease in eGFR was associated with a 0.04-unit decrease in CFR (P = 0.04).There was a strong interaction between eGFR and age (P = 0.006): in those ≥60 years old, GFR was strongly correlated with CFR (r = 0.55; P<0.0001). No significant correlation was noted in those <60 years old.
Reduced renal function was significantly associated with lower CFR in women with symptoms and signs of ischemia. Coronary microvascular dysfunction warrants additional study as a mechanism contributing to increased risk of cardiovascular events in CKD.
PMCID: PMC4423851  PMID: 25951606
22.  Effects of Verapamil SR and Atenolol on 24-Hour Blood Pressure and Heart Rate in Hypertension Patients with Coronary Artery Disease: An International Verapamil SR-Trandolapril Ambulatory Monitoring Substudy 
PLoS ONE  2015;10(4):e0122726.
Elevated nighttime blood pressure (BP) and heart rate (HR), increased BP and HR variability, and altered diurnal variations of BP and HR (nighttime dipping and morning surge) in patients with systemic hypertension are each associated with increased adverse cardiovascular events. However, there are no reports on the effect of hypertension treatment on these important hemodynamic parameters in the growing population of hypertensive patients with atherosclerotic coronary artery disease (CAD). This was a pre-specified subgroup analysis of the INternational VErapamil SR-Trandolapril STudy (INVEST), which involved 22,576 clinically stable patients aged ≥50 years with hypertension and CAD randomized to either verapamil SR- or atenolol-based hypertension treatment strategies. The subgroup consisted of 117 patients undergoing 24-hour ambulatory monitoring at baseline and after 1 year of treatment. Hourly systolic and diastolic BP (SBP and DBP) decreased after 1 year for both verapamil SR- and atenolol-based treatment strategies compared with baseline (P<0.0001). Atenolol also decreased hourly HR (P<0.0001). Both treatment strategies decreased SBP variability (weighted standard deviation: P = 0.012 and 0.021, respectively). Compared with verapamil SR, atenolol also increased the prevalence of BP and HR nighttime dipping among prior non-dippers (BP: OR = 3.37; 95% CI: 1.26 – 8.97; P = 0.015; HR: OR = 4.06; 95% CI: 1.35-12.17; P = 0.012) and blunted HR morning surge (+2.8 vs. +4.5 beats/min/hr; P = 0.019). Both verapamil SR- and especially atenolol-based strategies resulted in favorable changes in ambulatory monitoring parameters that have been previously associated with increased adverse cardiovascular events.
Trial Registration; NCT00133692
PMCID: PMC4383326  PMID: 25835002
24.  Predictors and outcomes of resistant hypertension among patients with coronary artery disease and hypertension 
Journal of hypertension  2014;32(3):635-643.
Resistant hypertension (res-HTN) is a challenging problem, but little is known of res-HTN in patients with coronary artery disease (CAD). In this post-hoc INternational VErapamil SR-Trandolapril STudy (INVEST) analysis, we assessed prevalence, predictors, and impact on outcomes of res-HTN in CAD patients with hypertension.
Participants (n=17 190) were divided into three groups according to achieved blood pressure (BP): controlled (BP <140/90 mmHg on three or fewer drugs); uncontrolled (BP ≥140/90mmHg on two or fewer drugs); or resistant (BP ≥140/90 mmHg on three drugs or any patient on at least four drugs).
The prevalence of res-HTN was 38%: significant predictors of res-HTN included heart failure [odds ratio (OR) 1.73], diabetes (OR 1.63), Black race (OR 1.50), and US residence (OR 1.50). Compared with controlled HTN, res-HTN had multivariate-adjusted association with higher risk of adverse outcomes {first occurrence of all-cause death, nonfatal myocardial infarction, or nonfatal stroke [hazard ratio 1.27, 95% confidence interval (CI) 1.13–1.43], and individual outcomes of all-cause death (hazard ratio 1.29, 95% CI 1.13–1.48), cardiovascular mortality (hazard ratio 1.47, 95% CI 1.21–1.78), and nonfatal stroke (hazard ratio 1.61, 95% CI 1.17–2.22), but not nonfatal myocardial infarction (hazard ratio 0.98, 95% CI 0.72–1.34)}. Adverse outcomes, except nonfatal stroke, did not differ in patients with res-HTN compared to uncontrolled HTN.
Res-HTN is common in patients with CAD and hypertension, associated with poor prognosis, and linked with a number of conditions. Emphasis should be placed on recognizing those at risk for res-HTN and future studies should examine whether more aggressive treatment of res-HTN improves outcomes.
PMCID: PMC4118668  PMID: 24299915
blood pressure; coronary artery disease; hypertension; INVEST; resistant hypertension
25.  Coronary Microvascular Reactivity to Adenosine Predicts Adverse Outcome in Women Evaluated for Suspected Ischemia: Results from the NHLBI Women's Ischemia Syndrome Evaluation (WISE) 
We investigated whether coronary microvascular dysfunction predicts major adverse outcomes during follow-up among women with signs and symptoms of ischemia.
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.
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.
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.
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.
PMCID: PMC2898523  PMID: 20579539
women; ischemia; adverse outcomes; microcirculation

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