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1.  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.
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.
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.
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)].
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.
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
2.  Cardiovascular and Mortality Risk of Apparent Resistant Hypertension in Women With Suspected Myocardial Ischemia: A Report From the NHLBI‐Sponsored WISE Study 
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.
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.
PMCID: PMC3959684  PMID: 24584740
hypertension; resistant hypertension; WISE; women
3.  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.
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.
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.
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).
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.
PMCID: PMC3846855  PMID: 24312563
4.  Improved diagnosis and prognosis using Decisions Informed by Combining Entities (DICE): results from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) 
To introduce an algorithmic approach to improve the interpretation of myocardial perfusion images in women with suspected myocardial ischemia.
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.
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.
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).
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.
PMCID: PMC3878119  PMID: 24400205
Modeling; prognosis; diagnosis; perfusion; imaging; women
5.  Treatment of Hypertension: Lower Is Better, Or Is It? 
Hypertension  2012;60(2):10.1161/HYPERTENSIONAHA.112.197632.
PMCID: PMC3832986  PMID: 22753207
6.  A degradable, bioactive, gelatinized alginate hydrogel to improve stem cell/growth factor delivery and facilitate healing after myocardial infarction 
Medical hypotheses  2012;79(5):673-677.
Despite remarkable effectiveness of reperfusion and drug therapies to reduce morbidity and mortality following myocardial infarction (MI), many patients have debilitating symptoms and impaired left ventricular (LV) function highlighting the need for improved post-MI therapies. A promising concept currently under investigation is intramyocardial injection of high-water content, polymeric biomaterial gels (e.g., hydrogels) to modulate myocardial scar formation and LV adverse remodeling. We propose a degradable, bioactive hydrogel that forms a unique microstructure of continuous, parallel capillary-like channels (Capgel). We hypothesize that the innovative architecture and composition of Capgel can serve as a platform for endogenous cell recruitment and drug/cell delivery, therefore facilitating myocardial repair after MI.
PMCID: PMC3725557  PMID: 22939314
7.  Enhancing the Function of CD34+ Cells by Targeting Plasminogen Activator Inhibitor-1 
PLoS ONE  2013;8(11):e79067.
Previously, we showed that transient inhibition of TGF- β1 resulted in correction of key aspects of diabetes-induced CD34+ cell dysfunction. In this report, we examine the effect of transient inhibition of plasminogen activator inhibitor-1 (PAI-1), a major gene target of TGF-β1 activation. Using gene array studies, we examined CD34+ cells isolated from a cohort of longstanding diabetic individuals, free of microvascular complications despite suboptimal glycemic control, and found that the cells exhibited reduced transcripts of both TGF-β1 and PAI-1 compared to age, sex, and degree of glycemic control-matched diabetic individuals with microvascular complications. CD34+ cells from diabetic subjects with microvascular complications consistently exhibited higher PAI-1 mRNA than age-matched non-diabetic controls. TGF- β1 phosphorodiamidate morpholino oligo (PMO) reduced PAI-1 mRNA in diabetic (p<0.01) and non-diabetic (p=0.05) CD34+ cells. To reduce PAI-1 in human CD34+ cells, we utilized PAI-1 siRNA, lentivirus expressing PAI-1 shRNA or PAI-1 PMO. We found that inhibition of PAI-1 promoted CD34+ cell proliferation and migration in vitro, likely through increased PI3(K) activity and increased cGMP production. Using a retinal ischemia reperfusion injury model in mice, we observed that recruitment of diabetic CD34+ cells to injured acellular retinal capillaries was greater after PAI-1-PMO treatment compared with control PMO-treated cells. Targeting PAI-1 offers a promising therapeutic strategy for restoring vascular reparative function in defective diabetic progenitors.
PMCID: PMC3815099  PMID: 24223881
Hypertension  2012;60(4):957-964.
