Publications by authors named "Chrisandra L Shufelt"

35 Publications

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

J Clin Endocrinol Metab 2021 Jan 28. Epub 2021 Jan 28.

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

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 VTE 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
January 2021

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

Aspirin for primary prevention of cardiovascular disease in women.

Menopause 2020 05;27(5):605-606

Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

For primary prevention, low-dose aspirin should be considered in women aged 40 to 70 years with a 10-year cardiovascular risk of 20% or more or in women with diabetes and a 10-year cardiovascular risk of 10% or more. The risk of bleeding outweighs the benefits in low-risk women and in women aged 70 years and older.
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http://dx.doi.org/10.1097/GME.0000000000001547DOI Listing
May 2020

Resting coronary velocity and myocardial performance in women with impaired coronary flow reserve: Results from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) study.

Int J Cardiol 2020 06 23;309:19-22. Epub 2020 Jan 23.

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

Background: Women with evidence of ischemia and no obstructive coronary arteries (INOCA) often have coronary microvascular dysfunction (CMD) indicated by impaired coronary flow reserve (CFR) to adenosine. Low CFR is associated with an adverse prognosis, including incident heart failure. Because the CFR calculation relies on the baseline intrinsic coronary vasomotor flow velocity, a major determinate of CFR and the degree of variation in baseline flow alone may be an important contributor to risk of adverse outcomes in women with CMD. A better understanding of baseline blood flow in the setting of low CFR and its association with myocardial performance would be helpful.

Methods: We evaluated 74 women who underwent invasive coronary reactivity testing in the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) study and had impaired CFR (<2.32). We assessed the relationship between coronary artery baseline average peak velocity (bAPV) at rest and cardiac magnetic resonance imaging measures of left ventricular (LV) structure and function.

Results: When stratified as low (<22 cm/s) versus high (≥22 cm/s) bAPV, there were no differences in cardiovascular risk factors, coronary plaque burden, or LV structure. However, low bAPV was associated with higher LV end-diastolic filling pressure (P = 0.04), lower LV ejection fraction (P = 0.001), and differences in late systolic and diastolic strain rates (P = 0.01 to 0.05).

Conclusions: In women with impaired CFR, low resting coronary flow velocity is associated with more adverse myocardial performance, which may contribute to risk for adverse outcomes and particularly heart failure in women with CMD.
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http://dx.doi.org/10.1016/j.ijcard.2020.01.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195998PMC
June 2020

Cardiovascular and pregnancy outcomes in women with coronary microvascular dysfunction: a case series.

Eur Heart J Case Rep 2019 Jun;3(2)

Barbra Streisand Women's Heart Center, Cedars-Sinai Smidt Heart Institute, Cedars-Sinai Medical Center, 127 S. San Vicente Boulevard, Suite A3600, Los Angeles, CA, USA.

Background: Coronary microvascular dysfunction (CMD) is associated with adverse cardiovascular outcomes. Coronary microvascular dysfunction is observed in women of childbearing age, however, the frequency of adverse pregnancy outcomes (APO) is unknown.

Case Summary: Women previously enrolled in a single centre prospective CMD registry diagnosed using invasive coronary reactivity testing were included. Among 279 women enrolled, 5 of 47 (10.6%) of childbearing age (18-44 years) subsequently became pregnant, representing a fertility rate of 36.8 births per 1000 women-years. None had history of hypertension, diabetes, or smoking. Four (80%) had a history of prior spontaneous miscarriage. Median age at CMD diagnosis was 32 years (IQR: 32-35). During pregnancy, most reported stable or improved angina, while one reported increased angina frequency, an emergency room visit and accelerated anti-anginal therapy. None experienced gestational hypertension, diabetes, pre-eclampsia, myocardial infarction, or death. Two (40%) experienced APO of preterm delivery and small neonate for gestational age. Following pregnancy, angina severity scores, and/or functional capacity decreased in three women (60%).

Discussion: In this first case-series of five women with CMD who became pregnant, increased angina and accelerated care during pregnancy and post-partum was not commonly observed. Fertility rates were lower than the national average, while prior spontaneous miscarriage and subsequent APO were higher. Further studies are warranted to understand and manage pregnancy in women with CMD, as well as the impact of pregnancy on longer term angina, functional capacity, and outcomes.
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http://dx.doi.org/10.1093/ehjcr/ytz071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601184PMC
June 2019

Vascular Function and Serum Lipids in Women with Spontaneous Preterm Delivery and Term Controls.

J Womens Health (Larchmt) 2019 11 7;28(11):1522-1528. Epub 2019 Aug 7.

