Blinded, randomized trial of sonographer versus AI cardiac function assessment.

Artificial intelligence (AI) has been developed for echocardiography1-3, although it has not yet been tested with blinding and randomization. Here we designed a blinded, randomized non-inferiority clinical trial (ClinicalTrials.gov ID: NCT05140642; no outside funding) of AI versus sonographer initial assessment of left ventricular ejection fraction (LVEF) to evaluate the impact of AI in the interpretation workflow. The primary end point was the change in the LVEF between initial AI or sonographer assessment and final cardiologist assessment, evaluated by the proportion of studies with substantial change (more than 5% change). From 3,769 echocardiographic studies screened, 274 studies were excluded owing to poor image quality. The proportion of studies substantially changed was 16.8% in the AI group and 27.2% in the sonographer group (difference of -10.4%, 95% confidence interval: -13.2% to -7.7%, P < 0.001 for non-inferiority, P < 0.001 for superiority). The mean absolute difference between final cardiologist assessment and independent previous cardiologist assessment was 6.29% in the AI group and 7.23% in the sonographer group (difference of -0.96%, 95% confidence interval: -1.34% to -0.54%, P < 0.001 for superiority). The AI-guided workflow saved time for both sonographers and cardiologists, and cardiologists were not able to distinguish between the initial assessments by AI versus the sonographer (blinding index of 0.088). For patients undergoing echocardiographic quantification of cardiac function, initial assessment of LVEF by AI was non-inferior to assessment by sonographers.

Left ventricular global longitudinal strain is worse in BRCA mutation positive breast cancer patients prior to cancer treatment and premature menopause.

PURPOSE: Breast cancer patients with mutations in human tumor suppressor genes BRCA1 and BRCA2 are at higher risk of cardiovascular disease (CVD) than the general population, as they are frequently exposed to cardiotoxic chemotherapy, anti-estrogen therapy, radiation, and/or oophorectomy for cancer-related treatment and prophylaxis. Animal and cell culture models suggest that BRCA mutations may play an independent role in heart failure. We sought to evaluate cardiac structure and function in female BRCA1 and BRCA2 mutation carriers with breast cancer compared to BRCA wildtype women with breast cancer. METHODS: We performed a 1:2 age- and hypertension-matched retrospective cohort study comparing BRCA1 and BRCA2 mutation carriers (n = 38) versus BRCA wildtype controls (n = 76) with a new diagnosis of breast cancer. Echocardiographic data were obtained within 6 months of breast cancer diagnosis and prior to chemotherapy, anti-estrogen therapy, radiation, or oophorectomy. Left ventricular global longitudinal strain (LV-GLS), a highly sensitive marker of LV function, was measured using QLab 15 (Philips Healthcare). RESULTS: In the total cohort of 114 patients with a new diagnosis of breast cancer, the median age was 45 ± 11 years and the prevalence of hypertension was 8%. There were no differences in traditional cardiovascular disease risk factors between cases and controls. BRCA carriers had lower LV-GLS (- 18.1% ± 4.7% vs. - 20.1% ± 3.8%, p = 0.02) and greater right atrial area (12.9 cm2 ± 2.7 cm2 vs. 11.8 cm2 ± 2.0 cm2, p = 0.04) compared to controls; however, both LV-GLS and right atrial area were within the normal range. Compared to controls, BRCA carriers had a trend toward worse LV posterior wall thickness (0.89 cm ± 0.15 cm vs. 0.83 cm ± 0.16 cm, p = 0.06) although not statistically significant. CONCLUSION: In women with newly diagnosed breast cancer and prior to treatment, LV-GLS was worse in BRCA1 and BRCA2 mutation carriers compared to those with BRCA wildtype. These findings suggest that BRCA mutations may be associated with subtle changes in cardiac function. Whether differences in GLS translate to increased cardiovascular risk in women with BRCA mutations needs to be further characterized.

Contributors to high left ventricular ejection fraction in women with ischemia and no obstructive coronary artery disease: Results from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) Study.

