Publications by authors named "Chrisandra Shufelt"

120 Publications

The Menopause Management Vacuum.

Cancer J 2022 May-Jun 01;28(3):191-195

Barbra Streisand Women's Heart Center, Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA.

Abstract: The burden of untreated menopause symptoms in midlife women is substantial and can result in reduced quality of life as well as lost work productivity, lost opportunities for advancement at work, and increased health care costs. Unfortunately, the health care system is largely unprepared to help women manage these symptoms, which have a mean duration of 7 to 9 years. Hormone therapy usage rates have plummeted following publication of the results of the Women's Health Initiative trials due to safety concerns. In addition, postgraduate medical training programs include minimal to no training on menopause management. These and other factors have contributed to what is essentially a menopause management vacuum. This vacuum created a market opportunity, particularly given the fact that midlife women are potent drivers of the global economy. In this review, we outline the menopause management gaps and discuss a multipronged approach to close these gaps and improve the care of midlife women.
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http://dx.doi.org/10.1097/PPO.0000000000000594DOI Listing
May 2022

Subclinical cardiovascular disease and polycystic ovary syndrome.

Fertil Steril 2022 May;117(5):912-923

Barbra Streisand Women's Heart Center, Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, California. Electronic address:

Polycystic ovary syndrome (PCOS) impacts approximately 6%-10% of women worldwide, with hallmark features of hyperandrogenism, irregular menses, infertility, and polycystic appearing ovaries on ultrasound. In addition, PCOS is associated with several endocrine and metabolic disorders, including obesity, insulin resistance and diabetes mellitus, hypertension, dyslipidemia and metabolic syndrome, which all increase the risk for subclinical cardiovascular disease (CVD), the presence of altered vascular endothelium without overt CVD. In this review, we summarize the most recent literature regarding subclinical CVD in women with PCOS, including markers such as flow-mediated dilation, arterial stiffness, coronary artery calcium scores, carotid intima-media thickness and visceral and epicardial fat.
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http://dx.doi.org/10.1016/j.fertnstert.2022.02.028DOI Listing
May 2022

Whom to Treat for Primary Prevention of Atherosclerotic Cardiovascular Disease: The Aspirin Dilemma.

JAMA Intern Med 2022 Apr 26. Epub 2022 Apr 26.

Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1001/jamainternmed.2022.1365DOI Listing
April 2022

Are we any WISER yet? Progress and contemporary need for smart trials to include women in coronary artery disease trials.

Contemp Clin Trials 2022 Apr 20;117:106762. Epub 2022 Apr 20.

Barbra Streisand Women's Heart Center, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. Electronic address:

Despite calls to ensure proportionate representation of both sexes in biomedical research, women continue to be underrepresented in cardiovascular disease (CVD) clinical trials. A comprehensive analysis of seven large suspected ischemic heart disease/coronary artery disease (IHD/CAD) clinical trials (PROMISE, ISCHEMIA, CIAO-ISCHEMIA, ORBITA, FAME, FAME 2 and COURAGE trial) provides understanding of contributions to barriers to enrollment of women and leads to strategies to address these barriers. Specifically, in the seven trials, enrollment of women did not exceed 27%, while numerous barriers are evident. Proposed strategies to improve women´s inclusion in clinical trials, include adding reproductive stage/estrogen status, attention to study design inclusion/exclusion criteria using female thresholds, consideration of diagnostic and intervention study design to be inclusive, increasing women and minorities in leadership positions, including sex as a biological variable (SABV) in study design and statistical analysis, and addressing social and race/ethnicity barriers. Dedicated action to actualizing these steps are needed at this time to developing diagnostic and therapeutic strategies resulting in better care and improved outcomes for CVD in women.
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http://dx.doi.org/10.1016/j.cct.2022.106762DOI Listing
April 2022

Sex-based differences in remote monitoring of biometric, psychometric and biomarker indices in stable ischemic heart disease.

Biol Sex Differ 2022 Apr 11;13(1):15. Epub 2022 Apr 11.

Barbra Streisand Women's Heart Center, Smidt Heart Institute, Cedars-Sinai Medical Center, 127 S. San Vicente Blvd, Suite A3206, Los Angeles, CA, 90048, USA.

Background: Sex-based differences are crucial to consider in the formulation of a personalized treatment plan. We evaluated sex-based differences in adherence and remotely monitored biometric, psychometric, and biomarker data among patients with stable ischemic heart disease (IHD).

Methods: The Prediction, Risk, and Evaluation of Major Adverse Cardiac Events (PRE-MACE) study evaluated patients with stable IHD over a 12-week period. We collected biometric and sleep data using remote patient monitoring via FitBit and psychometric data from Patient-Reported Outcomes Measurement Information System (PROMIS), Kansas City Cardiomyopathy (KCC) and Seattle Angina Questionnaire-7 (SAQ-7) questionnaires. Serum biomarker levels were collected at the baseline visit. We explored sex-based differences in demographics, adherence to study protocols, biometric data, sleep, psychometric data, and biomarker levels.

Results: There were 198 patients enrolled, with mean age 65.5 ± 11 years (± Standard deviation, SD), and 60% were females. Females were less adherent to weekly collection of PROMIS, KCC and SAQ-7 physical limitations questionnaires (all p < 0.05), compared to males. There was no difference in biometric physical activity. There was a statistically significant (p < 0.05) difference in sleep duration between sexes, with females sleeping 6 min longer. However, females reported higher PROMIS sleep disturbance scores (p < 0.001) and poorer psychometric scores overall (p < 0.05). A higher proportion of males had clinically significant elevations of median N-terminal pro-brain natriuretic peptide (p = 0.005) and high-sensitivity cardiac troponin levels (p < 0.001) compared to females.