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

Spontaneous preterm delivery (sPTD) is associated with a twofold increased risk of future maternal cardiovascular disease. We hypothesized that women with sPTD would demonstrate greater vascular dysfunction postpartum compared to women with term delivery. In a case-controlled, matched pilot study, we enrolled 20 women with sPTD (gestation ≤34 weeks), and 20 term control women (gestation ≥39 weeks) were matched for age (±5 years), parity, ethnicity, and route of delivery. Vascular function, serum lipids, C-reactive protein, and interleukin-6 were completed within 24-72 hours postpartum. Statistical analysis included paired -tests based on match and mixed effects linear regression models and adjusted for potential confounders. The mean age for sPTD and term controls was 33 ± 6 years and 32 ± 6 years, respectively. Women with sPTD had significantly lower augmentation index-75 (24.1% ± 16.1% vs. 39.9% ± 15.2%,  = 0.001) and central pulse pressure (29.1 ± 5.4 mmHg vs. 34.6 ± 4.7 mmHg,  = 0.004), but no difference in pulse wave velocity (5.1 ± 1.6 m/s vs. 5.6 ± 1.5 m/s,  = 0.12) compared to controls. Women with sPTD had significantly lower high-density lipoprotein cholesterol (59.4 ± 12.5 mg/dL vs. 67.6 ± 13.1 mg/dL,  = 0.035) compared to controls. Analysis of chorioamnionitis and magnesium sulfate did not alter the results. Women with sPTD have signs of lower smooth muscle tone in the early postpartum period compared to women with term delivery. Further research is required to understand mechanistic pathways in sPTD and future maternal cardiovascular disease risk.
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http://dx.doi.org/10.1089/jwh.2018.7427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862947PMC
November 2019

Age at Menarche and Risk of Cardiovascular Disease Outcomes: Findings From the National Heart Lung and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation.

J Am Heart Assoc 2019 06 5;8(12):e012406. Epub 2019 Jun 5.

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

Background Previous studies have reported an association between the timing of menarche and cardiovascular disease ( CVD ). However, emerging studies have not examined the timing of menarche in relation to role of estrogen over a lifetime and major adverse cardiac events ( MACE ). Methods and Results A total of 648 women without surgical menopause undergoing coronary angiography for suspected ischemia in the WISE (Women's Ischemia Syndrome Evaluation) study were evaluated at baseline and followed for 6 years (median) to assess major adverse CVD outcomes. MACE was defined as the first occurrence of all-cause death, nonfatal myocardial infarction, nonfatal stroke, or heart failure hospitalization. Age at menarche was self-reported and categorized (≤10, 11, 12, 13, 14, ≥15 years) with age 12 as reference. Total estrogen time and supra-total estrogen time were calculated. Cox regression analysis was performed adjusting for CVD risk factors. Baseline age was 57.9 ± 12 years (mean ± SD ), body mass index was 29.5 ± 6.5 kg/m, total estrogen time was 32.2 ± 8.9 years, and supra-total estrogen time was 41.4 ± 8.8 years. MACE occurred in 172 (27%), and its adjusted regression model was J-shaped. Compared with women with menarche at age 12 years, the adjusted MACE hazard ratio for menarche at ≤10 years was 4.53 (95% CI 2.13-9.63); and at ≥15 years risk for MACE was 2.58 (95% CI , 1.28-5.21). Conclusions History of early or late menarche was associated with a higher risk for adverse CVD outcomes. These findings highlight age at menarche as a potential screening tool for women at risk of adverse CVD events. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT00000554.
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http://dx.doi.org/10.1161/JAHA.119.012406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6645646PMC
June 2019

Hormone therapy and carotid intima-media thickness: the thick and thin of it.

Menopause 2019 01;26(1):5-6

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.0000000000001264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684248PMC
January 2019

Sex-Specific Physiology and Cardiovascular Disease.

Adv Exp Med Biol 2018;1065:433-454

Surgery and Physiology, Women's Health Research Center, College of Medicine, Mayo Clinic, Rochester, MN, USA.

Sex differences in cardiovascular diseases can be classified as those which are specific to one sex and those that differ in incidence, prevalence, etiology, symptomatology, response to treatment, morbidity, and mortality in one sex compared to the other. All sex differences in cardiovascular conditions have their basis in the combined expression of genetic and hormonal differences between women and men. This chapter addresses how understanding basic mechanisms of hormone responses, imaging diagnostics, and integration of genomics and proteomics has advanced diagnosis and improved outcomes for cardiovascular conditions, apart from those related to pregnancy that are more prevalent in women. These conditions include obstructive coronary artery disease, coronary microvascular dysfunction, spontaneous coronary artery dissection, diseases of the cardiac muscle including heart failure and takotsubo cardiomyopathy, and conditions related to neurovascular dysregulation including hot flashes and night sweats associated with menopause and effects of exogenous hormones on vascular function. Improvement in technologies allowing for noninvasive assessment of neuronally mediated vascular reactivity will further improve our understanding of the basic etiology of the neurovascular disorders. Consideration of sex, hormonal status, and pregnancy history in diagnosis and treatment protocols will improve prevention and outcomes of cardiovascular disease in women as they age.
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http://dx.doi.org/10.1007/978-3-319-77932-4_27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768431PMC
March 2019

Association of Spontaneous Preterm Delivery and Future Maternal Cardiovascular Disease.