BACKGROUND: There are sex differences in left ventricular ejection fraction (LVEF) relevant to prognosis where women experience greater mortality at relatively higher LVEF compared to men, yet mechanistic understanding of this adverse prognosis is limited. Women with suspected ischemia with no obstructive coronary disease (INOCA) develop heart failure with preserved ejection fraction (HFpEF), yet contributors to LVEF remain largely unknown. METHODS: In 370 women with suspected ischemia with no obstructive coronary disease (INOCA) who prospectively underwent cardiac magnetic resonance imaging (CMRI), we investigated the contributions of LV morphology, function, and myocardial perfusion reserve on LVEF using univariate and multiple linear regression. RESULTS: A majority 71% of participants had high LVEF (>65%), followed by 24% having normal LVEF (55%-65%), and only 5% having low EF (<55%). Baseline characteristics were comparable among the 3 groups, with the exception of age which was 6 years higher in the high LVEF group (P < .01). Women in the high LVEF group also had the lowest LV cavity volume, greatest LV mass-volume ratio, and highest LV end-systolic elastance (all P < .05, adjusted for age, BMI, diabetes, and blood pressure). Myocardial perfusion reserve index was low in all groups (mean MPRI < 2.1) but was not significantly different across the spectrum of LVEF (P = .458). CONCLUSIONS: Taken together, these data demonstrate that the majority of women with suspected INOCA have elevated LVEF related to smaller, thicker ventricles with greater contractility. Future work is needed to better understand the specific mechanisms driving morphologic and functional changes in women with INOCA, and relations to longer-term HFpEF and mortality. CLINICAL TRIALS REGISTRATION: NCT02582021.

Coronary Arterial Function and Disease in Women With No Obstructive Coronary Arteries.

Ischemic heart disease (IHD) is the leading cause of mortality in women. While traditional cardiovascular risk factors play an important role in the development of IHD in women, women may experience sex-specific IHD risk factors and pathophysiology, and thus female-specific risk stratification is needed for IHD prevention, diagnosis, and treatment. Emerging data from the past 2 decades have significantly improved the understanding of IHD in women, including mechanisms of ischemia with no obstructive coronary arteries and myocardial infarction with no obstructive coronary arteries. Despite this progress, sex differences in IHD outcomes persist, particularly in young women. This review highlights the contemporary understanding of coronary arterial function and disease in women with no obstructive coronary arteries, including coronary anatomy and physiology, mechanisms of ischemia with no obstructive coronary arteries and myocardial infarction with no obstructive coronary arteries, noninvasive and invasive diagnostic strategies, and management of IHD.

Improved Robustness for Deep Learning-based Segmentation of Multi-Center Myocardial Perfusion MRI Datasets Using Data Adaptive Uncertainty-guided Space-time Analysis.

BACKGROUND: Fully automatic analysis of myocardial perfusion MRI datasets enables rapid and objective reporting of stress/rest studies in patients with suspected ischemic heart disease. Developing deep learning techniques that can analyze multi-center datasets despite limited training data and variations in software (pulse sequence) and hardware (scanner vendor) is an ongoing challenge. METHODS: Datasets from 3 medical centers acquired at 3T (n = 150 subjects; 21,150 first-pass images) were included: an internal dataset (inD; n = 95) and two external datasets (exDs; n = 55) used for evaluating the robustness of the trained deep neural network (DNN) models against differences in pulse sequence (exD-1) and scanner vendor (exD-2). A subset of inD (n = 85) was used for training/validation of a pool of DNNs for segmentation, all using the same spatiotemporal U-Net architecture and hyperparameters but with different parameter initializations. We employed a space-time sliding-patch analysis approach that automatically yields a pixel-wise "uncertainty map" as a byproduct of the segmentation process. In our approach, dubbed Data Adaptive Uncertainty-Guided Space-time (DAUGS) analysis, a given test case is segmented by all members of the DNN pool and the resulting uncertainty maps are leveraged to automatically select the "best" one among the pool of solutions. For comparison, we also trained a DNN using the established approach with the same settings (hyperparameters, data augmentation, etc.). RESULTS: The proposed DAUGS analysis approach performed similarly to the established approach on the internal dataset (Dice score for the testing subset of inD: 0.896 ± 0.050 vs. 0.890 ± 0.049; p = n.s.) whereas it significantly outperformed on the external datasets (Dice for exD-1: 0.885 ± 0.040 vs. 0.849 ± 0.065, p < 0.005; Dice for exD-2: 0.811 ± 0.070 vs. 0.728 ± 0.149, p < 0.005). Moreover, the number of image series with "failed" segmentation (defined as having myocardial contours that include bloodpool or are noncontiguous in ≥1 segment) was significantly lower for the proposed vs. the established approach (4.3% vs. 17.1%, p < 0.0005). CONCLUSIONS: The proposed DAUGS analysis approach has the potential to improve the robustness of deep learning methods for segmentation of multi-center stress perfusion datasets with variations in the choice of pulse sequence, site location or scanner vendor.