G protein-coupled receptor kinases (GRKs) are important regulatory proteins for many G protein-coupled receptors, but little is known about GRK4 pharmacogenetics. We hypothesized three nonsynonymous GRK4 SNPs, R65L (rs2960306), A142V (rs1024323) and A486V (rs1801058) would be associated with blood pressure response to atenolol, but not hydrochlorothiazide, and would be associated with long term cardiovascular outcomes (all cause, death, nonfatal myocardial infarction, nonfatal stroke) in participants treated with an atenolol-based versus verapamil-SR-based antihypertensive strategy. GRK4 SNPs were genotyped in 768 hypertensive participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) trial. In Caucasians and African Americans, increasing copies of the variant 65L-142V haplotype were associated with significantly reduced atenolol-induced diastolic blood pressure lowering (−9.1 ± 6.8 vs −6.8 ± 7.1 vs −5.3 ± 6.4 mmHg in participants with 0, 1 and 2 copies of 65L-142V respectively; p=0.0088). 1460 participants with hypertension and coronary artery disease from the INternational VErapamil SR / Trandolapril STudy (INVEST) were genotyped and variant alleles of all three GRK4 SNPs were associated with increased risk for adverse cardiovascular outcomes in an additive fashion, with 486V homozygotes reaching statistical significance (Odds ratio 2.29 [1.48–3.55], p=0.0002). These effects on adverse cardiovascular outcomes were independent of antihypertensive treatment. These results suggest the presence of GRK4 variant alleles may be important determinants of blood pressure response to atenolol and risk for adverse cardiovascular events. The associations with GRK4 variant alleles were stronger in patients who were also ADRB1 389R-homozygotes, suggesting a potential interaction between these two genes.
PMCID: PMC3462355  PMID: 22949529
hypertension; GRK4; atenolol; beta-blocker; outcomes; ADRB1; pharmacogenetics
9.  Brachial Artery Constriction during Brachial Artery Reactivity Testing Predicts Major Adverse Clinical Outcomes in Women with Suspected Myocardial Ischemia: Results from the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study 
PLoS ONE  2013;8(9):e74585.
Limited brachial artery (BA) flow-mediated dilation during brachial artery reactivity testing (BART) has been linked to increased cardiovascular risk. We report on the phenomenon of BA constriction (BAC) following hyperemia.
To determine whether BAC predicts adverse CV outcomes and/or mortality in the women’s ischemic Syndrome Evaluation Study (WISE). Further, as a secondary objective we sought to determine the risk factors associated with BAC.
We performed BART on 377 women with chest pain referred for coronary angiography and followed for a median of 9.5 years. Forearm ischemia was induced with 4 minutes occlusion by a cuff placed distal to the BA and inflated to 40mm Hg > systolic pressure. BAC was defined as >4.8% artery constriction following release of the cuff. The main outcome was major adverse events (MACE) including all-cause mortality, non-fatal MI, non-fatal stroke, or hospitalization for heart failure.
BA diameter change ranged from -20.6% to +44.9%, and 41 (11%) women experienced BAC. Obstructive CAD and traditional CAD risk factors were not predictive of BAC. Overall, 39% of women with BAC experienced MACE vs. 22% without BAC (p=0.004). In multivariate Cox proportional hazards regression, BAC was a significant independent predictor of MACE (p=0.018) when adjusting for obstructive CAD and traditional risk factors.
BAC predicts almost double the risk for major adverse events compared to patients without BAC. This risk was not accounted for by CAD or traditional risk factors. The novel risk marker of BAC requires further investigation in women.
PMCID: PMC3776820  PMID: 24058592
10.  Increased wave reflection and ejection duration in women with chest pain and non-obstructive coronary artery disease: ancillary study from the Women’s Ischemia Syndrome Evaluation (WISE) 
Journal of hypertension  2013;31(7):1447-1455.