Conclusions: Among females and males with stable IHD, there are sex-based differences in remote monitoring behavior and data. Females are less adherent to psychometric data collection and report poorer psychometric and sleep quality scores than males. Elevated levels of biomarkers for MACE are more common in males. These findings may improve sex-specific understanding of IHD using remote patient monitoring.
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http://dx.doi.org/10.1186/s13293-022-00423-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8996611PMC
April 2022

Pregnancy and Reproductive Risk Factors for Cardiovascular Disease in Women.

Circ Res 2022 02 17;130(4):652-672. Epub 2022 Feb 17.

Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston (A.C.O., M.C.H.).

Beyond conventional risk factors for cardiovascular disease, women face an additional burden of sex-specific risk factors. Key stages of a woman's reproductive history may influence or reveal short- and long-term cardiometabolic and cardiovascular trajectories. Early and late menarche, polycystic ovary syndrome, infertility, adverse pregnancy outcomes (eg, hypertensive disorders of pregnancy, gestational diabetes, preterm delivery, and intrauterine growth restriction), and absence of breastfeeding are all associated with increased future cardiovascular disease risk. The menopause transition additionally represents a period of accelerated cardiovascular disease risk, with timing (eg, premature menopause), mechanism, and symptoms of menopause, as well as treatment of menopause symptoms, each contributing to this risk. Differences in conventional cardiovascular disease risk factors appear to explain some, but not all, of the observed associations between reproductive history and later-life cardiovascular disease; further research is needed to elucidate hormonal effects and unique sex-specific disease mechanisms. A history of reproductive risk factors represents an opportunity for comprehensive risk factor screening, refinement of cardiovascular disease risk assessment, and implementation of primordial and primary prevention to optimize long-term cardiometabolic health in women.
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http://dx.doi.org/10.1161/CIRCRESAHA.121.319895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8870397PMC
February 2022

Gender-Related Differences in Chest Pain Syndromes in the Frontiers in CV Medicine Special Issue: Sex & Gender in CV Medicine.

Front Cardiovasc Med 2021 17;8:744788. Epub 2021 Nov 17.

Barbra Streisand Women's Heart Center, Cedars-Sinai Smidt Heart Institute, Los Angeles, CA, United States.

Coronary artery disease (CAD) is the leading cause of morbidity and mortality among both women and men, yet women continue to have delays in diagnosis and treatment. The lack of recognition of sex-specific biological and socio-cultural gender-related differences in chest pain presentation of CAD may, in part, explain these disparities. Sex and gender differences in pain mechanisms including psychological susceptibility, the autonomic nervous system (ANS) reactivity, and visceral innervation likely contribute to chest pain differences. CAD risk scores and typical/atypical angina characterization no longer appear relevant and should not be used in women and men. Women more often have ischemia with no obstructive CAD (INOCA) and myocardial infarction, contributing to diagnostic and therapeutic equipoise. Existing knowledge demonstrates that chest pain often does not relate to obstructive CAD, suggesting a more thoughtful approach to percutaneous coronary intervention (PCI) and medical therapy for chest pain in stable obstructive CAD. Emerging knowledge regarding the central and ANS and visceral pain processing in patients with and without angina offers explanatory mechanisms for chest pain and should be investigated with interdisciplinary teams of cardiologists, neuroscientists, bio-behavioral experts, and pain specialists. Improved understanding of sex and gender differences in chest pain, including biological pathways as well as sociocultural contributions, is needed to improve clinical care in both women and men.
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http://dx.doi.org/10.3389/fcvm.2021.744788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8635525PMC
November 2021

Coronary microvascular dysfunction: Considerations for diagnosis and treatment.

Cleve Clin J Med 2021 Oct 1;88(10):561-571. Epub 2021 Oct 1.

Associate Director, Barbra Streisand Women's Heart Center, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA; Investigator, Women's Ischemia Trial to Reduce Events in Nonobstructive CAD (WARRIOR) NCT03417388; Investigator, Women's Ischemia Syndrome Evaluation (WISE) NCT00000554

Ischemia and no obstructive coronary artery disease (INOCA) is an increasingly recognized cause of angina, and it is more commonly diagnosed in women. Coronary microvascular dysfunction (CMD), or the abnormal dilation and constriction of the small vessels of the heart, is the underlying cause of INOCA in one-half of cases. This review discusses coronary microvascular pathophysiology, considerations for invasive coronary function testing and noninvasive diagnostic modalities, implications for management, and remaining knowledge gaps.
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http://dx.doi.org/10.3949/ccjm.88a.20140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8813544PMC
October 2021

Coronary endothelial dysfunction appears to be a manifestation of a systemic process: A report from the Women's Ischemia Syndrome Evaluation - Coronary Vascular Dysfunction (WISE-CVD) study.

PLoS One 2021 27;16(9):e0257184. Epub 2021 Sep 27.

Barbra Streisand Women's Heart Center, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America.

Background: Coronary microvascular dysfunction (CMD) is prevalent in symptomatic women with ischemia but no obstructive coronary artery disease (INOCA). Urine albumin-creatinine ratio (UACR) is a measure of renal microvascular endothelial dysfunction. Both are predictors of adverse cardiovascular events. It is unknown if CMD could be a manifestation of a systemic process. We evaluated the relationship between renal microvascular dysfunction and CMD as measured by invasive coronary function testing (CFT).

Methods And Results: We measured urine albumin and creatinine to provide UACR in 152 women enrolled in the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) study (2008-2015) with suspected INOCA who underwent CFT. Invasive CFT measures of endothelial and non-endothelial dependent coronary microvascular function were obtained. Subjects were divided into those with detectable (≥20 mg/g) and undetectable urine albumin (<20 mg/g). The group mean age was 54 ± 11 years, with a moderate cardiac risk factor burden including low diabetes prevalence, and a mean UACR of 12 ± 55 mg/g (range 9.5-322.7 mg/g). Overall, coronary endothelial-dependent variables (change in coronary blood flow and coronary diameter in response to cold pressor testing) had significant inverse correlations with log UACR (r = -0.17, p = 0.05; r = -0.18, p = 0.03, respectively).