Circulation 2018 02;137(8):865-871

Barbra Streisand Women's Heart Center, Cedars-Sinai Heart Institute (M.B.M., J.W., C.L.S., C.N.B.M.).

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.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.031403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5967638PMC
February 2018

Daily Activity Measured With Wearable Technology as a Novel Measurement of Treatment Effect in Patients With Coronary Microvascular Dysfunction: Substudy of a Randomized Controlled Crossover Trial.

JMIR Res Protoc 2017 Dec 20;6(12):e255. Epub 2017 Dec 20.

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

Background: Digital wearable devices provide a "real-world" assessment of physical activity and quantify intervention-related changes in clinical trials. However, the value of digital wearable device-recorded physical activity as a clinical trial outcome is unknown.

Objective: Because late sodium channel inhibition (ranolazine) improves stress laboratory exercise duration among angina patients, we proposed that this benefit could be quantified and translated during daily life by measuring digital wearable device-determined step count in a clinical trial.

Methods: We conducted a substudy in a randomized, double-blinded, placebo-controlled, crossover trial of participants with angina and coronary microvascular dysfunction (CMD) with no obstructive coronary artery disease to evaluate the value of digital wearable device monitoring. Ranolazine or placebo were administered (500-1000 mg twice a day) for 2 weeks with a subsequent 2-week washout followed by crossover to ranolazine or placebo (500-1000 mg twice a day) for an additional 2 weeks. The outcome of interest was within-subject difference in Fitbit Flex daily step count during week 2 of ranolazine versus placebo during each treatment period. Secondary outcomes included within-subject differences in angina, quality of life, myocardial perfusion reserve, and diastolic function.

Results: A total of 43 participants were enrolled in the substudy and 30 successfully completed the substudy for analysis. Overall, late sodium channel inhibition reduced within-subject daily step count versus placebo (mean 5757 [SD 3076] vs mean 6593 [SD 339], P=.01) but did not improve angina (Seattle Angina Questionnaire-7 [SAQ-7]) (P=.83). Among the subgroup with improved angina (SAQ-7), a direct correlation with increased step count (r=.42, P=.02) was observed.

Conclusions: We report one of the first studies to use digital wearable device-determined step count as an outcome variable in a placebo-controlled crossover trial of late sodium channel inhibition in participants with CMD. Our substudy demonstrates that late sodium channel inhibition was associated with a decreased step count overall, although the subgroup with angina improvement had a step count increase. Our findings suggest digital wearable device technology may provide new insights in clinical trial research.

Trial Registration: Clinicaltrials.gov NCT01342029; https://clinicaltrials.gov/ct2/show/NCT01342029 (Archived by WebCite at http://www.webcitation.org/6uyd6B2PO).
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http://dx.doi.org/10.2196/resprot.8057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752966PMC
December 2017

Mental stress peripheral vascular reactivity is elevated in women with coronary vascular dysfunction: Results from the NHLBI-sponsored Cardiac Autonomic Nervous System (CANS) study.

Int J Cardiol 2018 Jan 22;251:8-13. Epub 2017 Oct 22.

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

Background: Women with chest pain, ischemia, and no obstructive coronary artery disease often have coronary vascular dysfunction (CVaD). Peripheral vascular reactivity to mental stress may contribute mechanistic understanding of stress-induced ischemia in women with CVaD.

Methods: 62 women (41 CVaD and 21 controls) underwent mental stress testing (MST) with anger recall, mental arithmetic, and forehead cold pressor (COP) challenge. Emotional arousal was measured (Likert scale). Reactive hyperemia index (RHI) was calculated before and after MST by peripheral arterial tonometry (PAT). Stress PAT ratio (SPR) of pulse amplitude during stress to rest was obtained to measure vasoconstriction. Wilcoxson rank sum test was used for analysis.