The Society for Cardiovascular Magnetic Resonance Registry at 150,000.

BACKGROUND: Cardiovascular magnetic resonance (CMR) is increasingly utilized to evaluate expanding cardiovascular conditions. The Society for Cardiovascular Magnetic Resonance (SCMR) Registry is a central repository for real-world clinical data to support cardiovascular research, including those relating to outcomes, quality improvement, and machine learning. The SCMR Registry is built on a regulatory-compliant, cloud-based infrastructure that houses searchable content and Digital Imaging and Communications in Medicine images. The goal of this study is to summarize the status of the SCMR Registry at 150,000 exams. METHODS: The processes for data security, data submission, and research access are outlined. We interrogated the Registry and presented a summary of its contents. RESULTS: Data were compiled from 154,458 CMR scans across 20 United States sites, containing 299,622,066 total images (∼100 terabytes of storage). Across reported values, the human subjects had an average age of 58 years (range 1 month to >90 years old), were 44% (63,070/145,275) female, 72% (69,766/98,008) Caucasian, and had a mortality rate of 8% (9,962/132,979). The most common indication was cardiomyopathy (35,369/131,581, 27%), and most frequently used current procedural terminology code was 75561 (57,195/162,901, 35%). Macrocyclic gadolinium-based contrast agents represented 89% (83,089/93,884) of contrast utilization after 2015. Short-axis cines were performed in 99% (76,859/77,871) of tagged scans, short-axis late gadolinium enhancement (LGE) in 66% (51,591/77,871), and stress perfusion sequences in 30% (23,241/77,871). Mortality data demonstrated increased mortality in patients with left ventricular ejection fraction <35%, the presence of wall motion abnormalities, stress perfusion defects, and infarct LGE, compared to those without these markers. There were 456,678 patient-years of all-cause mortality follow-up, with a median follow-up time of 3.6 years. CONCLUSION: The vision of the SCMR Registry is to promote evidence-based utilization of CMR through a collaborative effort by providing a web mechanism for centers to securely upload de-identified data and images for research, education, and quality control. The Registry quantifies changing practice over time and supports large-scale real-world multicenter observational studies of prognostic utility.

Latest from the WISE: Contributions to the Understanding of Ischemia and Heart Failure among Women with No Obstructive Coronary Arteries.

Since 1996, the National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE) has been investigating pathophysiological processes underlying ischemic heart disease in women and related outcomes. Recent findings have focused on women with signs and symptoms of ischemia and no obstructive coronary arteries (INOCA) and their elevated risk for heart failure with preserved ejection fraction (HFpEF). This review summarizes the latest WISE findings related to INOCA and pre-HFpEF characteristics, addressing our understanding of contributions from traditional vs nontraditional risk factors in women.

Coronary Microvascular Dysfunction: What Clinicians and Investigators Should Know.