Pulsatile wave reflections augment central aortic systolic blood pressure (BP) and increase systolic pressure time integral (SPTI) thereby increasing left ventricular (LV) afterload and myocardial oxygen (MVO2) demand. When increased, such changes may contribute to myocardial ischemia and angina pectoris, especially when aortic diastolic time is decreased and myocardial perfusion pressure jeopardized. Accordingly, we examined pulse wave reflection characteristics and diastolic timing in a subgroup of women with chest pain (WISE) and no obstructive coronary artery disease (CAD).
Radial artery BP waveforms were recorded by applanation tonometry, and aortic BP waveforms derived. Data from WISE participants were compared with data from asymptomatic women (reference group) without chest pain matched for age, height, body mass index (BMI), mean arterial BP and heart rate (HR).
Compared with the reference group, WISE participants had higher aortic systolic and pulse BP and ejection duration (ED). These differences were associated with an increase in, augmentation index (AIx), and reflected pressure wave systolic duration. These modifications in wave reflection characteristics were associated with an increase in SPTI and wasted LV energy (Ew) and a decrease in pulse pressure amplification, myocardial viability ratio, and diastolic pressure time fraction (DPTF).
WISE participants with no obstructive CAD have changes in systolic wave reflections and diastolic timing that increase LV afterload, MVO2 demand, and Ew with the potential to reduce coronary artery perfusion. These alterations in cardiovascular function contribute to an undesirable mismatch in the MVO2 supply/demand that promotes ischemia and chest pain and may contribute to, or increase the severity of, future adverse cardiovascular events.
PMCID: PMC3766396  PMID: 23615325
wave reflection; augmentation index; central aortic pressure; wasted LV energy; WISE study
11.  Left Ventricular Energy Model Predicts Adverse Events in Women With Suspected Myocardial Ischemia: Results From The NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study 
To assess the prognostic value of a left ventricular energy-model in women with suspected myocardial ischemia.
The prognostic value of internal energy utilization (IEU) of the left ventricle in women with suspected myocardial ischemia is unknown.
Women (n=227, mean age 59±12 years, range 31-86), with symptoms of myocardial ischemia, underwent myocardial perfusion imaging (MPI) assessment for regional perfusion defects along with measurement of ventricular volumes separately by gated Single Photon Emission Computed Tomography (SPECT) (n= 207) and magnetic resonance imaging (MRI) (n=203). During follow-up (40±17 months), time to first major adverse cardiovascular event (MACE, death, myocardial infarction or hospitalization for congestive heart failure) was analyzed using MRI and gated SPECT variables.
Adverse events occurred in 31 (14%). Multivariable Cox models were formed for each modality: IEU and wall thickness by MRI (Chi-squared 34, p<0.005) and IEU and systolic blood pressure by gated SEPCT (Chi-squared 34, p<0.005). The models remained predictive after adjustment for age, disease history and Framingham risk score. For each Cox model, patients were categorized as high-risk if the model hazard was positive and not high-risk otherwise. Kaplan-Meier analysis of time to MACE was performed for high-risk vs. not high-risk for MR (log rank 25.3, p<0.001) and gated SEPCT (log rank 18.2, p<001) models.
Among women with suspected myocardial ischemia a high internal energy utilization has higher prognostic value than either a low EF or the presence of a myocardial perfusion defect assessed using two independent modalities of MR or gated SPECT.
PMCID: PMC3763744  PMID: 24015377
MRI Scans; SPECT; Hypertension; Myocardial Ischemia
12.  Timing of Hormone Therapy, Type of Menopause, and Coronary Disease in Women: Data from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) 
Menopause (New York, N.Y.)  2011;18(9):943-950.
To assess the relationship of timing of hormone therapy (HT) use with angiographic coronary artery disease (CAD) and cardiovascular disease (CVD) events in women with natural versus surgical menopause.
We studied 654 postmenopausal women undergoing coronary angiography for evaluation of suspected ischemia. Timing and type of menopause, HT use, and quantitative angiographic evaluations were obtained at baseline, and the women were followed for a median of 6 years for CVD events.
