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1.  Association of Aortic Stiffness and Wave Reflections with Coronary Flow Reserve in Women without Obstructive Coronary Artery Disease: An Ancillary Study from the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) 
American heart journal  2015;170(6):1243-1254.
Increased aortic stiffness and reduced coronary flow reserve (CFR) independently predict adverse outcomes. But information about relationships between arterial properties and CFR in subjects without obstructive coronary artery disease (CAD) is limited.
CFR was measured (Doppler flow wire and intracoronary adenosine) in 50 women (age 53±11 years) with symptoms and signs of myocardial ischemia without obstructive CAD. Aortic pulse wave velocity (aPWV), a measure of aortic stiffness, was obtained via catheter pullback; radial artery pressure waves were measured by applanation tonometry and central aortic pressure synthesized.
Overall, CFR (mean 2.61 ± 0.47) was significantly correlated with aPWV (r = −0.51), pulse wave amplification (r = 0.45), augmented pressure (AP, r = −0.48), augmentation index (AIx, r = −0.44), aortic systolic pressure (r = −0.49), left ventricular wasted energy (LVEw, r = −0.47) (all P < 0.001), systolic pressure time index (r = −0.37, P < 0.008), and rate pressure product (r = −0.29, P < 0.04). In the multiple regression model including aPWV, CFR was still significantly correlated with aPWV (P < 0.008) and aortic systolic pressure (P < 0.01). No other measures contributed significant additional information.
Women with CFR ≤2.5 vs. those with CFR >2.5 had greater aPWV (894 ± 117 vs. 747 ± 93 cm/sec, P < 0.001), AP (14 ± 4.9 vs. 11 ± 4.1 mmHg, P < 0.008), AIx (32 ± 6.6 vs. 27 ± 6.6%, P < 0.003), LVEw (30 ± 12 vs. 21 ± 10 dyne-sec/cm2 × 102, P < 0.02) and reduced pulse pressure amplification (1.20 ± .07 vs. 1.26 ± .10, P < 0.008) and pressure wave travel time (133 ± 7.3 vs. 138 ± 6.9 msec, P < 0.04).
Among symptomatic women without obstructive CAD, CFR was inversely related to aortic systolic pressure and indices of aortic stiffness. These changes in arterial properties increase LV afterload requiring the ventricle to generate additional, but wasted, energy that increases indices of myocardial oxygen demand, reduces CFR and increases vulnerability to ischemia.
PMCID: PMC4685957  PMID: 26678647
coronary microvascular dysfunction; coronary flow reserve; aortic pressure waveform; pulse wave analysis; pulse wave velocity; wave reflections; aortic stiffness
2.  Emergence of Nonobstructive Coronary Artery Disease: A Woman's Problem and Need for Change in Definition on Angiography 
Recognition of ischemic heart disease (IHD) is often delayed or deferred in women. Thus, many at risk for adverse outcomes are not provided specific diagnostic, preventive, and/or treatment strategies. This lack of recognition is related to sex-specific IHD pathophysiology that differs from traditional models using data from men with flow-limiting coronary artery disease (CAD) obstructions. Symptomatic women are less likely to have obstructive CAD than men with similar symptoms, and tend to have coronary microvascular dysfunction, plaque erosion, and thrombus formation. Emerging data document that more extensive, nonobstructive CAD involvement, hypertension, and diabetes are associated with major adverse events similar to those with obstructive CAD. A central emerging paradigm is the concept of nonobstructive CAD as a cause of IHD and related adverse outcomes among women. This position paper summarizes currently available knowledge and gaps in that knowledge, and recommends management options that could be useful until additional evidence emerges.
PMCID: PMC4618799  PMID: 26493665
Adverse outcomes; Ischemia; Sex-specific pathophysiology
3.  Impact of antibiotics on arterial blood pressure in a patient with resistant hypertension — A case report 
PMCID: PMC4711349  PMID: 26301638
Antibiotics; Resistant hypertension; Inflammation; Gut microbiota
4.  The Coronary Microcirculation in STEMI: The Next Frontier? 
European Heart Journal  2015;36(45):3178-3181.