PURPOSE OF REVIEW: Abnormal structure and function of the coronary microvasculature have been implicated in the pathophysiology of multiple cardiovascular disease processes. This article reviews recent research progress related to coronary microvascular dysfunction (CMD) and salient clinical takeaways. RECENT FINDINGS: CMD is prevalent in patients with signs and symptoms of ischemia and no obstructive epicardial coronary artery disease (INOCA), particularly in women. CMD is associated with adverse outcomes, including most frequently the development of heart failure with preserved ejection fraction. It is also associated with adverse outcomes in patient populations including hypertrophic cardiomyopathy, dilated cardiomyopathy, and acute coronary syndromes. In patients with INOCA, stratified medical therapy guided by invasive coronary function testing to define the subtype of CMD leads to improved symptoms. There are invasive and non-invasive methodologies to diagnose CMD that provide prognostic information and mechanistic information to direct treatment. Available treatments improve symptoms and myocardial blood flow; ongoing investigations aim to develop therapy to improve adverse outcomes related to CMD.

Invasive Coronary Assessment in Myocardial Ischemia with No Obstructive Coronary Arteries.

PURPOSE OF REVIEW: The purpose of this review is threefold: (i) to give an overview of well-established invasive methods for assessing patients with ischemia with no obstructive coronary arteries (INOCA) in the cardiac catheterization laboratory; (ii) to describe the prognostic and treatment implications based on these findings, and (iii) to discuss current knowledge gaps and future perspectives. RECENT FINDINGS: Recent studies have demonstrated that invasive coronary function testing not only allows for risk stratification of patients with INOCA but also guides medical therapy with improvement in symptoms and quality of life. Based on these findings, invasive coronary function assessment is now a class 2a recommendation in the 2021 ACC/AHA chest pain guideline to improve the diagnosis of coronary microvascular dysfunction and to enhance risk stratification. Invasive functional testing for patients with INOCA is well established and easily performed in the catheterization laboratory. Comprehensive invasive assessment is a key to differentiating INOCA endotypes and optimizing both medical therapy and preventive strategies including lifestyle modification.

Contemporary Diagnosis and Management of Patients with MINOCA.

PURPOSE OF REVIEW: Myocardial infarction with nonobstructive coronary arteries (MINOCA) is defined as acute myocardial infarction (MI) with angiographically no obstructive coronary artery disease or stenosis ≤ 50%. MINOCA is diagnostically challenging and complex, making it difficult to manage effectively. This condition accounts for 6-8% of all MI and poses an increased risk of morbidity and mortality after diagnosis. Prompt recognition and targeted management are essential to improve outcomes and our understanding of this condition, but this process is not yet standardized. This article offers a comprehensive review of MINOCA, delving deep into its unique clinical profile, invasive and noninvasive diagnostic strategies for evaluating MINOCA in light of the lack of widespread availability for comprehensive testing, and current evidence surrounding targeted therapies for patients with MINOCA. RECENT FINDINGS: MINOCA is not uncommon and requires comprehensive assessment using various imaging modalities to evaluate it further. MINOCA is a heterogenous working diagnosis that requires thoughtful approach to diagnose the underlying disease responsible for MINOCA further.

Coronary Optical Coherence Tomography and Cardiac Magnetic Resonance Imaging to Determine Underlying Causes of Myocardial Infarction With Nonobstructive Coronary Arteries in Women.

