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Percutaneous balloon mitral valvuloplasty (PBMV) is primarily performed for rheumatic mitral stenosis (MS). Therefore, limited data exist on PBMV in countries with a low incidence of rheumatic disease. Using the Nationwide Readmission Database, we examined trends in in-hospital mortality and 30-day readmission among patients who received PBMV for rheumatic and non-rheumatic MS. We also examined the change in 90-day hospitalization rate before vs after PBMV. Between 2016 and 2019, there were 1109 hospitalizations in which patients received PBMV for rheumatic (n = 955, 86.1%) vs non-rheumatic MS (n = 154, 13.9%). The all-cause in-hospital mortality for rheumatic and non-rheumatic MS did not change over time (0.9% → 2.0%, P = 0.94, and 5.9% → 9.5%, P = 0.09 respectively). Similarly, the 30-day readmission for patients with rheumatic and non-rheumatic MS did not change over time (12.4% → 9.9%, P = 0.26, and 4.4% → 10.5%, P = 0.30, respectively). The 90-day all-cause hospitalization rate remained the same before vs after PBMV for rheumatic and non-rheumatic MS (25.5% → 21.8%; P = 0.14, and 24.0% → 33.7%; P = 0.19, respectively). Although no statistically significant change was noted over time for trends in in-hospital mortality, 30-day readmission, or even in the change in 90-day all-cause hospitalizations before and after PBMV for both types of MS, among those with non-rheumatic MS, there was a signal of an increase in the in-hospital mortality, and 30-day readmission, even more, there was 29% relative increase in 90-day hospitalizations after PBMV. Future studies are needed to examine the role of PBMV in patients with non-rheumatic MS., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: There is a paucity of data regarding the sex-related differences in the trends and outcomes of trans-septal transcatheter mitral valve replacement (TS-TMVR)., Methods: The Nationwide Readmissions Database (2015-2018) was queried for admissions for TS-TMVR. Propensity matched analysis was conducted to compare outcomes with hospitalizations for TS-TMVR among women versus men. The main study outcome was in-hospital mortality., Results: Our final analysis included 2063 hospitalizations for TS-TMVR; of whom, 58.1% were women. The proportion of women among those undergoing TS-TMVR increased from 50% in 2015 to 60.2% in 2018 (P trend  = 0.04). Compared with men, women undergoing TS-TMVR were slightly younger, and had a distinct profile of comorbidities. After matching, there was no significant difference in in-hospital mortality among women versus men undergoing TS-TMVR (7.8% vs. 6.1%, OR = 1.30; 95% CI: 0.79-2.13). Subgroup analyzes showed an interaction toward higher mortality with women versus men among patients with CKD (P interaction  = 0.07). There were no significant differences between women and men in in-hospital complications or length of stay after TS-TMVR. Compared with men, women undergoing TS-TMVR were more likely to be discharged to a nursing facility (17.7% vs. 11.5%, p = 0.01) and had higher rates of 30-day readmissions (22.4% vs. 13.6%, p = 0.01)., Conclusion: This nationwide analysis showed an increase in the proportion of women among patients undergoing TS-TMVR during the study years. There were no differences in in-hospital mortality, in-hospital complications, or length of stay between both sexes following TS-TMVR. Women were more likely to be discharged to nursing facilities and had higher rates of readmission at 30 days even after propensity matching., (© 2022 Wiley Periodicals LLC.)

Objectives: To examine temporal trends, predictors, and outcomes of red blood cell (RBC) transfusion in patients undergoing transcatheter aortic valve replacement (TAVR) in the United States., Methods: We used the National Inpatient Sample databases to identify TAVR procedures performed between January 2012 and September 2015 in the United States. Patients were propensity matched (within the strata of overt and no bleeding) on the likelihood of receiving RBC transfusion, and in-hospital outcomes were compared between the 2 groups in the matched cohort., Results: Among 46,710 TAVR procedures performed during the study period, rates of RBC transfusion were 17.3% (95% confidence interval [CI], 16.1%-18.5%). RBC transfusion rates decreased significantly from 29.5% during the first quarter of 2012 to 10.8% during the third quarter of 2015 (P < .001). Older age, female sex, peripheral vascular disease, chronic kidney disease, anemia, coagulopathy, and fluid/electrolyte disorders were associated with increased odds, whereas elective admission, obesity, and endovascular access were associated with decreased odds of RBC transfusion. In the propensity-matched cohort (7995 pairs with and without RBC transfusion), RBC transfusion was associated with increased risk of in-hospital mortality, infection, and transient ischemic attack/stroke in patients without bleeding (odds ratio [OR] Mortality , 2.29; 95% CI, 1.31-4.02; OR Infection , 2.13; 95% CI, 1.03-4.39; OR Transient ischemic attack/Stroke, 3.36; 95% CI, 1.52-7.45), but not in those with overt bleeding (OR Mortality , 1.10; 95% CI, 0.68-1.48; OR Infection , 0.80; 95% CI, 0.45-1.45; OR Transient ischemic attack/Stroke , 1.16; 95% CI, 0.74-1.85); P interaction  < .05 for all., Conclusions: RBC transfusion is associated with worse clinical outcomes in TAVR patients without bleeding, but not in those with overt bleeding. The utility and optimal threshold for RBC transfusion in TAVR patients, especially among those with overt bleeding, warrants further prospective investigation., (Copyright © 2019 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: We evaluated the association between postprocedural packed red blood cell transfusion and morbidity and mortality among patients undergoing transcatheter aortic valve replacement., Methods: We retrospectively analyzed 429 patients with severe aortic stenosis who underwent transcatheter aortic valve replacement. Propensity-score adjusted multivariable logistic and Cox regression models were used to determine the association of packed red blood cell transfusion with the composite endpoint of death, myocardial infarction, and stroke at 30 days and in hospital, and 1-year mortality., Results: Patients receiving transfusions had a higher 30-day and in-hospital incidence of death, myocardial infarction, or stroke when compared with patients who did not receive transfusions (hazard ratio 2.03, 95% confidence interval: 1.02 to 4.07, p = 0.045; and hazard ratio 2.46, 95% confidence interval: 1.12 to 5.41, p = 0.025, respectively). Postprocedural transfusion was independently associated with 1-year mortality (hazard ratio 2.65, 95% confidence interval: 1.21 to 5.80, p = 0.015)., Conclusions: Packed red blood cell transfusion for patients undergoing transcatheter aortic valve replacement is associated with an increased incidence of adverse outcomes during hospitalization and at 30-day and 1-year follow-up., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: In a separate, contemporary cohort, we sought to confirm findings of the original Women's Ischemia Syndrome Evaluation (WISE)., Background: The original WISE observed a high prevalence of both invasively determined coronary endothelial and coronary microvascular dysfunction (CMD) that predicted adverse events in follow-up., Methods: We comparatively studied the WISE-Coronary Vascular Dysfunction (CVD) cohort (2009-2011), with signs and symptoms of ischemia but without significant CAD, to the original WISE (1997-2001) cohort. CMD was defined as coronary flow reserve (CFR) ≤2.5, or endothelial dysfunction as epicardial coronary artery constriction to acetylcholine (ACH), or <20% epicardial coronary dilation to nitroglycerin (NTG)., Results: In WISE (n=181) and WISE-CVD (n=235) women, mean age in both was 54 years, and 83% were white (WISE) vs 74% (WISE-CVD, p=0.04). Use of hormone replacement therapy was less frequent in WISE-CVD vs WISE (46% vs 57%, p=0.026) as was presence of hypertension (40% vs 52%, p=0.013), hyperlipidemia (20% vs 46%, p<0.0001), and smoking (46% vs 56%, p=0.036). Similar rates were observed in WISE-CVD and WISE cohorts for CMD (mean CFR 2.7±0.6 vs 2.6±0.8, p=0.35), mean change in diameter with intracoronary ACH (0.2±10.0 vs 1.6±12.8 mm, p=0.34), and mean change in diameter with intracoronary NTG (9.7±13.0 vs 9.8±13.5 mm, p=0.94), respectively., Conclusions: This study confirms prevalence of CMD in the contemporary WISE-CVD cohort similar to that of the original WISE cohort, despite a lower risk factor burden in WISE-CVD. Because these coronary functional abnormalities predict major adverse cardiac events, clinical trials of therapies targeting these abnormalities are indicated., Competing Interests: There are no relevant conflicts of interest of any of the authors to disclose., (Copyright © 2019 R. David Anderson et al.)