Conclusions: Among women with INOCA and relatively low risk factor including diabetes burden, renal microvascular dysfunction, measured by UACR, is related to coronary endothelial-dependent CMD. These results suggest that coronary endothelial-dependent function may be a manifestation of a systemic process. Enhancing efferent arteriolar vasodilatation in both coronary endothelial-dependent function and renal microvascular dysfunction pose potential targets for investigation and treatment.

Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT00832702.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0257184PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476029PMC
November 2021

Association of coronary microvascular dysfunction and cardiac bridge integrator 1, a cardiomyocyte dysfunction biomarker.

Clin Cardiol 2021 Nov 16;44(11):1586-1593. Epub 2021 Sep 16.

Barbra Streisand Women's Heart Center, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Background: Coronary microvascular dysfunction (CMD) is associated with heart failure with preserved ejection fraction (HFpEF); however, pathophysiology is not well described.

Hypothesis: We hypothesized that CMD in women with suspected ischemia with no obstructive coronary artery disease (INOCA) is associated with cardiomyocyte dysfunction reflected by plasma levels of a cardiomyocyte calcium handling protein, cardiac bridge integrator 1 (cBIN1).

Methods: Women with suspected INOCA undergoing coronary function testing were included. Coronary flow reserve, vasodilation to nitroglycerin, change in coronary blood flow (ΔCBF), and vasodilation to acetylcholine (ΔAch) were evaluated. cBIN1 score (CS) levels in these women (n = 39) were compared to women with HFpEF (n = 20), heart failure with reduced ejection fraction (HFrEF) (n = 36), and reference controls (RC) (n = 50). Higher CS indicates cardiomyocyte tubule dysfunction.

Results: INOCA, HFpEF, and HFrEF women were older than RC (p < .05). Higher CS was associated with vasoconstriction to acetylcholine (r = -0.43, p = .011) with a trend towards lower ΔCBF (r = 0.30, p = .086). Higher CS was specific for ΔAch and ΔCBF but had limited sensitivity. INOCA women had higher CS than RC, but lower CS than HFpEF/HFrEF groups (p < .001).

Conclusions: CS, a plasma biomarker indicating poor cardiomyocyte health, was higher in women with suspected INOCA as compared to RC, but lower than in women with HFpEF. Elevated CS in suspected INOCA patients represents an intermediate group between health and disease, supporting the hypothesis that CMD may progress to HFpEF. Larger prospective cohort studies are needed to confirm the pathophysiological relationship between cBIN1, CMD, and HFpEF.
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http://dx.doi.org/10.1002/clc.23726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8571552PMC
November 2021

Hormone therapy formulation, dose, route of delivery, and risk of hypertension: findings from the Women's Health Initiative Observational Study (WHI-OS).

Menopause 2021 07 26;28(10):1108-1116. Epub 2021 Jul 26.

Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Objective: Using data from the Women's Health Initiative Observational Study (WHI-OS), to determine the role of estrogen formulation, dose, route of delivery, and its combination with different progestogens on the risk for hypertension in the WHI-OS.

Methods: After excluding women with diagnosed hypertension, receiving antihypertensive medication, presenting with elevated blood pressure ( ≥ 140/90), and those not taking menopausal hormone therapy at baseline, 19,986 women remained eligible for the analyses. Using hierarchal modeling, proportional hazard rate calculation, and linear and logistic regression analyses, we evaluated incident treated hypertension and mean systolic and diastolic blood pressure changes at 3 years. Multivariable models were adjusted for age, race/ethnicity, education, smoking, physical activity, body mass index, history of treated diabetes, history of prescription medicines for high cholesterol, alcohol intake, hysterectomy, and bilateral oophorectomy.

Results: At 3 years, and compared with conjugated estrogens (CEE) with or without a progestin, the odds for newly treated hypertension were lower in women who used transdermal estradiol (0.85, 95% CI, 0.73-1.00) or oral estrone sulphate dominant preparations (0.83, 0.72-0.96). The odds of incident treated hypertension after 3 years did not vary according to dose of estrogen. The mean measured systolic blood pressure was minimally lower with transdermal estradiol (-1.20, 95% CI, -1.97 to -0.44) mm Hg and other oral Estrone dominant preparations (-0.83, 95% CI, -1.51 to -0.16) mm Hg at 3 years. For a given estrogen type, the magnitudes of the hazard ratio were similar for estrogen-alone compared with estrogen plus a progestogen. For women 10 or more years past menopause when they entered, the HR for incident self-reported treated hypertension was 1.26 (95% CI, 1.09-1.46) with higher dose CEE compared with 0.625 mg CEE. It was 0.87 (95% CI, 0.68-1.13) when given to women who were < 10 years after menopause when they entered the WHI-OS.

Conclusion: The risk of treated hypertension differed by formulation, dose, and years since menopause.
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http://dx.doi.org/10.1097/GME.0000000000001828DOI Listing
July 2021

Statin therapy in midlife women.

Menopause 2021 07 19;28(9):1067-1069. Epub 2021 Jul 19.

Barbra Streisand Women's Heart Center, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California.

Abstract: The menopause transition is associated with adverse changes to the lipid profile. Although there are no specific treatment guidelines for women, current evidence supports the use of statin therapy in women with 1) established clinical atherosclerotic cardiovascular disease (ASCVD); 2) primary hypercholesterolemia, with low-density lipoprotein cholesterol of 190 mg/dL (4.9 mmol/L) or higher; 3) diabetes mellitus regardless of ASCVD risk category (ages 40-75 y); and 4) for primary prevention of ASCVD in women at high risk (10-y risk, ≥20%) or intermediate risk (10-y risk, ≥7.5-20%) with the presence of guideline-derived risk enhancers (age 40-75 y) such as premature menopause or a history of preeclampsia.
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http://dx.doi.org/10.1097/GME.0000000000001802DOI Listing
July 2021

Global consensus recommendations on menopause in the workplace: A European Menopause and Andropause Society (EMAS) position statement.