BACKGROUND: Myocardial infarction with nonobstructive coronary arteries (MINOCA) occurs in 6% to 15% of myocardial infarctions (MIs) and disproportionately affects women. Scientific statements recommend multimodality imaging in MINOCA to define the underlying cause. We performed coronary optical coherence tomography (OCT) and cardiac magnetic resonance (CMR) imaging to assess mechanisms of MINOCA. METHODS: In this prospective, multicenter, international, observational study, we enrolled women with a clinical diagnosis of myocardial infarction. If invasive coronary angiography revealed <50% stenosis in all major arteries, multivessel OCT was performed, followed by CMR (cine imaging, late gadolinium enhancement, and T2-weighted imaging and T1 mapping). Angiography, OCT, and CMR were evaluated at blinded, independent core laboratories. Culprit lesions identified by OCT were classified as definite or possible. The CMR core laboratory identified ischemia-related and nonischemic myocardial injury. Imaging results were combined to determine the mechanism of MINOCA, when possible. RESULTS: Among 301 women enrolled at 16 sites, 170 were diagnosed with MINOCA, of whom 145 had adequate OCT image quality for analysis; 116 of these underwent CMR. A definite or possible culprit lesion was identified by OCT in 46.2% (67/145) of participants, most commonly plaque rupture, intraplaque cavity, or layered plaque. CMR was abnormal in 74.1% (86/116) of participants. An ischemic pattern of CMR abnormalities (infarction or myocardial edema in a coronary territory) was present in 53.4% (62/116) of participants undergoing CMR. A nonischemic pattern of CMR abnormalities (myocarditis, takotsubo syndrome, or nonischemic cardiomyopathy) was present in 20.7% (24/116). A cause of MINOCA was identified in 84.5% (98/116) of the women with multimodality imaging, higher than with OCT alone (P<0.001) or CMR alone (P=0.001). An ischemic cause was identified in 63.8% of women with MINOCA (74/116), a nonischemic cause was identified in 20.7% (24/116) of the women, and no mechanism was identified in 15.5% (18/116). CONCLUSIONS: Multimodality imaging with coronary OCT and CMR identified potential mechanisms in 84.5% of women with a diagnosis of MINOCA, 75.5% of which were ischemic and 24.5% of which were nonischemic, alternate diagnoses to myocardial infarction. Identification of the cause of MINOCA is feasible and has the potential to guide medical therapy for secondary prevention. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02905357.

Rationale and design of the Women's Ischemia Trial to Reduce Events in Nonobstructive CAD (WARRIOR) trial.

BACKGROUND: Approximately half of all women with anginal symptoms and/or signs of ischemia and no obstructive coronary artery disease (INOCA) referred for coronary angiography have elevated risk for major adverse cardiac events (MACE), poor quality of life and resource consumption. Yet, guidelines focus on symptom management while clinical practice typically advocates only reassurance. Pilot studies of INOCA subjects suggest benefit with intensive medical therapy (IMT) that includes high-intensity statins and angiotensin converting enzyme inhibitors (ACE-I) or receptor blockers (ARB) to provide the rationale for a randomized pragmatic trial to limit MACE. METHODS: The Women's IschemiA TRial to Reduce Events In Non-ObstRuctive CAD is a multicenter, prospective, randomized, blinded outcome evaluation (PROBE design) of a pragmatic strategy of IMT vs usual care (UC) in 4,422 symptomatic women with INOCA (NCT03417388) in approximately 70 United States sites. The hypothesis is that IMT will reduce the primary outcome of first occurrence of MACE by 20% vs. UC at ∼2.5 year followup. Secondary outcomes include quality of life, time to return to "duty"/work, healthcare utilization, angina, cardiovascular death and individual primary outcome components over 3 years follow-up. The study utilizes web-based data capture, e-consents, single IRB and centralized pharmacy distribution of strategy medications directly to patients' homes to reduce site and patient burden. A biorepository will collect blood samples to assess potential mechanisms. CONCLUSIONS: The results of this trial will provide important data necessary to inform guidelines regarding how best to manage this growing and challenging population of women with INOCA.

Coronary Vascular Function and Cardiomyocyte Injury: A Report From the WISE-CVD.