Infective endocarditis (IE) of prosthetic or bioprosthetic heart valves is a serious complication associated with significant morbidity and mortality. Data on the incidence, risk factors, and outcomes of IE after transcatheter aortic valve implantation (TAVI) in the United States are limited. We used the 2013 to 2014 Nationwide Readmissions Databases to determine the incidence of early IE after TAVI and surgical aortic valve replacement (SAVR) in the US. Clinical characteristics, independent predictors, and outcomes of patients with IE post-TAVI were examined. In 29,306 TAVI and 66,077 SAVR patients, the incidence rates of early IE were 1.7% (95% confidence interval [CI] 1.5% to 1.9%) and 2.5% (95% CI 2.3% to 2.9%) per person-year, respectively. In a propensity-matched cohort of 15,138 TAVI and 15,030 SAVR patients (weighted), there were no significant differences in the incidence rates of IE (1.7% [95% CI 1.4% to 2.0%] vs 1.9% [95% CI 1.6% to 2.2%] per person-year, log-rank p = 0.29) or in the median (interquartile range) time to IE (91 [48 to 146] vs 92 [61 to 214] days, p = 0.13). Staphylococcus (30.4%), Streptococcus (29.9%), and Enterococcus (20.5%) were the most common causative organisms of IE post-TAVI. Younger age, history of heart failure, need for permanent pacemaker placement, cardiac arrest, major bleeding, and sepsis during the index TAVI hospitalization were independently associated with an increased risk of IE. In-hospital mortality rate during readmission for IE was 15.6%. In conclusion, in a nationally representative cohort of TAVI patients in the US, the incidence rate of early IE was 1.7% per person-year. Age, co-morbid conditions, invasive procedures, and complications during the index hospitalization were associated with incident IE post-TAVI., (Copyright © 2018. Published by Elsevier Inc.)

Background: Transcatheter aortic valve replacement (TAVR) exposes patients to radiation., Objectives: We sought to identify factors associated with higher radiation exposure and to quantify their relative influence, which may inform reduction of this hazard., Methods: All TAVR procedures at Rhode Island Hospital between March 20, 2012 and February 12, 2017 were included. Procedures were performed by two co-primary operators using a Siemens Artis Zeego system. Radiation metrics were generated by the imaging system. The primary metric was dose-area product (DAP, Gy*cm 2 ), and secondary metrics were reference point air kerma (mGy) and fluoroscopy time (minutes). Data collected for the STS/ACC TVT Registry were utilized to develop a multivariable linear regression model predicting DAP., Results: In 294 TAVRs, median DAP was 169 Gy*cm 2 [interquartile range (IQR) 106-238]. The r 2 values for the full 27-variable DAP model and reduced eight-variable model were 0.457 and 0.420, respectively. Valve area, aortic insufficiency, and procedure year (suggesting absence of a learning curve) were non-significant predictors in the full model, while increasing weight, cutdown transfemoral access, higher pre-procedure creatinine and hemoglobin, and vascular complications predicted higher DAP in both models. Results were unchanged when DAP was log-transformed. Secondary models for air kerma and fluoroscopy time revealed similar predictors., Conclusion: Factors associated with increased procedural complexity and duration as well as radiation attenuation and scatter predict increased patient radiation exposure during TAVR. Modification of procedural technique, especially using percutaneous femoral vascular access, may facilitate reduction in exposure., (© 2017 Wiley Periodicals, Inc.)

Background: Information regarding the pathogenesis of ischemic heart disease (IHD) in women is limited. Sex-specific responses to atherosclerosis and coronary arterial remodelling in women versus men have been hypothesized, but limited study exists., Methods: Case-matched study of 174 women with suspected ischemia referred for coronary angiography: 87 with non-obstructive coronary artery disease (CAD) (no luminal diameter stenosis >20% in any coronary artery) and 87 age and ethnicity matched women with obstructive CAD. Groups were compared with regard to atheroma burden and coronary arterial remodelling assessed by coronary artery intravascular ultrasound (IVUS)., Results: IVUS revealed more extensive atheroma with obstructive CAD vs. those without obstructive CAD, with greater percent atheroma volume (PAV) (36.1%±9.8% vs. 25.4%±9.1%, P<0.0001), total atheroma volume (TAV) (140.8±58.7 vs. 98.8±46.9 mm 3 , P<0.0001) and percentage of images containing plaque (70.0%±30.5% vs. 35.7%±32.6%, P<0.0001). Adjusting for risk factors, PAV (35%±1% vs. 28%±1%, P=0.0008), TAV (131±7 vs. 115±7 mm 3 , P=0.110) and percentage of images containing plaque (66%±4% vs. 45%±5%, P=0.0008) remained greater with obstructive CAD. Obstructive CAD was associated with smaller lumen volumes (251.9±92.8 vs. 289.7±91.8 mm 3 , P=0.005), but surprisingly, the external elastic membrane (EEM) volume was very similar comparing the groups (392.7±128.1 vs. 388.6±113.7 mm 3 , P=0.910)., Conclusions: Our findings suggest that women referred to angiography for suspected ischemia, have differing patterns of coronary arterial response to injury with regard to accumulation of atherosclerosis and compensatory remodelling related to the presence and absence of obstructive CAD. Preservation and cultivation of compensatory arterial remodelling may be a novel CAD therapeutic target., Competing Interests: Conflicts of Interest: Dr. CN Bairey Merz reports personal honoraria and consulting from ACRWH (NIH Advisory Council), NIH-CASE (grant review study section), Springer International (book honorarium), Decision Support in Medicine LLC (book honorarium), and NHLBI Research Triangle Institute (RTI) International, as well as personal research grants for WISE HFpEF, RWISE, FAMRI, DoD, and California Institute for Precision Medicine. The other authors have no conflicts of interest to declare.