Maturitas 2021 Sep 21;151:55-62. Epub 2021 Jul 21.

Second Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Greece.

Introduction: Worldwide, there are 657 million women aged 45-59 and around half contribute to the labor force during their menopausal years. There is a diversity of experience of menopause in the workplace. It is shaped not only by menopausal symptoms and context but also by the workplace environment. It affects quality of life, engagement, performance, motivation and relations with employers.

Aim: To provide recommendations for employers, managers, healthcare professionals and women to make the workplace environment more menopause supportive, and to improve women's wellbeing and their ability to remain in work.

Materials And Methods: Literature review and consensus of expert opinion.

Summary Recommendations: Workplace health and wellbeing frameworks and policies should incorporate menopausal health as part of the wider context of gender and age equality and reproductive and post-reproductive health. Workplaces should create an open, inclusive and supportive culture regarding menopause, involving, if available, occupational health professionals and human resource managers working together. Women should not be discriminated against, marginalized or dismissed because of menopausal symptoms. Health and allied health professionals should recognize that, for some women, menopausal symptoms can adversely affect the ability to work, which can lead to reduction of working hours, underemployment or unemployment, and consequently financial insecurity in later life.
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http://dx.doi.org/10.1016/j.maturitas.2021.06.006DOI Listing
September 2021

Cardiovascular disease (CVD) risk scores, age, or years since menopause to predict cardiovascular disease in the Women's Health Initiative.

Menopause 2021 05 3;28(6):610-618. Epub 2021 May 3.

Barbra Streisand Women's Heart Center, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA.

Objective: To assess the utility of cardiovascular disease (CVD) risk scores compared to age or years since menopause for prediction of CVD events in the WHI clinical trials.

Methods: Briefly, in the randomized clinical trial 27,347 postmenopausal women age 50 to 79 years entered from 1993 to 1998. Women with a uterus (16,608) were randomized to receive daily oral conjugated equine estrogen (CEE) (0.625 mg) plus medroxyprogesterone acetate (2.5 mg) (5.7 years or placebo), while women with a hysterectomy (10,739) were randomized to receive daily oral CEE (0.625 mg) alone or placebo (7.2 y). CVD risk scores were assessed at baseline and CVD events were adjudicated throughout the follow-up period to the end of the main study phase and to the end of cumulative follow-up. The median follow-up time after the start of the randomized clinical trial to the end of the main study phase was 8.2 years. The median follow-up time to the end of cumulative follow-up was 17.6 years. We compared The American Heart Association/American College of Cardiology (AHA/ACC) and Framingham Heart Study risk scores to age or years since menopause all obtained at baseline to predict subsequent CVD events. The absolute event rates, hazard ratios, and C-statistics (Uno Concordance from Cox proportional models) were compared.

Results: Overall, the hazard ratios for CVD events were highest with calculated CVD scores calculated at trial onset both at the end of the main study (ranging from 2.02 to 10.8 for Q2-Q5, compared to Q1) and at cumulative follow-up (ranging from 1.76 to 8.86 for Q2-Q5, compared to Q1). While older age and years since menopause at baseline were also associated with higher CVD event rates, better risk prediction was accomplished by using CVD risk scores. The Framingham Heart Study BMI score had the highest C-statistic at the end of the main study (0.711) and after 17.6 years through the end of follow-up (0.689).

Conclusions: CVD risk scores can help identify postmenopausal women at higher risk for CVD beyond age or time since menopause. Risk scoring that better estimates vascular aging may facilitate CVD risk prevention. When performed prior to initiation of menopausal hormone therapy, scores can better inform HT risk/benefit discussions.
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http://dx.doi.org/10.1097/GME.0000000000001753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141005PMC
May 2021

Don't "weight" until menopause: identifying cardiovascular risk during the transition.

Menopause 2021 04 26;28(6):608-609. Epub 2021 Apr 26.

Barbra Streisand Women's Heart Center, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA.

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http://dx.doi.org/10.1097/GME.0000000000001795DOI Listing
April 2021

Angina relates to coronary flow in women with ischemia and no obstructive coronary artery disease.

Int J Cardiol 2021 06 1;333:35-39. Epub 2021 Mar 1.

Barbra Streisand Women's Heart Center, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address:

Background: Women with suspected ischemia and no obstructive coronary artery disease (INOCA) often have coronary microvascular dysfunction (CMD) as measured by impaired coronary flow reserve (CFR), which is associated with angina and adverse cardiovascular events. CFR is a ratio of hyperemic to baseline average peak velocity (bAPV), and the relation of baseline flow to angina is not understood.

Methods: We evaluated 259 women enrolled in the WISE-Coronary Vascular Dysfunction (WISE-CVD) project with suspected CMD who underwent invasive coronary functional testing. We analyzed variables stratified by high (e.g. ≥22 cm/s) vs low (<22 cm/s) bAPV, using t-test or Wilcoxon rank; linear and multivariable regression was used with bAPV as a continuous variable.

Results: Women with high bAPV had worse Seattle Angina Questionnaire (SAQ) angina frequency (58 ± 26 vs 67 ± 25, p = 0.005) and SAQ-7 scores (57 ± 22 vs 62 ± 21, p = 0.03), with higher nitrate (p = 0.02) and ranolazine use (p = 0.03). The high bAPV subgroup also had lower CFR (p < 0.001)). Linear regression related higher bAPV with lower SAQ-7 (p = 0.01) and lower angina frequency scores (p = 0.001). These results remained significant in multivariable modelling adjusting for baseline differences (p < 0.04). SAQ-7 was significantly predicted by bAPV.