PMCID: PMC4664837  PMID: 26409009
5.  Angina treatments and prevention of cardiac events: an appraisal of the evidence 
Angina pectoris is the symptomatic manifestation of transient myocardial ischaemia. At the most fundamental level, angina arises when myocardial oxygen demand exceeds the ability of the coronary circulation to provide adequate oxygen delivery to maintain normal myocardial metabolic function. In vivo, the balance of oxygen demand and delivery is a complex physiological process that can be altered by a variety of interventions. Lifestyle modification is a cornerstone of cardiovascular disease management, with or without angina. Additional pharmaceutical and physical interventions are usually applied to patients with angina. Mechanisms of action for these interventions include heart rate modulation, vascular smooth muscle relaxation, metabolic manipulation, revascularization, and others. A number of these interventions have overlapping mechanisms that target angina. Additionally, some interventions may directly or indirectly prevent or delay adverse outcomes such as myocardial infarction or death. This review summarizes current evidence for many applied ischaemia treatments documented to modify angina and comments on available evidence relating to improvement in cardiovascular outcomes.
PMCID: PMC4700909  PMID: 26740801
Ischaemic heart disease; Coronary artery disease; Secondary prevention; Pharmacological therapies
6.  What Causes Myocardial Infarction in Women Without Obstructive Coronary Artery Disease? 
Circulation  2011;124(13):1404-1406.
PMCID: PMC5008236  PMID: 21947933
7.  Mental Stress and Myocardial Ischemia: Young Women at Risk 
PMCID: PMC5079056  PMID: 27559073
Editorials; ischemia; ischemic heart disease; sex differences; stress; women; Cardiovascular Disease; Mental Health; Risk Factors; Women; Secondary Prevention
8.  PTPRD gene associated with blood pressure response to atenolol and resistant hypertension 
Journal of hypertension  2015;33(11):2278-2285.
The aim of this study is to identify single-nucleotide polymorphisms (SNPs) influencing blood pressure (BP) response to the β-blocker atenolol.
Genome-wide association analysis of BP response to atenolol monotherapy was performed in 233 white participants with uncomplicated hypertension in the pharmacogenomic evaluation of antihypertensive responses study. Forty-two polymorphisms with P less than 10−5 for association with either diastolic or systolic response to atenolol monotherapy were validated in four independent groups of hypertensive individuals (total n = 2114).
In whites, two polymorphisms near the gene PTPRD (rs12346562 and rs1104514) were associated with DBP response to atenolol (P = 3.2 × 10−6 and P = 5.9 × 10−6, respectively) with directionally opposite association for response to hydrochlorothiazide in another group of 228 whites (P = 0.0018 and P = 0.00012). A different polymorphism (rs10739150) near PTPRD was associated with response to atenolol in 150 black hypertensive individuals (P = 8.25 ×10−6). rs12346562 had a similar trend in association with response to bisoprolol (a different β-blocker) in 207 Finnish men in the genetics of drug responsiveness in essential hypertension study. In addition, an intronic single-nucleotide polymorphism (rs4742610) in the PTPRD gene was associated with resistant hypertension in whites and Hispanics in the international verapamil SR trandolapril study (meta-analysis P = 3.2 × 10−5).
PTPRD was identified as a novel locus potentially associated with BP response to atenolol and resistant hypertension in multiple ethnic groups.
PMCID: PMC4788379  PMID: 26425837
atenolol; blood pressure response; genome-wide association study; pharmacogenomic evaluation of antihypertensive responses; pharmacogenomics; PTPRD; resistant hypertension
9.  Identification of Bone Marrow Cell Subpopulations Associated With Improved Functional Outcomes in Patients With Chronic Left Ventricular Dysfunction: An Embedded Cohort Evaluation of the FOCUS-CCTRN Trial 
Cell transplantation  2015;25(9):1675-1687.