Objectives: The authors sought to examine outcomes and identify independent predictors of mortality among patients undergoing urgent/emergent transcatheter aortic valve replacement (TAVR)., Background: Data on urgent/emergent TAVR as a rescue therapy for decompensated severe aortic stenosis (AS) are limited., Methods: The Society of Thoracic Surgeons and the American College of Cardiology Transcatheter Valve Therapy (STS/ACC TVT) Registry linked with Centers for Medicare & Medicaid Services claims was used to identify patients who underwent urgent/emergent versus elective TAVR between November 2011 and June 2016. Outcomes assessed were device success rate, in-hospital major adverse events, and 30-day and 1-year mortality. Independent predictors of mortality after urgent/emergent TAVR were examined., Results: Of 40,042 patients who underwent TAVR, 3,952 (9.9%) were urgent/emergent (median STS PROM score 11.8 [interquartile range: 7.6 to 17.9]). Device success rate was statistically lower, but not clinically different after urgent/emergent versus elective TAVR (92.6% vs. 93.7%; p = 0.007). Rates of major and/or life-threatening bleeding, major vascular complications, myocardial infarction, stroke, new permanent pacemaker placement, conversion to SAVR, and paravalvular regurgitation were similar between the 2 groups. Compared with elective TAVR, patients undergoing urgent/emergent TAVR had higher rates of acute kidney injury and/or new dialysis (8.2% vs. 4.2%; p < 0.001), 30-day mortality (8.7% vs. 4.3%, adjusted hazard ratio: 1.28, 95% confidence interval: 1.10 to 1.48), and 1-year mortality (29.1% vs. 17.5%, adjusted hazard ratio: 1.20, 95% confidence interval: 1.10 to 1.31). In patients undergoing urgent/emergent TAVR, non-femoral access and cardiopulmonary bypass were associated with increased risk, whereas use of balloon-expandable valve was associated with decreased risk of 30-day and 1-year mortality., Conclusions: Urgent/emergent TAVR is feasible with acceptable outcomes and may be a reasonable option in a selected group of patients with severe AS., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Contributory risk factors to premature coronary artery disease (CAD) in premenopausal women are poorly understood and data on this subset of women is lacking. There is growing evidence that the process of inflammation is a part of the atherosclerotic process. Mechanistic insights from animal work suggest that the profile of circulating cytokines reflects both endothelial integrity and the presence of immune and progenitor cells. Significant differences in pro- and anti-inflammatory cytokine concentrations between patients with and without CAD exist. Young women with obstructive CAD may experience differences in pro-inflammatory cytokines and the recruitment of reparative cells that secrete T-Helper (Th2 cytokines compared to women without CAD. Thus, cytokine balance may play a role in obstructive CAD in young women. In this pilot study we set out to identify an array of circulating inflammatory marker profiles which could be useful for the development of risk assessment and preventive strategies. We tested the hypothesis that an increase in serologic Th1 cytokines relative to Th2)/hematopoietic regulatory (HR) cytokines is related to premature coronary atherosclerosis in premenopausal women., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Development of membranous ventricular septal defects (VSD) is a rare complication of transcatheter aortic valve replacements (TAVR), and is recognized using intraoperative and postoperative imaging. We present two cases of this rare but serious complication; one was successfully managed conservatively and the other with valve-in-valve therapy. Management strategies for post-TAVR VSDs varies, but should be individualized to the clinical scenario. We performed a literature search and sought to identify various risk factors which may predispose patients to the development of VSD after TAVR., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Sudden cardiac death (SCD) is often the first presentation of ischemic heart disease; however, there is limited information on SCD among women with and without obstructive coronary artery disease (CAD). We evaluated SCD incidence in the WISE (Women's Ischemia Syndrome Evaluation) study., Methods and Results: Overall, 904 women with suspected ischemic heart disease with preserved ejection fraction and core laboratory coronary angiography were followed for outcomes. In case of death, a death certificate and/or a physician or family narrative of the circumstances of death was obtained. A clinical events committee rated all deaths as cardiovascular or noncardiovascular and as SCD or non-SCD. In total, 96 women (11%) died over a median of 6 years (maximum: 8 years). Among 65 cardiovascular deaths, 42% were SCD. Mortality per 1000 person-hours increased linearly with CAD severity (no CAD: 5.8; minimal: 15.9; obstructive: 38.6; P <0.0001). However, the proportion of SCD was similar across CAD severity: 40%, 58%, and 38% for no, minimal, and obstructive CAD subgroups, respectively ( P value not significant). In addition to traditional risk factors (age, diabetes mellitus, smoking), a history of depression ( P =0.018) and longer corrected QT interval ( P =0.023) were independent SCD predictors in the entire cohort. Corrected QT interval was an independent predictor of SCD in women without obstructive CAD ( P =0.033)., Conclusions: SCD contributes substantially to mortality in women with and without obstructive CAD. Corrected QT interval is the single independent SCD risk factor in women without obstructive CAD. In addition to management of traditional risk factors, these data indicate that further investigation should address mechanistic understanding and interventions targeting depression and corrected QT interval in women., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Importance: With the approval of transcatheter aortic valve replacement (TAVR) for patients with severe symptomatic aortic stenosis at intermediate surgical risk, TAVR volume is projected to increase exponentially in the United States. The 30-day readmission rate for TAVR was recently reported at 17.9%. The association between institutional TAVR volume and the 30-day readmission metric has not been examined., Objective: To assess the association between hospital TAVR volume and 30-day readmission., Design, Setting, and Participants: In this observational study, we used the 2014 Nationwide Readmissions Database to identify hospitals with established TAVR programs (performing at least 5 TAVRs in the first quarter of 2014). Based on annual TAVR volume, hospitals were classified as low (<50), medium (≥50 to <100), and high (≥100) volume. Rates, causes, and costs of 30-day readmissions were compared between low-, medium-, and high-volume hospitals. Data were analyzed from November to December 2016., Exposure: Transcatheter aortic valve replacement., Main Outcomes and Measures: Thirty-day readmissions., Results: Of 129 hospitals included in this study, 20 (15.5%) were categorized as low volume, 47 (36.4%) as medium volume, and 62 (48.1%) as high volume. Of 16 252 index TAVR procedures, 663 (4.1%), 3067 (18.9%), and 12 522 (77.0%) were performed at low-, medium-, and high-volume hospitals, respectively. Thirty-day readmission rates were significantly lower in high-volume compared with medium-volume (adjusted odds ratio, 0.76; 95% CI, 0.68-0.85; P < .001) and low-volume (adjusted odds ratio, 0.75; 95% CI, 0.60-0.92; P = .007) hospitals. Noncardiac readmissions were more common in low-volume hospitals (65.6% vs 60.6% in high-volume hospitals), whereas cardiac readmissions were more common in high-volume hospitals (39.4% vs 34.4% in low-volume hospitals). There were no significant differences in length of stay and costs per readmission among the 3 groups (mean [SD], 5.5 [5.0] days vs 5.9 [7.5] days vs 6.0 [5.8] days; P = .74, and $13 886 [18 333] vs $14 135 [17 939] vs $13 432 [15 725]; P = .63, respectively)., Conclusions and Relevance: We report for the first time, to our knowledge, an inverse association between hospital TAVR volume and 30-day readmissions. Lower readmission at higher-volume hospitals was associated with significantly lower cost to the health care system.