Conclusions: Among women with suspected INOCA, angina relates to high bAPV, a result supported by the concomitant greater use of anti-anginal drugs. These results suggest that high bAPV contributes to impaired CFR and may represent a specific pathophysiologic contributor to CMD and may be a treatment target in INOCA subjects.
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http://dx.doi.org/10.1016/j.ijcard.2021.02.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107128PMC
June 2021

Diastolic dysfunction in women with ischemia and no obstructive coronary artery disease: Mechanistic insight from magnetic resonance imaging.

Int J Cardiol 2021 05 2;331:1-7. Epub 2021 Feb 2.

The University of Texas at Arlington, Arlington, TX, USA; Barbra Streisand Women's Heart Center, Cedars-Sinai Smidt Heart Institute, Los Angeles, CA, USA. Electronic address:

Background: Ischemia with no obstructive coronary artery disease (INOCA) is prevalent in women and is associated with increased risk of developing heart failure with preserved ejection fraction (HFpEF); however, the mechanism(s) contributing to this progression remains unclear. Given that diastolic dysfunction is common in women with INOCA, defining mechanisms related to diastolic dysfunction in INOCA could identify therapeutic targets to prevent HFpEF.

Methods: Cardiac MRI was performed in 65 women with INOCA and 12 reference controls. Diastolic function was defined by left ventricular early diastolic circumferential strain rate (eCSRd). Contributors to diastolic dysfunction were chosen a priori as coronary vascular dysfunction (myocardial perfusion reserve index [MPRI]), diffuse myocardial fibrosis (extracellular volume [ECV]), and aortic stiffness (aortic pulse wave velocity [aPWV]).

Results: Compared to controls, eCSRd was lower in INOCA (1.61 ± 0.33/s vs. 1.36 ± 0.31/s, P = 0.016); however, this difference was not exaggerated when the INOCA group was sub-divided by low and high MPRI (P > 0.05) nor was ECV elevated in INOCA (29.0 ± 1.9% vs. 28.0 ± 3.2%, control vs. INOCA; P = 0.38). However, aPWV was higher in INOCA vs. controls (8.1 ± 3.2 m/s vs. 6.1 ± 1.5 m/s; P = 0.045), and was associated with eCSRd (r = -0.50, P < 0.001). By multivariable linear regression analysis, aPWV was an independent predictor of decreased eCSRd (standardized β = -0.39, P = 0.003), as was having an elevated left ventricular mass index (standardized β = -0.25, P = 0.024) and lower ECV (standardized β = 0.30, P = 0.003).

Conclusions: These data provide mechanistic insight into diastolic dysfunction in women with INOCA, identifying aortic stiffness and ventricular remodeling as putative therapeutic targets.
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http://dx.doi.org/10.1016/j.ijcard.2021.01.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026746PMC
May 2021

Menopausal Hormone Therapy and Cardiovascular Disease: The Role of Formulation, Dose, and Route of Delivery.

J Clin Endocrinol Metab 2021 04;106(5):1245-1254

Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Context: This mini-review provides an overview of menopausal hormone therapy (HT) and cardiovascular disease (CVD) risk, with a focus on the role of hormone formulation, dose, and route of delivery.

Methods: This summary is based on authors' knowledge in the field of menopausal HT and supplemented by a PubMed search using the terms "menopause hormone therapy," "transdermal," "estradiol," "conjugated estrogens," "bioidentical," "cardiovascular disease," "lipoproteins," "glucose," "progestogens," "low dose."

Results: Available evidence indicates that oral unopposed estrogens have a favorable effect on lipoprotein levels, glycemia, insulin, and CVD risk; however, the addition of progestogens blunts the lipid-related effects. The progestogen with the smallest attenuating effect is micronized progesterone. Transdermal estrogens have less effect on coagulation, inflammation, and lipids than oral estrogens and observational studies suggest they pose a lower risk of venous thromboembolism and stroke than oral estrogens. Clinical effects of hormones were not consistently dose dependent.

Conclusions: Although HT continues to have an important role in menopause management, it is not recommended for primary or secondary CVD prevention. Different formulations, doses, and routes of delivery of HT have different effects on cardiometabolic markers and risks of clinical CVD events. However, long-term trials evaluating clinical outcomes with transdermal and other alternate HT regimens are limited.
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http://dx.doi.org/10.1210/clinem/dgab042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063246PMC
April 2021

Prior Oral Contraceptive Use and Longer Term Mortality Outcomes in Women with Suspected Ischemic Heart Disease.

J Womens Health (Larchmt) 2021 03 21;30(3):377-384. Epub 2021 Jan 21.

Barbra Streisand Women's Heart Center, Cedars-Sinai Smidt Heart Institute, Los Angeles, California, USA.

Previous Women's Ischemia Syndrome Evaluation (WISE) work demonstrated prior oral contraceptive (OC) use was associated with lower coronary artery disease (CAD) in women with suspected ischemia. The association of prior OC use with longer term all-cause and cardiovascular disease (CVD) mortality is unclear. WISE women undergoing coronary angiography for suspected ischemia (enrolled 1996-2001) with prior OC use history and 10-year follow-up data were analyzed. A blinded core laboratory assessed atherosclerotic CAD severity. Kaplan-Meier analyses evaluated prior OC use relative to all-cause and CVD mortality. Cox regression analyses adjusted for baseline differences. Mediation, interaction, and multicollinearity were analyzed. Our 686 women had a mean age 62.5 ± 9.6 years, multiple cardiac risk factors, and 39% previously used OC. Prior OC users were younger, with less lipid-lowering medication use and lower atherosclerotic CAD severity scores (all  < 0.05). Prior OC use was associated with lower 10-year all-cause ( = 0.007) and CVD mortality ( = 0.019). After adjustment, this was no longer significant ( = 0.77 and  = 0.90, respectively). Atherosclerotic CAD severity score mediated one-third of the observed association. Prior OC use was associated with increased CVD mortality among women with very elevated menopausal systolic blood pressure (SBP). Unadjusted prior OC use was associated with lower longer-term all-cause and CVD mortality. One-third of this observed effect appears mediated by the atherosclerotic CAD severity score. Prior OC was adversely associated with CVD mortality in women with very elevated menopausal SBP. Additional investigation is needed to understand the potential benefits and harms of prior OC use. Clinical Trial Number: NCT00000554, or https://www.clinicaltrials.gov/ct2/show/NCT00000554.
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http://dx.doi.org/10.1089/jwh.2020.8743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098756PMC
March 2021