Ever users of HT had a significantly lower prevalence of obstructive CAD compared to never users (age-adjusted OR=0.41 [0.28, 0.60]). Naturally menopausal women initiating HT at age <55 years had lower CAD severity compared to never users (age-adjusted beta [SE] = −6.23 [1.50], p<0.0001) while those initiating HT age ≥55 years did not differ statistically from never users (−3.34 [2.13], p=0.12). HT use remained a significant predictor of obstructive CAD when adjusting for a “healthy user” model OR 0.44 [0.30, 0.73] (p=0.002). An association between HT and fewer CVD events was observed only in the natural menopause group (HR [95%CI] = 0.60[0.41, 0.88], p=0.009) but became non-significant when adjusting for presence or severity of obstructive CAD.
Using quantitative measurements of timing and type of menopause and HT use, earlier initiation of HT was associated with less angiographic CAD in women with natural but not surgical menopause. Our data suggest that the effect of HT use on reduced cardiovascular event rates is mediated by the presence or absence of angiographic obstructive atherosclerosis.
PMCID: PMC3747738  PMID: 21532511
cardiovascular disease; menopause; hormone therapy; atherosclerosis
13.  Simple Integer Risk Score to Determine Prognosis of Patients With Hypertension and Chronic Stable Coronary Artery Disease 
It is difficult to accurately determine prognosis of patients with hypertension and chronic stable coronary artery disease (CAD). Our aim was to construct a risk score for predicting important adverse events in this population.
Methods and Results
Patients with hypertension and chronic stable CAD enrolled in the INternational VErapamil‐SR/Trandolapril STudy (INVEST) comprised the study cohort. Candidate predictor variables were obtained from patients with at least 1 postbaseline visit. Patients were divided into development (n=18 484) and validation cohorts (n=2054). Cox regression model identified predictors of the primary outcome: all‐cause mortality, myocardial infarction, or stroke at a mean follow‐up of 2.3 years. The hazard ratio of each variable was rounded to the nearest integer to construct score weights. A score 0 to 4 defined low‐risk, 5 to 6 intermediate‐risk and ≥7 high‐risk. The following variables were retained in the final model: age, residence, body mass index, on‐treatment heart rate and BP, prior myocardial infarction, heart failure, stroke/transient ischemic attack, smoking, diabetes, peripheral arterial disease, and chronic kidney disease. The primary outcome occurred in 2.9% of the low‐risk group, 6.5% of the intermediate‐risk group, and 18.0% of the high‐risk group (P for trend <0.0001). The model was good at discriminating those who had an event versus those who did not (C‐statistic=0.75). The model performed well in a validation cohort (C‐statistic=0.77).
Readily available clinical variables can rapidly stratify patients with hypertension and chronic stable CAD into useful risk categories.
PMCID: PMC3828777  PMID: 23948642
clinical decision rule; coronary artery disease; coronary heart disease; ischemic heart diseae; prognosis; risk score
14.  Effect of the Use and Timing of Bone Marrow Mononuclear Cell Delivery on Left Ventricular Function After Acute Myocardial Infarction: The TIME Randomized Trial 
While the delivery of cell therapy following ST segment myocardial infarction (STEMI) has been evaluated in previous clinical trials, the influence of the timing of cell delivery on the effect on left ventricular (LV) function has not been analyzed in a trial that randomly designated the time of delivery.
To determine 1) the effect of intracoronary autologous bone marrow mononuclear cell (BMC) delivery following STEMI on recovery of global and regional LV function and 2) if timing of BMC delivery (3 versus 7 days following reperfusion) influences this effect.
Design, Setting, and Patients
Between July 17, 2008 and November 15, 2011, 120 patients were enrolled in a randomized, 2×2 factorial, double-blind, placebo-controlled trial of the National Heart, Lung, and Blood Institute (NHLBI)-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) of patients with LV dysfunction (LV Ejection Fraction (LVEF) ≤45%) following successful primary percutaneous coronary intervention (PCI) of anterior STEMI.