Background: The association between migraine headache and cardiovascular events has been inconsistent. This study determines the long-term risk of cardiovascular events among women with and without a history of migraine headache who were under evaluation for suspected myocardial ischemia in the Women's Ischemia Syndrome Evaluation (WISE)., Methods: The WISE is a National Heart, Lung and Blood Institute-sponsored prospective, multicenter study that aims to improve myocardial ischemia evaluation in women. A total of 936 women presenting with symptoms of myocardial ischemia underwent structured data collection and coronary angiography. Information pertaining to migraine headache was available in 917 women. All-cause mortality data were available on all women for a median of 9.5 years, and nonfatal cardiovascular event data were available on 888 women for a median of 6.5 years., Results: A total of 224 (24.4%) women reported a history of migraine headache. Compared with women who did not report a history of migraine headache, women with a history of migraine headache had an increased adjusted risk of cardiovascular event (cardiovascular death, nonfatal myocardial infarction, heart failure, or stroke) (hazard ratio 1.83; 95% confidence interval, 1.22-2.75) at a median follow-up of 6.5 years. This result was driven mainly by a twofold increase in the risk of stroke (hazard ratio 2.33; 95% confidence interval, 1.16-4.68)., Conclusion: Among women being evaluated for ischemic heart disease, those reporting a history of migraine headache had increased risk of future cardiovascular events on long-term follow-up. This risk was primarily driven by a more-than twofold increase in the risk of stroke., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The Windkessel model of the cardiovascular system, both in its original wind-chamber and flow-pipe form, and in its electrical circuit analog has been used for over a century to modeled left ventricular ejection conditions. Using parameters obtained from aortic flow we formed a Flow Index that is proportional to the impedance of such a "circuit". We show that the impedance varies with ejection fraction (EF) in a manner characteristic of a resonant circuit with multiple resonance points, with each resonance point centrally located in a small range of EF values, i.e., corresponding to multiple contiguous EF bands., Methods: Two target populations were used: (I) a development group comprising male and female subjects (n=112) undergoing cardiovascular magnetic resonance (CMR) imaging for a variety of cardiac conditions. The Flow Index was developed using aortic flow data and its relationship to left ventricular EF was shown. (II) An illustration group comprised of female subjects from the Women's Ischemia Syndrome Evaluation (WISE) (n=201) followed for 5 years for occurrence of major adverse cardiovascular events (MACE). Flow data was not available in this group but since the Flow Index was related to the EF we noted the MACE rate with respect to EF., Results: The EFs of the development population covered a wide range (9%-76%) traversing six Flow Index resonance bands. Within each Flow Index resonance band the impedance varied from highly capacitive at the lower range of EF through minimal impedance at resonance, to highly inductive at the higher range of EF, which is characteristic of a resonant circuit. When transitioning from one EF band to a higher band, the Flow Index made a sudden transition from highly inductive to capacitive impedance modes. MACE occurred in 26 (13%) of the WISE (illustration) population. Distance in EF units (Delta center ) from the central location between peaks of MACE activity was derived from EF data and was predictive of MACE rate with an area under the receiver operator curve of 0.73. Of special interest, Delta center was highly predictive of MACE in the sub-set of women with EF >60% (AUC 0.79) while EF was no more predictive than random chance (AUC 0.48)., Conclusions: A Flow Index that describes impedance conditions of left ventricular ejection can be calculated using data obtained completely from the ascending aorta. The Flow Index exhibits a periodic variation with EF, and in a separate illustration population the occurrence of MACE was observed to exhibit a similar periodic variation with EF, even in cases of normal EF., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Transcatheter aortic valve replacement (TAVR) is now an accepted pathway for aortic valve replacement for patients who are at prohibitive, severe and intermediate risk for traditional aortic valve surgery. However, with this rising uptrend and adaptation of this new technology, vascular complications and their management remain an Achilles heel for percutaneous aortic valve replacement. The vascular complications are an independent predictor of mortality for patients undergoing TAVR. Early recognition of these complications and appropriate management is paramount. In this article, we review the most commonly encountered vascular complications associated with currently approved TAVR devices and their optimal percutaneous management techniques.

Background: Readmissions after cardiac procedures are common and contribute to increased healthcare utilization and costs. Data on 30-day readmissions after transcatheter aortic valve replacement (TAVR) are limited., Methods and Results: Patients undergoing TAVR (International Classification of Diseases-Ninth Revision-CM codes 35.05 and 35.06) between January and November 2013 who survived the index hospitalization were identified in the Nationwide Readmissions Database. Incidence, predictors, causes, and costs of 30-day readmissions were analyzed. Of 12 221 TAVR patients, 2188 (17.9%) were readmitted within 30 days. Length of stay >5 days during index hospitalization (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.24-1.73), acute kidney injury (HR, 1.23; 95% CI, 1.05-1.44), >4 Elixhauser comorbidities (HR, 1.22; 95% CI, 1.03-1.46), transapical TAVR (HR, 1.21; 95% CI, 1.05-1.39), chronic kidney disease (HR, 1.20; 95% CI, 1.04-1.39), chronic lung disease (HR, 1.16; 95% CI, 1.01-1.34), and discharge to skilled nursing facility (HR, 1.16; 95% CI, 1.01-1.34) were independent predictors of 30-day readmission. Readmissions were because of noncardiac causes in 61.8% of cases and because of cardiac causes in 38.2% of cases. Respiratory (14.7%), infections (12.8%), bleeding (7.6%), and peripheral vascular disease (4.3%) were the most common noncardiac causes, whereas heart failure (22.5%) and arrhythmias (6.6%) were the most common cardiac causes of readmission. Median length of stay and cost of readmissions were 4 days (interquartile range, 2-7 days) and $8302 (interquartile range, $5229-16 021), respectively., Conclusions: Thirty-day readmissions after TAVR are frequent and are related to baseline comorbidities, TAVR access site, and post-procedure complications. Awareness of these predictors can help identify and target high-risk patients for interventions to reduce readmissions and costs., (© 2016 American Heart Association, Inc.)

Background: 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., Methods: 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 (MRI QL ) and semi-quantitatively (MRI SQ ) 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., Results: 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 MRI SQ (0.78 vs . 0.54), MRI QL (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)., Conclusions: 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., Competing Interests: The authors have no conflicts of interest to declare.

Unlabelled: 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., Methods: 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 or receptor blocker were randomized to aldosterone blockade or placebo. The primary outcome at 16 weeks was percent change in coronary diameter to acetylcholine, and secondary outcome, coronary flow reserve to adenosine, both adjusted for baseline reactivity., Results: 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 acetylcholine 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 = .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 = .66)., Conclusion: 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 nonobstructive CAD., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Background: TIMI frame count (TFC) predicts outcomes in patients with obstructive coronary artery disease (CAD); it remains unclear whether TFC predicts outcomes in patients without obstructive CAD., Methods: TFC was determined in a sample of women with no obstructive CAD enrolled in the Women's Ischemia Syndrome Evaluation (WISE) study. Because TFC is known to be higher in the left anterior descending artery (LAD), TFC determined in the LAD was divided by 1.7 to provide a corrected TFC (cTFC)., Results: A total of 298 women, with angiograms suitable for TFC analysis and long-term (6-10 year) follow up data, were included in this sub-study. Their age was 55±11 years, most were white (86%), half had a history of smoking, and half had a history of hypertension. Higher resting cTFC was associated with a higher rate of hospitalization for angina (34% in women with a cTFC >35, 15% in women with a cTFC ≤35, P<0.001). cTFC provided independent prediction of hospitalization for angina after adjusting for many baseline characteristics. In this cohort, resting cTFC was not predictive of major events (myocardial infarction, heart failure, stroke, or all-cause death), cardiovascular events, all-cause mortality, or cardiovascular mortality., Conclusions: In women with signs and symptoms of ischemia but no obstructive CAD, resting cTFC provides independent prediction of hospitalization for angina. Larger studies are required to determine if resting TFC is predictive of major events in patients without obstructive coronary artery disease.