Relationship between coronary function testing and migraine: results from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction project.

Vessel Plus 2021 1;5. Epub 2021 Aug 1.

Barbra Streisand Women's Heart Center, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Aim: To determine the relationship between coronary vascular dysfunction and history of migraines in women with suspected ischemia and no obstructive coronary arteries (INOCA).

Methods: In the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction study, 402 women with suspected INOCA answered baseline angina questionnaires, including the Seattle Angina Questionnaire (SAQ). Coronary function testing (CFT) performed in a subgroup of 252 women evaluated for nonendothelial and endothelial-dependent coronary vascular function. Wilcoxon rank sum test, -test, and linear regression models were performed.

Results: Of the 252 women who underwent CFT, 126 (50%) women reported migraine history. Compared to women who reported no migraines, women with migraines were younger and more were premenopausal. They had more angina at rest, with strong emotions, and hot/cold temperatures, as well as angina that wakes them from sleep ( < 0.05 for all). Women with migraines also scored worse on SAQ angina frequency and quality of life < 0.01 for both). There was no difference in prevalence of coronary vascular dysfunction in the two groups. In addition, linear regression models demonstrated no significant age-adjusted differences in absolute CFT variables.

Conclusion: Among women with suspected INOCA, migraine history is prevalent and women with migraines have worse angina compared to those without migraines. Coronary vascular dysfunction diagnosed by CFT does not appear to relate to migraine history.
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http://dx.doi.org/10.20517/2574-1209.2021.55DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9075042PMC
August 2021

N-Terminal pro-B-type natriuretic peptide and coronary microvascular dysfunction in women with preserved ejection fraction: A report from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) study.

PLoS One 2020 3;15(12):e0243213. Epub 2020 Dec 3.

Barbra Streisand Women's Heart Center, Cedars-Sinai Heart Institute, Los Angeles, CA, United States of America.

Background: Women with symptoms and signs of ischemia, preserved left ventricular ejection fraction (LVEF), and no obstructive coronary artery disease (CAD), often have coronary microvascular dysfunction (CMD), and are at risk of future heart failure with preserved ejection fraction (HFpEF). N-terminal pro-B-type natriuretic peptide (NT-proBNP) is used to evaluate HF and myocardial ischemia. Relationships between NT-proBNP and CMD are not well defined in this population.

Methods: We evaluated resting NT-proBNP levels in 208 women with symptoms and signs of ischemic heart disease, preserved LVEF and no obstructive CAD undergoing clinically indicated invasive coronary flow reserve (CFR) as a measure of CMD-related ischemia and resting left ventricular end-diastolic pressure (LVEDP). Chi-square testing was used for categorical variables and ANOVA or Kruskal-Wallis tests were used for continuous variables.

Results: Overall, 79% had an elevated resting LVEDP, and mean NT-proBNP was 115 ± 158 pg/mL. NT-proBNP levels correlated directly with age (r = 0.28, p = <0.0001), and indirectly with body mass index (r = -0.21, p = 0.0006), but did not independently associate with CFR. When stratified by NT-proBNP thresholds, higher NT-proBNP was initially associated with lower CFR, which did not persist with adjustment for multiple testing (p = 0.01 and 0.36, respectively).

Conclusion: Among women with symptoms and signs of ischemia, preserved LVEF, no obstructive CAD, and undergoing clinically indicated functional coronary angiography (FCA) for suspected CMD, while a majority had elevated resting LVEDP, we failed to find an independent association between CFR and NT-proBNP, although stratified clinical thresholds may relate to lower CFR. Further work is needed to investigate if these findings support the hypothesis that CMD-related ischemia may be a precursor to HFpEF.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243213PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714343PMC
January 2021

Feasibility of Patient-Centric Remote Dried Prediction, Risk, and Evaluation of Major Adverse Cardiac Events (PRE-MACE) Study.

Biodemography Soc Biol 2019 Oct-Dec;65(4):313-322

Advanced Clinical Biosystems Research Institute, Cedars-Sinai Smidt Heart Institute, Cedars-Sinai Medical Center , Los Angeles, CA, USA.

: Remote patient monitoring can shift important data collection opportunities to low-cost settings. Here, we evaluate whether the quality of blood-samples taken by patients at home differs from samples taken from the same patients by clinical staff. We examine the effects of socio-demographic and patient reported outcomes (PRO) survey data on remote blood sampling compliance and quality. : Samples were collected both in-clinic by study-staff and remotely by subjects at home. During cataloging the samples were graded for quality. We used chi-squared tests and logistic regressions to examine differences in quality and compliance between samples taken in-clinic versus samples taken by subjects at-home. : 64.6% of in-clinic samples and 69.7% of samples collected remotely at home received a (compared to ) quality grade (chi2 = 4.91; =.03). Regression analysis found remote samples had roughly 1.5 times higher odds of being quality compared to samples taken in-clinic ( <.001; 95% CI 1.18-2.03). Increased anxiety reduced odds of contributing a sample ( =.04; 95% CI.95-1.0). Response rates were significantly higher for in-clinic sampling (95.8% vs 89.8%; <.001). : Blood-samples taken by patients at home using a microsampling device yielded higher quality samples than those taken in-clinic.
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http://dx.doi.org/10.1080/19485565.2020.1765735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8464354PMC
August 2021

Phytoestrogen blood levels and adverse outcomes in women with suspected ischemic heart disease.