Intracoronary infusion of 150 × 106 BMCs or placebo (randomized 2:1 BMC:placebo) within 12 hours of aspiration and processing administered at Day 3 or Day 7 (randomized 1:1) post-PCI.
Main Outcome Measures
Co-primary endpoints were: 1) Change in global (LVEF) and regional (wall motion) LV function in infarct and border zones at 6 months measured by cardiac magnetic resonance imaging and 2) Change in LV function as affected by timing of treatment on Day 3 versus Day 7. Secondary endpoints included major adverse cardiovascular events as well as changes in LV volumes and infarct size.
Patient mean age was 56.9±10.9 years with 87.5% male. At 6 months, LVEF increased similarly in both BMC (45.2±10.6 to 48.3±13.3 %) and placebo groups (44.5±10.8 to 47.8±13.6 %). No detectable treatment effect on regional LV function was observed in either infarct or border zones. Differences between therapy groups in the change in global LV function over time when treated at Day 3 (−0.9±2.9%, 95% CI 6.6 to 4.9%, p=0.763) or Day 7 (1.1±2.9%, 95% CI −4.7 to 6.9, p=0.702) were not significant, nor were they different from each other. Also, timing of treatment had no detectable effect on recovery of regional LV function. Major adverse events were rare with no difference between groups.
Patients with STEMI, who underwent successful primary PCI and administration of intra-coronary BMCs at either 3 or 7 days following the event, had recovery of global and regional LV function similar to placebo
Trial Registration Number, NCT00684021
PMCID: PMC3652242  PMID: 23129008
15.  Cell tracking and the development of cell-based therapies: a view from the Cardiovascular Cell Therapy Research Network 
JACC. Cardiovascular imaging  2012;5(5):559-565.
Cell-based therapies are being developed for myocardial infarction (MI) and its consequences (e.g. heart failure) as well as refractory angina and critical limb ischemia. The promising results obtained in pre-clinical studies led to the translation of this strategy to clinical studies. To date, the initial results have been mixed: some studies showed benefit, while in others no benefit was observed. There is a growing consensus among the scientific community that a better understanding of the fate of transplanted cells (e.g., cell homing and viability over time) will be critical for the long term success of these strategies and that future studies should include an assessment of cell homing, engraftment and fate as an integral part of the trial design. In this review, different imaging methods and technologies will be discussed within the framework of the physiological answers that the imaging strategies can provide, with special focus on the inherent regulatory issues.
PMCID: PMC3632261  PMID: 22595165
16.  Effect of Transendocardial Delivery of Autologous Bone Marrow Mononuclear Cells on Functional Capacity, Left Ventricular Function, and Perfusion in Chronic Ischemic Heart Failure: The FOCUS-CCTRN Trial 
Previous studies utilizing autologous bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy have demonstrated safety and suggested efficacy. The FOCUS protocol was designed to assess efficacy of a larger cell dose in an adequately well-powered phase II study.
To determine if administration of BMCs through transendocardial injections improves myocardial perfusion, reduces left ventricular (LV) end systolic volume, or enhances maximal oxygen consumption in patients with coronary artery disease (CAD), LV dysfunction, and limiting heart failure and/or angina.
Design, Setting, and Patients
This is a 100 million cell, first-in-man randomized, double-blind, placebo-controlled trial was performed by the National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) in symptomatic patients (NYHA II-III and/or CCS II-IV) receiving maximal medical therapy, with a left ventricular ejection fraction (LVEF)≤45%, perfusion defect by single-photon emission tomography (SPECT), and CAD not amenable to revascularization.
All patients underwent bone marrow aspiration, isolation of BMCs using a standardized automated system performed locally, and transendocardial injection of 100 million BMCs or placebo (2:1 BMC: placebo).