In the current study, we sought to identify bone marrow-derived mononuclear cell (BM-MNC) subpopulations associated with a combined improvement in left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and maximal oxygen consumption (VO2 max) in patients with chronic ischemic cardiomyopathy 6 months after receiving transendocardial injections of autologous BM-MNCs or placebo. For this prospectively planned analysis, we conducted an embedded cohort study comprising 78 patients from the FOCUS-Cardiovascular Cell Therapy Research Network (CCTRN) trial. Baseline BM-MNC immunophenotypes and progenitor cell activity were determined by flow cytometry and colony-forming assays, respectively. Previously stable patients who demonstrated improvement in LVEF, LVESV, and VO2 max during the 6-month course of the FOCUS-CCTRN study (group 1, n = 17) were compared to those who showed no change or worsened in one to three of these endpoints (group 2, n = 61) and to a subset of patients from group 2 who declined in all three functional endpoints (group 2A, n = 11). Group 1 had higher frequencies of B-cell and CXCR4+ BM-MNC subpopulations at study baseline than group 2 or 2A. Furthermore, patients in group 1 had fewer endothelial colony-forming cells and monocytes/macrophages in their bone marrow than those in group 2A. To our knowledge, this is the first study to show that in patients with ischemic cardiomyopathy, certain bone marrow-derived cell subsets are associated with improvement in LVEF, LVESV, and VO2 max at 6 months. These results suggest that the presence of both progenitor and immune cell populations in the bone marrow may influence the natural history of chronic ischemic cardiomyopathy—even in stable patients. Thus, it may be important to consider the bone marrow composition and associated regenerative capacity of patients when assigning them to treatment groups and evaluating the results of cell therapy trials.
PMCID: PMC5088500  PMID: 26590374
Bone marrow; Heart failure; Ischemic cardiomyopathy; Stem cells; Cell therapy
10.  Use of bio-informatics assessment schema (BIAS) to improve diagnosis and prognosis of myocardial perfusion data: results from the NHLBI-sponsored women’s ischemia syndrome evaluation (WISE) 
We introduce an algorithmic approach to optimize diagnostic and prognostic value of gated cardiac single photon emission computed tomography (SPECT) and magnetic resonance (MR) myocardial perfusion imaging (MPI) modalities in women with suspected myocardial ischemia. The novel approach: bio-informatics assessment schema (BIAS) forms a mathematical model utilizing MPI data and cardiac metrics generated by one modality to predict the MPI status of another modality. The model identifies cardiac features that either enhance or mask the image-based evidence of ischemia. For each patient, the BIAS model value is used to set an appropriate threshold for the detection of ischemia.
Women (n=130), with symptoms and signs of suspected myocardial ischemia, underwent MPI assessment for regional perfusion defects using two different modalities: gated SPECT and MR. To determine perfusion status, MR data were evaluated qualitatively (MRIQL) and semi-quantitatively (MRISQ) while SPECT data were evaluated using conventional clinical criteria. Evaluators were masked to results of the alternate modality. These MPI status readings were designated “original”. Two regression models designated “BIAS” models were generated to model MPI status obtained with one modality (e.g., MRI) compared with a second modality (e.g., SPECT), but importantly, the BIAS models did not include the primary Original MPI reading of the predicting modality. Instead, the BIAS models included auxiliary measurements like left ventricular chamber volumes and myocardial wall thickness. For each modality, the BIAS model was used to set a progressive threshold for interpretation of MPI status. Women were then followed for 38±14 months for the development of a first major adverse cardiovascular event [MACE: CV death, nonfatal myocardial infarction (MI) or hospitalization for heart failure]. Original and BIAS-augmented perfusion status were compared in their ability to detect coronary artery disease (CAD) and for prediction of MACE.
Adverse events occurred in 14 (11%) women and CAD was present in 13 (10%). There was a positive correlation of maximum coronary artery stenosis and BIAS score for MRI and SPECT (P<0.001). Receiver operator characteristic (ROC) analysis was conducted and showed an increase in the area under the curve of the BIAS-augmented MPI interpretation of MACE vs. the original for MRISQ (0.78 vs. 0.54), MRIQL (0.78 vs. 0.64), SPECT (0.82 vs. 0.63) and the average of the three readings (0.80±0.02 vs. 0.60±0.05, P<0.05).