Eur J Clin Nutr 2021 05 8;75(5):829-835. Epub 2020 Nov 8.

Barbra Streisand Women's Heart Center, Cedars-Sinai Smidt Heart Institute, Los Angeles, CA, USA.

Background/objectives: Prior studies linked higher blood phytoestrogen (phytoE) levels of daidzein to beneficial lipoprotein profiles, and higher genistein levels related to worse coronary microvascular dysfunction in women with suspected ischemic heart disease (IHD). However, relationships to adverse outcomes remain unclear. We investigated the associations between eight serum phytoE and major adverse cardiac events (MACE) including myocardial infarction, stroke, hospitalization for heart failure and angina, cardiovascular and all-cause mortality, in women undergoing functional coronary angiography (FCA) for suspected ischemia.

Subjects/methods: We evaluated 143 women enrolled in the Women's Ischemia Syndrome Evaluation (1996-2001) for serum phytoE levels and 10-year outcomes. Median follow-up duration was 6.08 years (range 0.01-8.16) for time to MACE and 9.11 years (range 0.01-11.08 years) for time to death. Kaplan-Meier plots were analyzed and Cox regression models adjusted for age, body mass index, hypertension, diabetes, dyslipidemia and tobacco use.

Results: The median age was 54.7 (range 20.6-76.1) years and BMI was 29.3 (range 18.4-57.2). Of the cohort, 80.4% had nonobstructive coronary artery disease, 56% had hypertension, 22.4% had diabetes, 58.1% had dyslipidemia and 59.4% of the women used tobacco. Each unit decrease in log glycitin was associated with increased MACE hazard (HR 1.97, 95% [CI 1.23, 3.14], p = 0.005). Glycitin absence was associated with earlier angina hospitalization (log rank p = 0.05). After 6 years, MACE increased with each unit decrease in log genistein (HR 6.17, 95% [CI 1.81, 20.8], p = 0.0036). Other phytoE did not show statistically significant associations with outcomes.

Conclusions: Among women with suspected IHD undergoing clinically indicated invasive FCA, low serum glycitin was associated with increased MACE and earlier angina hospitalization, while low genistein was associated with increased MACE after 6 years. Future studies are needed regarding phytoE, nutrition, outcomes and possibly supplementation.
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http://dx.doi.org/10.1038/s41430-020-00800-6DOI Listing
May 2021

The Masquerading, Masculinizing Tumor: A Case Report and Review of the Literature.

J Womens Health (Larchmt) 2021 07 29;30(7):1047-1051. Epub 2020 Sep 29.

Barbra Streisand Women's Heart Center, Cedars-Sinai Medical Center, Smidt Heart Institute, Los Angeles, California, USA.

Androgen-producing tumors in women are rare neoplasms that can cause secondary virilizing characteristics. Of patients presenting with symptoms of hyperandrogenism, these tumors are found in ∼0.2% of cases. Androgen-producing tumors can arise from the ovary or the adrenal gland. Those arising from the ovary are rare, accounting for <5% of all ovarian tumors. This case presents a hilar Leydig cell tumor of the ovary, which resulted in secondary virilization of a 45-year-old female 2 months after cessation of combined oral contraceptives (COC). Laboratory findings showed markedly elevated total and free testosterone concentrations with normal dehydroepiandrosterone sulfate, however neither pelvic ultrasound nor magnetic resonance imaging demonstrated any masses. Venous sampling under fluoroscopy revealed supraphysiologic testosterone concentrations from the right ovarian vein suggesting the source. The patient underwent bilateral salpingo-oophorectomy revealing a 1.3 cm hilar cell tumor of the right ovary. This article reviews the clinical features, diagnosis, and treatment of hilar Leydig cell tumors and describes the long-term complications of supraphysiologic testosterone levels. As the tumor presented after cessation of COC, we also review the mechanisms by which COC might suppress supraphysiologic androgen levels and mask the secondary virilizing effects of androgen-producing tumors.
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http://dx.doi.org/10.1089/jwh.2020.8548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290302PMC
July 2021

Hormonal Contraception in Women With Hypertension.

JAMA 2020 Oct;324(14):1451-1452

Smidt Heart Institute, Barbra Streisand Women's Heart Center, Cedars-Sinai Medical Center, Los Angeles, California.

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http://dx.doi.org/10.1001/jama.2020.11935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528006PMC
October 2020

Can We Improve Cardiovascular Disease for Women Using Data Under Our Noses?: A Need for Changes in Policy and Focus.

JAMA Cardiol 2020 12;5(12):1398-1400

Barbra Streisand Women's Heart Center, Cedars-Sinai Smidt Heart Institute, Los Angeles, California.

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http://dx.doi.org/10.1001/jamacardio.2020.4117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074640PMC
December 2020

Biometric and Psychometric Remote Monitoring and Cardiovascular Risk Biomarkers in Ischemic Heart Disease.

J Am Heart Assoc 2020 09 8;9(18):e016023. Epub 2020 Sep 8.

Barbra Streisand Women's Heart Center Smidt Heart Institute Cedars-Sinai Medical Center Los Angeles CA.