Objectives: To introduce an algorithmic approach to improve the interpretation of myocardial perfusion images in women with suspected myocardial ischemia., Background: Gated single photon emission computed tomography (SPECT) and magnetic resonance (MR) myocardial perfusion imaging (MPI) approaches have relatively poor diagnostic and prognostic value in women with suspected myocardial ischemia. Here we introduce an approach: Decisions Informed by Combining Entities (DICE) that forms a mathematical model utilizing MPI and cardiac dimensions generated by one modality to predict the perfusion status of another modality. The effect of the model is to systematically incorporate cardiac metrics that influence the interpretation of perfusion images, leading to greater consistency in designation of myocardial perfusion status between studies., Methods: Women (n=213), with suspected myocardial ischemia, underwent MPI assessment for regional perfusion defects using two modalities: gated SPECT (n=207) and MR imaging (n=203). To determine perfusion status, MR data were evaluated qualitatively and semi-quantitatively while SPECT data were evaluated using conventional clinical criteria. These perfusion status readings were designated "Original". Four regression models were generated to model perfusion status obtained with one modality [e.g., semi-quantitative magnetic resonance imaging (MRI)] against another modality (e.g., SPECT) and a threshold applied (DICE modeling) to designate perfusion status as normal or low. The DICE models included perfusion status, left ventricular (LV) chamber volumes and myocardial wall thickness. Women were followed for 40±16 months for the development of first major adverse cardiovascular event (MACE: CV death, nonfatal myocardial infarction (MI) or hospitalization for congestive heart failure). Original and DICE perfusion status were compared in their ability to detect high-grade coronary artery disease (CAD) and for prediction of MACE., Results: Adverse events occurred in 25 (12%) women and CAD was present in 34 (16%). In receiver-operator characteristic (ROC) analysis for CAD detection, the average area under the curve (AUC) for DICE vs. Original status was 0.77±0.03 vs. 0.70±0.03, P<0.01. Similarly, in Kaplan-Meier survival analysis the average log-rank statistic was higher for DICE vs. the Original readings (10.6±5.2 vs. 3.0±0.6, P<0.05)., Conclusions: While two data sets are required to generate the DICE models no knowledge of follow-up results is needed. DICE modeling improved diagnostic and prognostic value vs. the Original interpretation of the myocardial perfusion status.

Background: Women presenting with signs and symptoms of myocardial ischemia frequently have no or nonobstructive coronary artery disease (CAD)., Objective: This study aimed to investigate the associations between angiographic measures and longer-term clinical outcomes among women with signs and symptoms of ischemia referred for coronary angiography., Methods: A prospective cohort analysis of women referred for coronary angiography and enrolled in the National Heart, Lung, and Blood Institute-sponsored WISE was performed. An angiographic severity score was prospectively developed, assigning points for any stenosis weighted by stenosis severity, location, and collaterals and was then tested for prediction for adverse outcome in 917 women, over a median of 9.3 years., Setting: The study was conducted in referral centers., Patients: Women with signs and/or symptoms of myocardial ischemia referred for coronary angiography were consecutively consented and enrolled in a prospective study., Main Outcome Measures: Main outcomes included first occurrence of cardiovascular death or nonfatal myocardial infarction. Hospitalization for angina was a secondary outcome., Results: Cardiovascular death or myocardial infarction at 10 years occurred in 6.7%, 12.8%, and 25.9% of women with no, nonobstructive, and obstructive CAD (P < .0001), respectively. Cumulative 10-year cardiovascular death or myocardial infarction rates showed progressive, near-linear increases for each WISE CAD severity score range of 5, 5.1 to 10, 10.1 to 20, 20.1 to 50, and >50. The optimal threshold in the WISE severity score classifications for predicting cardiovascular mortality was >10 (eg, 5.0-10 vs 10.1-89), with both a sensitivity and specificity of 0.64 and an area under the curve of 0.64 (P = .02, 95% CI 0.59-0.68)., Conclusions: Among women with signs and symptoms of ischemia, nonobstructive CAD is common and associated with adverse outcomes over the longer term. The new WISE angiographic score appears to be useful for risk prediction in this population., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Objective: Wave reflections augment central aortic SBP 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 (Women's Ischemia Syndrome Evaluation, WISE) and no obstructive coronary artery disease (CAD)., Methods: 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, BMI, mean arterial BP, and heart rate., Results: Compared with the reference group, WISE participants had higher aortic SBP and pulse BP and ejection duration. These differences were associated with increased augmentation index and reflected pressure wave systolic duration. These modifications in wave reflection characteristics were associated with increased SPTI and wasted LV energy (Ew) and a decrease in pulse pressure amplification, myocardial viability ratio, and diastolic pressure time fraction., Conclusion: 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.

Objectives: To assess the prognostic value of a left ventricular energy-model in women with suspected myocardial ischemia., Background: The prognostic value of internal energy utilization (IEU) of the left ventricle in women with suspected myocardial ischemia is unknown., Methods: 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., Results: 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., Conclusions: 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.