Increasing values of the BIAS score generated by both MRI and SPECT corresponded to the increasing prevalence of CAD and MACE. The BIAS-augmented detection of ischemia better predicted MACE compared with the Original reading for the MPI data for both MRI and SPECT.
PMCID: PMC5059395  PMID: 27747165
Modeling; prognosis; diagnosis; myocardial perfusion imaging (MPI); women
11.  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
12.  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
13.  Association between High Endocardial Unipolar Voltage and Improved Left Ventricular Function in Patients with Ischemic Cardiomyopathy 
Texas Heart Institute Journal  2016;43(4):291-296.
We know that endocardial mapping reports left ventricular electrical activity (voltage) and that these data can predict outcomes in patients undergoing traditional revascularization. Because the mapping data from experimental models have also been linked with myocardial viability, we hypothesized an association between increased unipolar voltage in patients undergoing intramyocardial injections and their subsequent improvement in left ventricular performance.
For this exploratory analysis, we evaluated 86 patients with left ventricular dysfunction, heart-failure symptoms, possible angina, and no revascularization options, who were undergoing endocardial mapping. Fifty-seven patients received bone marrow mononuclear cell (BMC) injections and 29 patients received cell-free injections of a placebo.
The average mapping site voltage was 9.7 ± 2 mV, and sites with voltage of ≥6.9 mV were engaged by needle and injected (with BMC or placebo). For all patients, at 6 months, left ventricular ejection fraction (LVEF) improved, and after covariate adjustment this improvement was best predicted by injection-site voltage. For every 2-mV increase in baseline voltage, we detected a 1.3 increase in absolute LVEF units for all patients (P=0.038). Multiple linear regression analyses confirmed that voltage and the CD34+ count present in bone marrow (but not treatment assignment) were associated with improved LVEF (P=0.03 and P=0.014, respectively).
In an exploratory analysis, higher endocardial voltage and bone marrow CD34+ levels were associated with improved left ventricular function among ischemic cardiomyopathy patients. Intramyocardial needle injections, possibly through stimulation of angiogenesis, might serve as a future therapy in patients with reduced left ventricular function and warrants investigation.
PMCID: PMC4979383  PMID: 27547135
Bone marrow cells; comparative study; electrophysiologic techniques, cardiac; endocardium; heart failure/therapy; mapping; multicenter study; recovery of function; ventricular dysfunction, left
14.  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
15.  Safety of Routine Invasive Versus Selective Invasive Therapy in Women with Non-ST-Elevation Acute Coronary Syndrome 
Cardiology and Therapy  2015;5(1):43-50.
Prior studies suggested that a routine invasive approach in the management of non-ST-elevation acute coronary syndrome (NSTE-ACS) is beneficial in men, but the data are less conclusive in women. One study conducted exclusively in women found that routine invasive therapy was associated with a markedly increased risk of major bleeding. This pilot randomized controlled trial compared the safety of a routine invasive versus a selective invasive strategy among women.
Women with NSTE-ACS and an additional high-risk characteristic were randomized to a routine invasive versus a selective invasive strategy. The primary outcome was the risk of major bleeding. The secondary outcome was the first occurrence of all-cause death, myocardial infarction, stroke, re-hospitalization for ACS, or major bleeding within 6 months.
Twenty-three women were assigned to routine invasive therapy and 17 to selective invasive therapy. Twenty-seven women (68%) had elevated troponin T (mean 0.33 ng/mL) and/or creatinine kinase-MB (mean 23 ng/mL). The risk of major bleeding was similar with both approaches (P = 0.99). At 6 months, the secondary outcome occurred in 9% of the routine invasive group versus 18% of the selective invasive group (risk ratio = 0.49, 95% confidence interval 0.09–2.63, P = 0.63).
This pilot study demonstrated that a routine invasive approach is safe in women. There was suggestion of benefit from routine invasive therapy compared with selective invasive therapy. These data could be used to design an appropriately powered trial to determine the optimal management strategy among women with NSTE-ACS.