Background Patients with stable ischemic heart disease represent a heterogeneous population at variable risk for major adverse cardiac events (MACE). Because MACE typically occurs outside the hospital, we studied whether biometric and psychometric remote patient monitoring are associated with MACE risk biomarkers. Methods and Results In 198 patients with stable ischemic heart disease (mean age 65±11 years, 60% women), we evaluated baseline measures, including biometric (FitBit 2) and psychometric (acquired via smartphone-administered patient-reported outcomes) remote monitoring, in the PRE-MACE (Prediction, Risk, and Evaluation of Major Adverse Cardiac Events) study. In multivariable adjusted regression analyses, we examined the association of these measures with biomarkers of MACE risk, including NT-proBNP (N-terminal pro-b-type natriuretic peptide), u-hs-cTnI (ultra-high sensitivity cardiac-specific troponin I), and hs-CRP (high-sensitivity C-reactive) protein. Both biometric and psychometric measures were associated with NT-proBNP. Specifically, step count, heart rate, physical activity, global health score, and physical function score were all inversely related, whereas physical limitation score was directly related (≤0.05 for all). However, only biometric measures (step count and heart rate) were associated with u-hs-cTnI (inversely related, <0.05), while only the psychometric measures of physical limitation were associated with hs-CRP (directly related, ≤0.05). Conclusions In stable ischemic heart disease patients, remotely monitored measures were associated with MACE risk biomarkers. Both biometric and psychometric measures were related to NT-proBNP. In contrast, biometric measures were uniquely related to u-hs-cTnI, while psychometric indices were uniquely related to hs-CRP. Further investigation could assess the predictive value of these metrics for MACE in ischemic heart disease.
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http://dx.doi.org/10.1161/JAHA.120.016023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726999PMC
September 2020

After menopause, is an enlarging middle, an enlarging cardiovascular risk factor?

Menopause 2020 09;27(9):974-975

Barbra Streisand Women's Heart Center, Cedars-Sinai Smidt Heart Institute, Los Angeles, CA.

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http://dx.doi.org/10.1097/GME.0000000000001620DOI Listing
September 2020

Left ventricular mass and myocardial scarring in women with hypertensive disorders of pregnancy.

Open Heart 2020 08;7(2)

Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA

Aims: Hypertensive disorders of pregnancy (HDP) predict future cardiovascular events. We aim to investigate relations between HDP history and subsequent hypertension (HTN), myocardial structure and function, and late gadolinium enhancement (LGE) scar.

Methods And Results: We evaluated a prospective cohort of women with suspected ischaemia with no obstructive coronary artery disease (INOCA) who underwent stress/rest cardiac magnetic resonance imaging (cMRI) with LGE in the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction study. Self-reported history of pregnancy and HDP (gestational HTN, pre-eclampsia, toxaemia and eclampsia) were collected at enrollment. In our cohort of 346, 20% of women report a history of HDP. HDP history was associated with 3.2-fold increased odds of HTN. Women with a history of HDP and HTN had higher cMRI measured left ventricular (LV) mass compared with women with HDP only (99.4±2.6 g vs 87.7±3.2 g, p=0.02). While we found a similar frequency of LGE scar, we observed a trend towards increased LGE scar size (5.1±3.4 g vs 8.0±3.4 g, p=0.09) among the women with HDP history compared to women without.

Conclusion: In a high-risk cohort of women with suspected INOCA, 20% had a history of HDP. Women with HDP history were more likely to develop HTN. Our study demonstrates higher LV mass in women with HDP and concomitant HTN. Although the presence of LGE scar was not different in women with and without HDP history, we observed a trend towards larger scar size in women with HDP. Future studies are needed to better assess the relationship of HDP and cardiac morphology and LGE scarring in a larger cohort of women.
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http://dx.doi.org/10.1136/openhrt-2020-001273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412584PMC
August 2020

Temporal Trends in Angina, Myocardial Perfusion, and Left Ventricular Remodeling in Women With No Obstructive Coronary Artery Disease Over 1-Year Follow-Up: Results From WISE-CVD.

J Am Heart Assoc 2020 07 24;9(13):e016305. Epub 2020 Jun 24.

Barbra Streisand Women's Heart Center Cedars Sinai Smidt Heart Institute Los Angeles CA.

Background Women with ischemia and no obstructive coronary artery disease are increasingly recognized and found to be at risk for major adverse cardiovascular events. Methods and Results In 214 women with suspected ischemia and no obstructive coronary artery disease who completed baseline and 1-year follow-up vasodilatory stress cardiac magnetic resonance imaging, we investigated temporal trends in angina (Seattle Angina Questionnaire [SAQ]), myocardial perfusion reserve index, blood pressure, and left ventricular (LV) remodeling and function from baseline to 1-year follow-up and explored associations between these different parameters. We observed concordant positive trends in 4/5 SAQ domains, SAQ-7, myocardial perfusion reserve index, blood pressure, LV mass, and LV mass-to-volume ratio. There was no association between SAQ-7 improvement and myocardial perfusion reserve index improvement over 1-year follow-up (=0.1). Higher indexed LV end-diastolic volume and time to peak filling rate at baseline were associated with increased odds of clinically relevant SAQ-7 improvement (odds ratio [OR], 1.05; 95% CI, 1.0-1.1; and OR, 2.40; 95% CI, 1.1-5.0, respectively). Hypertension was associated with decreased odds of SAQ-7 improvement (OR, 0.41; 95% CI, 0.19-0.91). Conclusions In women with ischemia and no obstructive coronary artery disease clinically treated with cardiac medications over 1 year, we observed concurrent temporal trends toward improvement in SAQ, myocardial perfusion reserve index, blood pressure, LV mass, and LV mass-to volume ratio. We showed that abnormalities in LV morphology and diastolic function at baseline were predictive of clinically significant improvement in angina at follow-up, whereas history of hypertension was associated with lower odds. Future studies are needed to assess the mechanisms and treatments responsible for the improvements we observed. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT02582021.
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http://dx.doi.org/10.1161/JAHA.119.016305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670509PMC
July 2020
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