Main Outcome Measures
Three co-primary endpoints assessed at 6 months were changes in (a) LV end systolic volume (LVESV) by echocardiography, (b) maximal oxygen consumption (MVO2), and (c) reversibility on SPECT. Secondary measures included other SPECT measures, magnetic resonance imaging (MRI), echocardiography, clinical improvement, and major adverse cardiac events (MACE). Phenotypic and functional analyses of the cell product were performed by the CCTRN Biorepository lab.
Of 153 consented patients, a total of 92 (82 men; average age, 63 years) were randomized (n= 61 BMC, 31 placebo) at 5 sites between April 29, 2009 and April 18, 2011. Changes in LVESV index, (−0.9 ± 11.3 mL/m2; P = 0.733; 95% CI, −6.1 to 4.3), MVO2 (1.0 ± 2.9; P = 0.169; 95% CI, −0.42 to 2.34), percent reversible defect change, (−1.2 ± 23.3; P = 0.835; 95% CI, −12.50 to 10.12), and incidence of MACEwere not statistically significant. However, in an exploratory analysis the change in LVEF across the entire cohort by therapy group was significant (2.7 ± 5.2%; P = 0.030; 95% CI, 0.27 to 5.07).
This is the largest cell therapy trial of autologous BMCs in patients with ischemic LV dysfunction. In patients with chronic ischemic heart disease, transendocardial injection of BMCs compared to placebo did not improve LVESV, MVO2, or reversibility on SPECT.
PMCID: PMC3600947  PMID: 22447880
Chronic CAD; Ischemic Heart Failure; Chronic Angina; bone marrow mononuclear cells; cardiac performance
17.  Effect of Intracoronary Delivery of Autolologous Bone Marrow Mononuclear Cells Two to Three Weeks Following Acute Myocardial Infarction on Left-Ventricular Function: The LateTIME Randomized Trial 
Clinical trial results suggest that intracoronary delivery of autologous bone marrow mononuclear cells (BMCs) may improve left ventricular (LV) function when administered within the first week following myocardial infarction (MI). However, since a substantial number of patients may not present for early cell delivery, we investigated the efficacy of autologous BMC delivery 2–3 weeks post-MI.
To determine if intracoronary delivery of autologous BMCs improves global and regional LV function when delivered 2–3 weeks following first MI.
Design, Setting, and Patients
LateTIME is a randomized, double-blind, placebo-controlled trial of the National Heart, Lung, and Blood Institute - sponsored Cardiovascular Cell Therapy Research Network (CCTRN) of 87 patients with significant LV dysfunction (LVEF ≤ 45%) following successful primary percutaneous coronary intervention (PCI).
Intracoronary infusion of 150 × 106 autologous BMCs (total nucleated cells) or placebo (2:1 BMC:placebo) was performed within 12 hours of bone marrow aspiration after local automated cell processing.
Main Outcome Measures
The primary endpoints were changes in global (LVEF) and regional (wall motion) LV function in the infarct and border zone from baseline to 6 months as measured by cardiac MRI at a core lab blinded to treatment assignment Secondary endpoints included changes in LV volumes and infarct size.
87 patients were randomized between July 2008 and February 2011: mean age = 57 ± 11 yrs, 83% male. Harvesting, processing, and intracoronary delivery of BMCs in this setting was feasible and safe. The change from baseline to six months in the BMC group, when compared to the placebo group, for LVEF (48.7 to 49.2% vs. 45.3 to 48.8%; Difference = −3.0, 95% CI −7.0 to 0.9), wall motion in the infarct zone (6.2 to 6.5 vs. 4.9 to 5.9 mm; Difference = −0.7, 95% CI −2.8 to 1.3), and wall motion in the border zone (16.0 to 16.6 mm vs. 16.1 to 19.3 mm; Difference = −2.6; 95% CI −6.0 to 0.8) were not statistically significant. There was no significant change in LV volumes and infarct volumes decreased by a similar amount in both groups at 6 months compared to baseline.