Electronic supplementary material
The online version of this article (doi:10.1007/s40119-015-0055-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4906082  PMID: 26661893
Major bleeding; Myocardial infarction; Non-ST-elevation acute coronary syndrome; Sex differences; Women
16.  Acute Kidney Injury After Transcatheter Aortic Valve Replacement 
American journal of nephrology  2015;41(0):370-371.
PMCID: PMC4514544  PMID: 26113253
transcatheter aortic valve replacement; acute kidney injury; aortic stenosis
17.  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
18.  Multiple Causes for Ischemia Without Obstructive CAD: Not a Short List 
Circulation  2015;131(12):1044-1046.
PMCID: PMC4664445  PMID: 25712204
Hypertension  2015;65(6):1331-1340.
Emerging evidence suggests that gut microbiota is critical in the maintenance of physiological homeostasis. The present study was designed to test the hypothesis that dysbiosis in gut microbiota is associated with hypertension since genetic, environmental, and dietary factors profoundly influence both gut microbiota and blood pressure. Bacterial DNA from fecal samples of two rat models of hypertension and a small cohort of patients was used for bacterial genomic analysis. We observed a significant decrease in microbial richness, diversity, and evenness in the spontaneously hypertensive rat, in addition to an increased Firmicutes to Bacteroidetes ratio. These changes were accompanied with decreases in acetate- and butyrate-producing bacteria. Additionally, the microbiota of a small cohort of human hypertension patients was found to follow a similar dysbiotic pattern, as it was less rich and diverse than that of control subjects. Similar changes in gut microbiota were observed in the chronic angiotensin II infusion rat model, most notably decreased microbial richness and an increased Firmicutes to Bacteroidetes ratio. In this model, we evaluated the efficacy of oral minocycline in restoring gut microbiota. In addition to attenuating high blood pressure, minocycline was able to rebalance the dysbiotic hypertension gut microbiota by reducing the Firmicutes to Bacteroidetes ratio. These observations demonstrate that high BP is associated with gut microbiota dysbiosis, both in animal and human hypertension. They suggest that dietary intervention to correct gut microbiota could be an innovative nutritional therapeutic strategy for hypertension.
PMCID: PMC4433416  PMID: 25870193
Hypertension; Microbiota; Dysbiosis; Minocycline; Butyrate
21.  Angiotensin-converting enzyme 2 inhibits high-mobility group box 1 and attenuates cardiac dysfunction post-myocardial ischemia 
High-mobility group box 1 (HMGB1) triggers and amplifies inflammation cascade following ischemic injury, and its elevated levels are associated with adverse clinical outcomes in patients with myocardial infarction (MI). Angiotensin-converting enzyme 2 (ACE2), a key member of vasoprotective axis of the renin-angiotensin system (RAS), regulates cardiovascular functions and exerts beneficial effects in cardiovascular disease. However, the association between HMGB1 and ACE2 has not been studied. We hypothesized that overexpression of ACE2 provides cardioprotective effects against MI via inhibiting HMGB1 and inflammation. ACE2 knock-in (KI) mice and littermate wild-type (WT) controls were subjected to either sham or coronary artery ligation surgery to induce MI. Heart function was assessed 4 weeks after surgery using echocardiography and Millar catheterization. Tissues were collected for histology and analysis of the expression of HMGB1, RAS components, and inflammatory cytokines. ACE2 in the heart of the ACE2 KI mice was 58-fold higher than WT controls. ACE2-MI mice exhibited a remarkable preservation of cardiac function and reduction of infarct size in comparison to WT-MI mice. Notably, ACE2 overexpression significantly reduced the MI-induced increase in apoptosis, macrophage infiltration, and HMGB1 and pro-inflammatory cytokine expression (TNF-α and IL-6). Moreover, in an in vitro study, ACE2 activation prevented the hypoxia-induced cell death and upregulation of HMGB1 in adult cardiomyocytes. This protective effect is correlated with downregulation of HMGB1 and downstream pro-inflammatory cascades, which could be useful for the development of novel treatment for ischemic heart disease.
PMCID: PMC4842346  PMID: 26498282
ACE2; Myocardial infarction; HMGB1; Inflammation
22.  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
23.  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
24.  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
25.  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

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