Objectives: This study evaluated the safety of coronary reactivity testing (CRT) in symptomatic women with evidence of myocardial ischemia and no obstructive coronary artery disease (CAD)., Background: Microvascular coronary dysfunction (MCD) in women with no obstructive CAD portends an adverse prognosis of a 2.5% annual major adverse cardiovascular event (MACE) rate. The diagnosis of MCD is established by invasive CRT, yet the risk of CRT is unknown., Methods: The authors evaluated 293 symptomatic women with ischemia and no obstructive CAD, who underwent CRT at 3 experienced centers. Microvascular function was assessed using a Doppler wire and injections of adenosine, acetylcholine, and nitroglycerin into the left coronary artery. CRT-related serious adverse events (SAEs), adverse events (AEs), and follow-up MACE (death, nonfatal myocardial infarction [MI], nonfatal stroke, or hospitalization for heart failure) were recorded., Results: CRT-SAEs occurred in 2 women (0.7%) during the procedure: 1 had coronary artery dissection, and 1 developed MI associated with coronary spasm. CRT-AEs occurred in 2 women (0.7%) and included 1 transient air microembolism and 1 deep venous thrombosis. There was no CRT-related mortality. In the mean follow-up period of 5.4 years, the MACE rate was 8.2%, including 5 deaths (1.7%), 8 nonfatal MIs (2.7%), 8 nonfatal strokes (2.7%), and 11 hospitalizations for heart failure (3.8%)., Conclusions: In women undergoing CRT for suspected MCD, contemporary testing carries a relatively low risk compared with the MACE rate in these women. These results support the use of CRT by experienced operators for establishing definitive diagnosis and assessing prognosis in this at-risk population. (Women's Ischemia Syndrome Evaluation [WISE]; NCT00832702)., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: We investigated the role of the renin-angiotensin system in women with signs and symptoms of ischemia without obstructive coronary artery disease (CAD). Although microvascular dysfunction has been suggested to explain this syndrome and recently was found to predict adverse outcomes, the mechanisms and treatments remain unclear., Methods: In a substudy within the WISE, 78 women with microvascular dysfunction (coronary flow reserve [CFR] <3.0 following adenosine) and no obstructive CAD were randomly assigned to either an angiotensin-converting enzyme inhibition (ACE-I) with quinapril or a placebo treatment group. The primary efficacy parameter was CFR at 16 weeks adjusted for baseline characteristics and clinical site. The secondary response variable was freedom from angina symptoms assessed using the Seattle Angina Questionnaire., Results: A total of 61 women completed the 16-week treatment period with repeat CFR measurements, and treatment was well tolerated. For the primary outcome, at 16 weeks, CFR improved more with ACE-I than placebo (P < .02). For the secondary outcome of symptom improvement, ACE-I treatment (P = .037) and CFR increase (P = .008) both contributed., Conclusions: Microvascular function improves with ACE-I therapy in women with signs and symptoms of ischemia without obstructive CAD. This improvement is associated with reduction in angina. The beneficial response of the coronary microvasculature was limited to women with lower baseline CFR values, suggesting that the renin-angiotensin system may be more involved among women with more severe microvascular defects., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Objective: The aim of this study was to assess the relationship of the timing of hormone therapy (HT) use with angiographic coronary artery disease (CAD) and cardiovascular disease (CVD) events in women with natural versus surgical menopause., Methods: We studied 654 postmenopausal women undergoing coronary angiography for the 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., Results: Ever users of HT had a significantly lower prevalence of obstructive CAD compared with never users (age-adjusted odds ratio, 0.41 [0.28-0.60]). Women with natural menopause initiating HT before age 55 years had lower CAD severity compared with never users (age-adjusted β [SE] = -6.23 [1.50], P < 0.0001), whereas those initiating HT at age 55 years or more did not differ statistically from never users (-3.34 [2.13], P = 0.12). HT use remained a significant predictor of obstructive CAD when adjusted for a "healthy user" model (odds ratio, 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 (hazard ratio [95% CI], 0.60 [0.41-0.88]; P = 0.009) but became nonsignificant when adjusted for the presence or severity of obstructive CAD., Conclusions: Using the quantitative measurements of the 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.

Atherosclerosis is the major cause of coronary artery disease (CAD), and oxidized LDL (oxLDL) is believed to play a key role in the initiation of the atherosclerotic process. Recent studies show that inflammation and autoimmune reactions are also relevant in atherosclerosis. In this study, we examined the association of antibodies against oxLDL (anti-oxLDL) with the severity of CAD in 558 Women's Ischemia Syndrome Evaluation (WISE) study samples (465 whites; 93 blacks) determined by coronary stenosis (< 20%, 20%-49%, > 50% stenosis). We also examined the relationship of anti-oxLDL with serum lipid levels and nine candidate genes including APOE, APOH, APOA5, LPL, LRP1, HL, CETP, PON1, and OLR1. IgM anti-oxLDL levels were significantly higher in the >20% stenosis group than in the ≥ 20% stenosis group in whites (0.69 ± 0.02 vs. 0.64 ± 0.01, respectively; P = 0.02). IgM anti-oxLDL levels correlated significantly with total cholesterol (r² = 0.01; P = 0.03) and LDL cholesterol (r² = 0.017; P = 0.004) in whites. Multiple regression analysis revealed a suggestive association of LPL/S447X single-nucleotide polymorphism (SNP) with both IgG anti-oxLDL (P = 0.02) and IgM anti-oxLDL (P = 0.07), as well as between IgM anti-oxLDL and the OLR1/3'UTR SNP (P = 0.020). Our data suggest that higher IgM anti-oxLDL levels may provide protection against coronary stenosis and that genetic variation in some candidate genes are determinants of anti-oxLDL levels.

Aims: Using intravascular ultrasound (IVUS), we sought to characterize coronary morphology in women with chest pain without major epicardial obstructive coronary artery disease (CAD). We have previously observed an unexpectedly high rate of adverse outcomes among women with chest pain and normal or insignificant obstructive CAD. Information about the presence and characteristics of coronary atherosclerosis in these women could provide insight into the mechanisms related to increased risk, as well as improved diagnosis, prevention, and treatment., Methods: Women (n = 100) with suspected ischemia without obstructive CAD (>50% stenosis) underwent IVUS of a left coronary segment with measurements by a core lab masked to clinical and angiographic findings., Results: Angiograhic core lab analysis found 69.6% of patients had no (≤20%) and 30.4% had minimal (20-<50%) CAD. IVUS segmental images were interpretable by the core lab in 92 women, with 19 (21%) having no atherosclerosis (intimal-medial thickness <0.5 mm). In the remaining 73 women (79%), percent atheroma volume was 27 ± 8% and mean maximum plaque thickness was 0.53 ± 0.22 mm. Thirty-eight women with atherosclerosis (53%) had ≥30% of interrogated vessel involved. The average vessel involvement was 40%, and the maximum plaque thickness was 1.27 mm. The number of risk factors strongly correlated with percent atheroma volume (r = 0.53, P < 0.0001) and percent vessel involvement (r = 0.51, P < 0.0001), with the strongest independent predictor of both being age. Remodeling was assessed in 59/73 women (81%), and 73% had evidence of positive remodeling., Conclusions: In symptomatic women without significant luminal obstructive CAD, we observed a high prevalence of atherosclerosis with positive remodeling and preserved lumen size. These findings may help explain increased risk and emphasize need for improved diagnostic and treatment options for women with concealed CAD., (©2010, Wiley Periodicals, Inc.)