OBJECTIVE: Women with symptoms or signs of myocardial ischemia but no obstructive coronary artery disease (INOCA) often have coronary vascular dysfunction and elevated risk for adverse cardiovascular events. We hypothesized that u-hscTnI (ultra-high-sensitivity cardiac troponin I), a sensitive indicator of ischemic cardiomyocyte injury, is associated with coronary vascular dysfunction in women with INOCA. Approach and Results: Women (N=263) with INOCA enrolled in the WISE-CVD study (Women's Ischemic Syndrome Evaluation-Coronary Vascular Dysfunction) underwent invasive coronary vascular function testing and u-hscTnI measurements (Simoa HD-1 Analyzer; Quanterix Corporation, Lexington, MA). Logistic regression models, adjusted for traditional cardiovascular risk factors were used to evaluate associations between u-hscTnI and coronary vascular function. Women with coronary vascular dysfunction (microvascular constriction and limited coronary epicardial dilation) had higher plasma u-hscTnI levels (both P=0.001). u-hscTnI levels were associated with microvascular constriction (odds ratio, 1.38 per doubling of u-hscTnI [95% CI, 1.03-1.84]; P=0.033) and limited coronary epicardial dilation (odds ratio, 1.37 per doubling of u-hscTnI [95% CI, 1.04-1.81]; P=0.026). u-hscTnI levels were not associated with microvascular dilation or coronary epicardial constriction. CONCLUSIONS: Our findings indicate that higher u-hscTnI is associated with coronary vascular dysfunction in women with INOCA. This suggests that ischemic cardiomyocyte injury in the setting of coronary vascular dysfunction has the potential to contribute to adverse cardiovascular outcomes observed in these women. Additional studies are needed to confirm and investigate mechanisms underlying these findings in INOCA. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00832702.

Design, methodology and baseline characteristics of the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD).

A significant number of women with signs and symptoms of ischemia with no obstructive coronary artery disease (INOCA) have coronary vascular dysfunction detected by invasive coronary reactivity testing (CRT). However, the noninvasive assessment of coronary vascular dysfunction has been limited. METHODS: The Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) was a prospective study of women with suspected INOCA aimed to investigate whether (1) cardiac magnetic resonance imaging (CMRI) abnormalities in left ventricular morphology and function and myocardial perfusion predict CRT measured coronary microvascular dysfunction, (2) these persistent CMRI abnormalities at 1-year follow-up predict persistent symptoms of ischemia, and (3) these CMRI abnormalities predict cardiovascular outcomes. By design, a sample size of 375 women undergoing clinically indicated invasive coronary angiography for suspected INOCA was projected to complete baseline CMRI, a priori subgroup of 200 clinically indicated CRTs, and a priori subgroup of 200 repeat 1-year follow-up CMRIs. RESULTS: A total of 437 women enrolled between 2008 and 2015, 374 completed baseline CMRI, 279 completed CRT, and 214 completed 1-year follow-up CMRI. Mean age was 55±â€¯11 years, 93% had 20%-50% coronary stenosis, and 7% had <20% stenosis by angiography. CONCLUSIONS: The WISE-CVD study investigates the utility of noninvasive CMRI to predict coronary vascular dysfunction in comparison to invasive CRT, and the prognostic value of CMRI abnormalities for persistent symptoms of ischemia and cardiovascular outcomes in women with INOCA. WISE-CVD will provide new understanding of a noninvasive imaging modality for future clinical trials.

Even "WISE-R?"-an Update on the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation.

PURPOSE OF REVIEW: For over 20 years, the Women's Ischemia Syndrome Evaluation (WISE), a program sponsored by the National Heart, Lung, and Blood Institute, has explored diverse and important aspects of ischemic heart disease in women. RECENT FINDINGS: Women with symptoms and signs of ischemia but no significant epicardial obstructive coronary artery disease (INOCA) were documented to be at elevated risk for recurrent angina hospitalization, major adverse cardiac events, death, and health resource consumption rivaling those with obstructive coronary disease. WISE investigators have advanced our understanding of cardiovascular outcomes, systemic manifestations, psychological variables, socioeconomic factors, genetic contributions, hormonal status, advanced imaging, coronary functional findings, biomarkers, patient-reported outcomes, and treatments pertaining to women with this disease entity. This review delves into the WISE findings subsequent to a prior review1, postulates directions for future research, and asks are we "Even 'WISE-R?'".

KPT-9274, an Inhibitor of PAK4 and NAMPT, Leads to Downregulation of mTORC2 in Triple Negative Breast Cancer Cells.