Among patients with MI and LV dysfunction following reperfusion with PCI, intracoronary infusion of autologous BMCs compared to intracoronary placebo infusion, 2–3 weeks after PCI did not improve global or regional function at 6 months.
PMCID: PMC3600981  PMID: 22084195
Acute myocardial infarction; bone marrow mononuclear cells; LVEF; cardiac MRI
18.  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”
PMCID: PMC1861458  PMID: 17322502
angina; iscahemic heart disease; women
20.  Effects of Pharmacologic Therapy on Health-Related Quality of Life in Elderly Patients with Atrial Fibrillation: A Systematic Review of Randomized and Nonrandomized Trials 
This systematic review assessed the impact of atrial fibrillation (AF) and pharmacotherapy on health-related quality of life (HRQOL) in elderly patients. Highly prevalent in the elderly, AF is associated with morbidity and symptoms affecting HRQOL. A PubMed and EMBASE search (1999–2010) was conducted using the terms atrial fibrillation, elderly, quality of life, Medicare, and Medicaid. In all, 504 articles were identified and 15 were selected (studies examining pharmacotherapy [rate or rhythm control] and HRQOL in AF patients with a mean age ≥ 65 years). Information, including study design, cohort size, and HRQOL instruments utilized, was extracted. Five observational studies, 5 randomized trials comparing rate and rhythm control, 3 randomized trials investigating pharmacologic agents, and 2 trials examining HRQOL, depression, and anxiety were identified. Elderly AF patients had reduced HRQOL versus patients in normal sinus rhythm, particularly in domains related to physical functioning. HRQOL may be particularly affected in older AF patients. Although data do not indicate whether a pharmacologic intervention or single treatment strategy—namely rate versus rhythm control—is better at improving HRQOL, either of these strategies and many pharmacologic interventions may improve HRQOL in elderly AF patients. Based on reviewed data, an algorithm is suggested to optimize HRQOL among elderly patients.
PMCID: PMC3563302  PMID: 23400444
aged; antiarrhythmic agents; arrhythmia; atrial fibrillation; health-related quality of life
21.  Developing Mechanistic Insights into Cardiovascular Cell Therapy: Cardiovascular Cell Therapy Research Network (CCTRN) Biorepository Core Laboratory Rationale 
American heart journal  2011;162(6):973-980.
Moderate improvements in cardiac performance have been reported in some clinical settings after delivery of bone marrow mononuclear cells to patients with cardiovascular disease (CVD). However, mechanistic insights into how these cells impact outcomes are lacking. To address this, the NHLBI Cardiovascular Cell Therapy Research Network (CCTRN) established a Biorepository Core for extensive phenotyping and cell function studies, and storing bone marrow and peripheral blood for 10 years. Analyzing cell populations and cell function in the context of clinical parameters and clinical outcomes, after cell or placebo treatment, empower the development of novel diagnostic and prognostics. Developing such biomarkers that define the safety and efficacy of cell therapy is a major Biorepository aim.
PMCID: PMC3236502  PMID: 22137069
22.  Syndrome X and Microvascular Coronary Dysfunction 
Circulation  2011;124(13):1477-1480.
PMCID: PMC3210740  PMID: 21947935
23.  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
Pharmacogenetics and genomics  2011;21(6):333-340.
Liver X receptor-α (LXRA) is a nuclear receptor that regulates genes important in cholesterol homeostasis and inflammation. Several single nucleotide polymorphisms (SNPs) in the LXRA gene have been previously associated with metabolic phenotypes (dyslipidemia and elevated BMI). Metabolic dysregulation is a major contributor to coronary disease; therefore, we assessed LXRA in INVEST-GENES, a genetic-substudy of a large clinical trial in patients with hypertension and coronary artery disease.