Objectives: The purpose of this study was to assess the prognostic value of global magnetic resonance (MR) myocardial perfusion imaging (MPI) in women with suspected myocardial ischemia and no obstructive (stenosis <50%) coronary artery disease (CAD)., Background: The prognostic value of global MR-MPI in women without obstructive CAD remains unknown., Methods: Women (n = 100, mean age 57 ± 11 years, age range 31 to 76 years), with symptoms of myocardial ischemia and with no obstructive CAD, as assessed by coronary angiography, underwent MR-MPI and standard functional assessment. During follow-up (34 ± 16 months), time to first adverse event (death, myocardial infarction, or hospitalization for worsening anginal symptoms) was analyzed using global MPI and left ventricular ejection fraction (EF) data., Results: Adverse events occurred in 23 (23%) women. Using univariable Cox proportional hazards regression modeling, variables found to be predictive of adverse events were global MR-MPI average uptake slope (p < 0.05), the ratio of MR-MPI peak signal amplitude to uptake slope (p < 0.05), and EF (p < 0.05). Two multivariable Cox models were formed, 1 using variables that were performance site dependent: ratio of MR-MPI peak amplitude to uptake slope together with EF (chi square: 13, p < 0.005); and a model using variables that were performance site independent: MR-MPI slope and EF (chi square: 12, p < 0.005). Each of the 2 multivariable models remained predictive of adverse events after adjustment for age, disease history, and Framingham risk score. For each of the Cox models, patients were categorized as high risk if they were in the upper quartile of the model and as not high risk otherwise. Kaplan-Meier analysis of time to event was performed for high risk versus not high risk for site-dependent (log rank: 15.2, p < 0.001) and site-independent (log rank: 13.0, p < 001) models., Conclusions: Among women with suspected myocardial ischemia and no obstructive CAD, MR-MPI-determined global measurements of normalized uptake slope and peak signal uptake, together with global functional assessment of EF, appear to predict prognosis., (Copyright © 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Compared with men, women have more evidence of myocardial ischemia with no obstructive coronary artery disease. Although low endogenous estrogen levels are associated with endothelial dysfunction, the role of low-dose hormone therapy has not been fully evaluated. We postulate that a 12-week duration of low-dose hormone replacement therapy is associated with myocardial ischemia and endothelial dysfunction., Methods and Results: Using a multicenter, randomized, placebo-controlled design, subjects were randomized to receive either 1 mg norethindrone/10 microg ethinyl estradiol or placebo for 12 weeks. Chest pain and menopausal symptoms, cardiac magnetic resonance spectroscopy, brachial artery reactivity, exercise stress testing, and psychosocial questionnaires were evaluated at baseline and exit. Recruitment was closed prematurely because of failure to recruit after publication of the Women's Health Initiative hormone trial. Of the 35 women who completed the study, there was less frequent chest pain in the treatment group compared with the placebo group (P = .02) at exit. Women taking 1 mg norethindrone/10 microg ethinyl estradiol also had significantly fewer hot flashes/night sweats (P = .003), less avoidance of intimacy (P = .05), and borderline differences in sexual desire and vaginal dryness (P = .06). There were no differences in magnetic resonance spectroscopy, brachial artery reactivity, compliance, or reported adverse events between the groups., Conclusions: These data suggest that low-dose hormone therapy improved chest pain symptoms, menopausal symptoms, and quality of life, but did not improve ischemia or endothelial dysfunction. Given that it was not possible to enroll the prespecified sample size, these results should not be considered definitive., (Copyright 2010 Mosby, Inc. All rights reserved.)

Background: Depression is associated with clinical events and premature mortality among patients with established coronary artery disease (CAD). Typically, however, studies in this area focus only on baseline symptom severity and lack any data concerning symptom duration or symptom history., Objectives: To describe and compare the relationships between 2 measures of depression-assessed in the form of depression symptom severity and reported treatment history-with atherosclerosis risk factors and major clinical events in a sample of women with suspected myocardial ischemia., Design: Follow-up study of women who completed a diagnostic CAD protocol, including cardiac symptoms, coronary angiography, ischemic testing, and assessments of depression symptom severity and reported treatment history., Setting: The Women's Ischemia Syndrome Evaluation (WISE), a National Heart, Lung, and Blood Institute (NHLBI)-sponsored multicenter study assessing cardiovascular function using state-of-the-art techniques in women referred for coronary angiography to evaluate chest pain or suspected myocardial ischemia., Participants: Five hundred five women (mean age, 53.4 years) enrolled in WISE and followed up for a mean of 4.9 years., Main Outcome Measures: Incidence of cardiac events, including myocardial infarction, stroke, and heart failure, and total mortality., Results: Relative to those with no or less stable depression symptoms, women with elevated depression symptoms and a reported treatment history showed higher rates of smoking, hypertension, and poorer education and an increased incidence of death and cardiac events (multivariate-adjusted risk ratio, 3.1; 95% confidence interval, 1.5-6.3; P = .001)., Conclusions: Among women with suspected myocardial ischemia, a combination of depressive symptom severity and treatment history was a strong predictor of an elevated CAD risk profile and increased risk of cardiac events compared with those without depression or with only 1 of the 2 measured depression markers. These findings reinforce the importance of assessing mental health factors in women at elevated CAD risk. Focusing only on baseline depression symptom severity may provide an incomplete picture of CAD risk.

Aims: Women with chest pain but without obstructive coronary artery disease (CAD) are considered at low risk for cardiovascular (CV) events, but half continue to experience debilitating chest pain over many years. This study compared CV outcomes in women with persistent chest pain (PChP) vs. those without PChP., Methods and Results: We studied 673 Women's Ischaemia Syndrome Evaluation (WISE) participants with chest pain undergoing coronary angiography for suspected myocardial ischaemia and at least 1 year of follow-up. PChP was defined as self-reported continuing chest pain after 1 year. Events occurring after that year were recorded for a median of 5.2 years. We compared CV event rates for women with and without PChP in subgroups with and without obstructive CAD. The median age was 58 years, 20% were racial minorities, 45% had PChP, 39% had obstructive CAD. Among women without CAD, those with PChP had more than twice the rate of composite CV events (P = 0.03), that included non-fatal myocardial infarctions (P = 0.11), strokes (P = 0.03), congestive heart failure (P = 0.38), and CV deaths (P = 0.73), compared with those without PChP. In women with CAD, there was no difference in composite CV events in those with and without PChP (P = 0.72)., Conclusion: Among women undergoing coronary angiography for suspected myocardial ischaemia, PChP in women with no obstructive CAD predicted adverse CV outcomes. Such women might benefit from additional evaluation and aggressive risk factor modification therapy.

Background: Coronary artery microvascular dysfunction is prevalent in women with chest pain in the absence of obstructive coronary artery disease (CAD) and is manifested by attenuated coronary flow reserve (CFR). Markers of inflammation and endothelial cell activation have been found to be elevated in patients with chest pain but without CAD. The relationship between inflammation, endothelial activation, and CFR is not known., Methods: Ninety-four women with chest pain in the absence of obstructive angiographic CAD underwent catheterization-based assessment of CFR and measurement of levels of inflammatory markers (n = 78) and endothelial cell activation in the NHLBI WISE study., Results: Coronary flow reserve did not correlate with levels of C-reactive protein (high-sensitivity C-reactive protein) (rs = -0.07, P = .53), interleukin (IL)-6 (rs = -0.12, P = .31), IL-18 (rs = 0.14, P = .23), tumor necrosis factor alpha (rs = -0.09, P = .43), transforming growth factor beta1 (rs = 0.02, P = .84), and soluble intracellular adhesion molecule-1 (rs = 0.04, P = .68). Median levels of markers of inflammation and endothelial cell activation did not differ between the 57 women with abnormal CFR (< 2.5) and the 37 women with normal coronary microvascular function (high-sensitivity C-reactive protein 0.32 vs 0.25 mg/dL, P = .80; IL-6 2.89 vs 2.39 pg/mL, P = .63; IL-18 218 vs 227 pg/mL, P = .59; tumor necrosis factor alpha 2.7 vs 2.4 pg/mL, P = .43; transforming growth factor beta1 9928 vs 12436 pg/mL, P = .76; soluble intracellular adhesion molecule-1 286 vs 287 pg/mL, P = .95). Multivariable models demonstrated no evidence of associations between markers of inflammation and of endothelial cell activation and CFR., Conclusions: Coronary microvascular dysfunction is not associated with markers of inflammation and endothelial cell activation in women with chest pain in the absence of obstructive CAD. These results suggest that inflammation and endothelial cell activation may not play a pathophysiological role in coronary microvascular dysfunction.