Triple negative breast cancer (TNBC) is difficult to treat due to lack of druggable targets. We have found that treatment with the small molecule inhibitor KPT-9274 inhibits growth of TNBC cells and eventually leads to cell death. KPT-9274 is a dual specific inhibitor of PAK4 and Nicotinamide Phosphoribosyltransferase (NAMPT). The PAK4 protein kinase is often highly expressed in TNBC cells and has important roles in cell growth, survival, and migration. Previously we have found that inhibition of PAK4 leads to growth inhibition of TNBC cells both in vitro and in vivo. Likewise, NAMPT has been shown to be dysregulated in cancer due to its role in cell metabolism. In order to understand better how treating cells with KPT-9274 abrogates TNBC cell growth, we carried out an RNA sequencing of TNBC cells treated with KPT-9274. As a result, we identified Rictor as an important target that is inhibited in the KPT-9274 treated cells. Conversely, we found that Rictor is predicted to be activated when PAK4 is overexpressed in cells, which suggests a role for PAK4 in the regulation of Rictor. Rictor is a component of mTORC2, one of the complexes formed by the serine/threonine kinase mTOR. mTOR is important for the control of cell growth and metabolism. Our results suggest a new mechanism by which the KPT-9274 compound may block the growth of breast cancer cells, which is via inhibition of mTORC2 signaling. Consistent with this, sequencing analysis of PAK4 overexpressing cells indicates that PAK4 has a role in activation of the mTOR pathway.

Association of Spontaneous Preterm Delivery and Future Maternal Cardiovascular Disease.

Cardiovascular disease (CVD) risk factors are well established. However, little is known about a woman's cardiovascular response to pregnancy, which appears to be an early marker of future maternal CVD risk. Spontaneous preterm delivery (sPTD) has been associated with a ≤3-fold increased risk of maternal CVD death later in life compared with having a term delivery. This review focuses on 3 key areas to critically assess the association of sPTD and future maternal CVD risk: (1) CVD risk factors, (2) inflammatory biomarkers of interest, and (3) specific forms of vascular dysfunction, such as endothelial function and arterial stiffness, and mechanisms by which each may be linked to sPTD. The association of sPTD with subsequent future maternal CVD risk suggests that a woman's abnormal response to pregnancy may serve as her first physiological stress test. These findings suggest that future research is needed to understand why women with sPTD may be at risk for CVD to implement effective interventions earlier in a woman's life.

Prevalence of Coronary Endothelial and Microvascular Dysfunction in Women with Symptoms of Ischemia and No Obstructive Coronary Artery Disease Is Confirmed by a New Cohort: The NHLBI-Sponsored Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD).

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.

Women's health: making cardiovascular disease real.

PURPOSE OF REVIEW: When patients are seen for persistent chest pain in the absence of obstructive coronary artery disease, the physician must decide if the symptoms are due to myocardial ischemia in order to guide treatment. RECENT FINDINGS: Recent findings indicate that ischemia due to coronary microvascular dysfunction (CMD) is associated with subclinical coronary atherosclerosis and an adverse prognosis. Therapeutic probe trials suggest that antiatherosclerotic and anti-ischemic therapeutic strategies may be useful. A large randomized clinical trial of high-intensity statin, maximally tolerated angiotensin-converting-enzyme inhibitor or angiotensin receptor blocker and low-dose aspirin (WARRIOR NCT#03417388) is in progress. SUMMARY: The diagnosis of CMD should be considered in patients with persistent angina, evidence of myocardial ischemia and normal coronary angiogram. Because of the associated adverse prognosis of CMD , conservative empiric treatment or further diagnostic evaluation of the coronary microvasculature can be performed. Diagnosis involves the measurement of coronary blood blow in response to a vasodilator agent invasively or noninvasively. Treatment of CMD can include the use of traditional antianginal and antiatherosclerotic medications. Clinical trials are needed to assess therapeutic strategies on the outcomes of cardiovascular disease and quality of life, in order to develop evidence-based guidelines.