Seven tag SNPs in the LXRA gene region (NR1H3) were selected for study: rs11039149, rs12221497, rs2279238, rs7120118, rs326213, rs11039159 and rs10501321. 1059 subjects were genotyped from the INVEST-GENES case-control set (Verapamil-SR or Atenolol based treatment strategies), comprised of 297 cases frequency matched approximately 2.5:1 with event-free controls by sex and race. The primary outcome was defined as first occurrence of all-cause death, nonfatal MI, or nonfatal stroke. Adjusted odds ratios (OR) were calculated using logistic regression.
Three of the seven SNPs were associated with significant effects on the primary outcome in Non-Blacks. The variant G allele of rs11039149 and the variant A allele of rs12221497 were associated with reduced risk of experiencing the primary outcome (OR: 0.62, CI: 0.45-0.85, P=0.003 and OR: 0.60, CI: 0.39-0.91, P=0.016 respectively). The rs2279238 genotype was associated with a significant increase in risk for the primary outcome (OR: 1.42, CI: 1.03-1.95, P=0.03). Furthermore, there was a significant genotype-treatment strategy interaction for carriers of the variant T allele of rs2279238 (OR for Verapamil SR strategy compared to Atenolol: 2.86, CI: 1.50-5.46, P=0.0015). Diplotype analyses revealed that the SNPs are rarely co-inherited and support the directionally opposite effects of the SNPs on the primary outcome.
LXRA genotypes were associated with variable risk for cardiovascular outcomes and pharmacogenetic effect in INVEST-GENES. These novel findings suggest LXRA is a genetic/pharmacogenetic target that should be further explored.
PMCID: PMC3093636  PMID: 21562465
LXRA; Nuclear Receptor; Pharmacogenetics; Polymorphisms; Cardiovascular Disease; Hypertension; Atenolol; Verapamil
25.  Cholesteryl Ester Transfer Protein (CETP) Polymorphisms Affect mRNA Splicing, HDL Levels, and Sex-Dependent Cardiovascular Risk 
PLoS ONE  2012;7(3):e31930.
Polymorphisms in and around the Cholesteryl Ester Transfer Protein (CETP) gene have been associated with HDL levels, risk for coronary artery disease (CAD), and response to therapy. The mechanism of action of these polymorphisms has yet to be defined. We used mRNA allelic expression and splice isoform measurements in human liver tissues to identify the genetic variants affecting CETP levels. Allelic CETP mRNA expression ratios in 56 human livers were strongly associated with several variants 2.5–7 kb upstream of the transcription start site (e.g., rs247616 p = 6.4×10−5, allele frequency 33%). In addition, a common alternatively spliced CETP isoform lacking exon 9 (Δ9), has been shown to prevent CETP secretion in a dominant-negative manner. The Δ 9 expression ranged from 10 to 48% of total CETP mRNA in 94 livers. Increased formation of this isoform was exclusively associated with an exon 9 polymorphism rs5883-C>T (p = 6.8×10−10) and intron 8 polymorphism rs9930761-T>C (5.6×10−8) (in high linkage disequilibrium with allele frequencies 6–7%). rs9930761 changes a key splicing branch point nucleotide in intron 8, while rs5883 alters an exonic splicing enhancer sequence in exon 9.
The effect of these polymorphisms was evaluated in two clinical studies. In the Whitehall II study of 4745 subjects, both rs247616 and rs5883T/rs9930761C were independently associated with increased HDL-C levels in males with similar effect size (rs247616 p = 9.6×10−28 and rs5883 p = 8.6×10−10, adjusted for rs247616). In an independent multiethnic US cohort of hypertensive subjects with CAD (INVEST-GENE), rs5883T/rs9930761C alone were significantly associated with increased incidence of MI, stroke, and all-cause mortality in males (rs5883: OR 2.36 (CI 1.29–4.30), p = 0.005, n = 866). These variants did not reach significance in females in either study. Similar to earlier results linking low CETP activity with poor outcomes in males, our results suggest genetic, sex-dependent CETP splicing effects on cardiovascular risk by a mechanism independent of circulating HDL-C levels.
PMCID: PMC3293889  PMID: 22403620

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