Background: Exercise testing, a major diagnostic modality in individuals with suspected coronary artery disease (CAD), has in general demonstrated less overall diagnostic accuracy in women compared to men. As part of the WISE, a modified protocol was examined with the intention of improving reliability of exercise testing., Methods: Criteria for entry in the WISE study include clinically indicated coronary angiography. Exercise testing was performed using a protocol modified to be more appropriate for women. The study population consisted of 96 women, mean age of 55.8 y (range 34-77), who completed exercise treadmill test (ETT). Most (78%) were postmenopausal; 96% had >or =2 risk factors for CAD., Results: By core laboratory angiography, 29/96 women had stenosis > or =50% in at least one coronary artery. Of these 29 women, 9 had abnormal ETT, yielding overall sensitivity of 31%. The remaining 20 women had normal (12/29, 41%) or nondiagnostic (8/29, 28%) studies. Among the 67 women with minimal or no coronary stenosis, 35 had no ischemic ST-segment changes during ETT, yielding overall specificity of 52%. Analysis with exclusion of women with nondiagnostic studies yielded sensitivity and specificity of 43% and 66%, respectively. The presence of coronary artery stenosis and inability to perform ETT, but not results of testing, predicted the outcomes of myocardial infarction, heart failure, and death., Conclusions: Exercise treadmill test appears to be of limited diagnostic value in women with suspected myocardial ischemia referred for coronary angiography. Sensitivity and specificity remain poor even with modified exercise protocol and core laboratory angiographic analysis. These findings merit consideration in view of current guidelines that recommend exercise testing in women with suspected CAD.

Background: Recently revised American College of Cardiology/American Heart Association guidelines have suggested that exercise test scores be used in decisions concerning patients with suspected coronary artery disease (CAD). Pretest and exercise test scores derived for use in women without known CAD have not been tested in women with a low prevalence of CAD., Methods: Within the Women's Ischemia Syndrome Evaluation (WISE) study, we evaluated 563 women undergoing coronary angiography for suspected myocardial ischemia. The prevalence of angiographic CAD was 26%. Overall, 189 women underwent treadmill exercise testing. Prognostic end points included death, myocardial infarction, stroke, and revascularization., Results: Each score stratified women into 3 probability groups (P <.001) according to the prevalence of coronary disease: Pretest: low 20/164 (12%), intermediate 53/245 (22%), high 75/154 (49%); Exercise test: low 11/83 (13%), intermediate 22/74 (30%), high 17/32 (53%). However, the Duke score did not stratify as well: low 7/46 (15%), intermediate 36/126 (29%), high 6/17 (35%); P =.44. When pretest and exercise scores were considered together, the best stratification with the exercise test score was in the intermediate pretest group (P <.03). The Duke score did not stratify this group at all (P =.98). Pretest and exercise test scores also stratified women according to prognostic end points: pretest--low 7/164 (4.3%), intermediate 28/245 (11.4%), high 27/154 (17.5%), P <.01; exercise test--low 4/83 (4.8%) and intermediate-high 17/106 (16%), P =.014., Conclusion: Both pretest and exercise test scores performed better than the Duke score in stratifying women with a low prevalence of angiographic CAD. The exercise test score appears useful in women with an intermediate pretest score, consistent with American College of Cardiology/American Heart Association guidelines.

Paraoxonase (PON), a high-density lipoprotein-associated enzyme, is believed to protect against low-density lipoprotein oxidation and thus affects the risk of coronary artery disease (CAD). Three polymorphisms in the PON1 (Leu55Met and Gln192Arg) and PON2 (Ser311Cys) genes have been shown to be associated with the risk of CAD in several European or European-derived populations. In the present study, we examined the associations between these three markers and the severity of CAD as determined by the number of diseased coronary artery vessels in 711 subjects (589 whites and 122 blacks) from the Women's Ischemia Syndrome Evaluation (WISE) study. WISE is a National Heart, Lung, and Blood Institute-sponsored multicenter study designed to address issues related to ischemic-heart-disease recognition and diagnosis in women. Subjects were classified as having normal/minimal CAD (<20% stenosis), mild CAD (20%-49% stenosis), and significant CAD (>/=50% stenosis). The women who had >/=50% stenosis were further classified into groups with one-, two-, or three-vessel disease if any of the three coronary arteries had diameter stenosis >/=50%. No significant association was found between the PON polymorphisms and stenosis severity in either white or black women. However, among white women, when data were stratified by the number of diseased vessels, the frequency of the PON1 codon 192 Arg/Arg genotype was significantly higher in the group with three-vessel disease than in the other groups (those with one-vessel and two-vessel disease) combined (17.02% vs. 4.58%; P=.0066). Similarly, the frequency of the PON2 codon 311 Cys/Cys genotype was significantly higher in the group with three-vessel disease than in the other groups combined (15.22% vs. 4.61%; P=.018). The adjusted odds ratios for the development of three-vessel disease were 2.80 (95% confidence interval 1.06-7.37; P=.038) for PON1 codon 192 Arg/Arg and 3.68 (95% confidence interval 1.26-10.68; P=.017) for PON2 codon 311 Cys/Cys. Our data indicate that the severity of CAD, in terms of the number of diseased vessels, may be affected by common genetic variation in the PON gene cluster, on chromosome 7.

Background: Noninvasive methods are needed for the identification of women at highest risk for coronary artery disease (CAD) who might benefit most from aggressive preventive therapy. Identification of brachial artery atherosclerosis, which correlates with coronary artery atherosclerosis, may be useful to estimate or stratify CAD risk. Because atherosclerosis disrupts the arterial architecture that regulates vessel size, we hypothesized that noninvasively measured large brachial artery diameter is a manifestation of atherosclerosis that is associated with angiographic CAD in women with chest pain., Methods: We examined 376 women (mean age, 57.1 years) with chest pain in the National Heart, Lung, and Blood Institute's Women's Ischemia Syndrome Evaluation study who underwent B-mode ultrasound scan measurement of brachial artery diameter at rest and during hyperemic stress (to quantify flow-mediated dilation), quantitative coronary angiography, and risk factor assessment., Results: Large resting brachial artery diameter was associated with significant angiographic CAD (3.90 +/- 0.79 mm vs 3.52 +/- 0.59 mm in women with CAD vs no CAD; P <.001). Impaired flow-mediated dilation, which correlated with resting diameter (r = -0.17; P =.001), was weakly associated with significant CAD (2.74% +/- 7.11% vs 4.48% +/- 9.52% in CAD vs no CAD; P =.046). After adjustment for age, body size, and CAD risk factors, women with large resting brachial artery diameters (>4.1 mm) had 3.6-fold increased odds (95% confidence interval, 1.8 to 7.1; P <.001) of significant angiographic CAD compared with those with small brachial arteries (