Results: Mean age of CVaD and control groups was 58±9 and 55±10years (p=0.73). Baseline RHI correlated with coronary endothelial function (r=0.36, p=0.03) and inversely with RHI change post-MST (r=-0.51, p<0.001). During MST, 10% of controls reported chest pain vs. 41% of CVaD subjects (p=0.01). RHI did not change significantly after MST in either group. CVaD subjects had lower SPR vs. controls during mental arithmetic (0.54 [0.15, 1.46] vs. 0.67 [0.36, 1.8], p=0.039), not evident in the other tasks. Vasoconstriction inversely correlated with anxiety (r=-3.4, p=0.03), frustration (r=-0.37, p=0.02), and feeling challenged (r=-0.37, p=0.02) in CVaD but not controls.

Conclusions: Mental stress peripheral vascular reactivity is elevated in women with CVaD compared to controls. Elevated vascular reactivity may be one contributor to stress-induced chest pain in CVaD. Interventions that modulate vasoconstrictive responses may be of benefit and should be tested in clinical trials in women with CVaD.
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http://dx.doi.org/10.1016/j.ijcard.2017.10.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870901PMC
January 2018

Role of Stress Cardiac Magnetic Resonance Imaging in Women with Suspected Ischemia but No Obstructive Coronary Artery Disease.

J Radiol Nurs 2017 Sep 30;36(3):180-183. Epub 2017 Aug 30.

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

Objective: Signs and symptoms of ischemia but no obstructive coronary artery disease (CAD) is often a diagnostic dilemma in women. The use of stress cardiac magnetic resonance imaging (CMRI) for advanced diagnostic assessment in these patients is a non-ionizing radiation option, but the diagnostic utility in this population is unknown. We examined the diagnostic role of stress CMRI in our patient population of these women.

Methods: We analyzed 113 consecutive female patients from 2/2006-11/2007 who had prior cardiac evaluations for signs and symptoms of ischemia but no obstructive CAD who underwent stress CMRI, which included anatomic, functional, adenosine stress perfusion and delayed enhancement imaging.

Results: The population demographics of 113 women included a mean age of 55±12.2 years with an average body mass index (BMI) of 25 ± 4.5. Overall, 43% had hypertension, 4% had diabetes and 3% were smokers. Overall, 80/113 (70%) demonstrated abnormal stress CMRI results. The majority of patients demonstrated findings consistent with subendocardial perfusion abnormalities suggestive of coronary microvascular dysfunction (CMD). Of note, 3 patients (4%) were diagnosed with congenital coronary anomalies or cardiomyopathy not detected in prior cardiac evaluations.

Conclusion: Among women with signs and symptoms of ischemia but no obstructive CAD, stress CMRI is frequently abnormal and is valuable in diagnosis of CMD. Stress CMRI appears useful for advanced diagnostic assessment in these diagnostically challenged patients.
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http://dx.doi.org/10.1016/j.jradnu.2017.04.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5654630PMC
September 2017

Hypothalamic Amenorrhea and the Long-Term Health Consequences.

Semin Reprod Med 2017 05 28;35(3):256-262. Epub 2017 Jun 28.

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

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http://dx.doi.org/10.1055/s-0037-1603581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374026PMC
May 2017

Typical angina is associated with greater coronary endothelial dysfunction but not abnormal vasodilatory reserve.

Clin Cardiol 2017 Oct 12;40(10):886-891. Epub 2017 Jun 12.

Division of Cardiology, University of Florida, Gainesville, Florida, USA.

Background: Typical angina (TA) is defined as substernal chest pain precipitated by physical exertion or emotional stress and relieved with rest or nitroglycerin. Women and elderly patients are usually have atypical symptoms both at rest and during stress, often in the setting of nonobstructive coronary artery disease (CAD).

Hypothesis: To further understand this, we performed subgroup analysis comparing subjects who presented with TA vs nontypical angina (NTA) using baseline data of patients with nonobstructive CAD and coronary microvascular dysfunction (CMD) enrolled in a clinical trial.

Methods: 155 subjects from the RWISE study were divided into 2 groups based on angina characteristics: TA (defined as above) and NTA (angina that does not meet criteria for TA). Coronary reactivity testing (responses to adenosine, acetylcholine, and nitroglycerin), cardiac magnetic resonance-determined myocardial perfusion reserve index (MPRI), baseline Seattle Angina Questionnaire (SAQ), and Duke Activity Status Index (DASI) scores were evaluated.

Results: The mean age was 55 ± 10 years; Overall, 30% of subjects had TA. Baseline shortness of breath, invasively assessed acetylcholine-mediated coronary endothelial function, and SAQ score were worse in the TA group (all P < 0.05), whereas adenosine-mediated coronary flow reserve, MPRI, and DASI score were similar to the NTA group.

Conclusions: Among subjects with CMD and no obstructive CAD, those with TA had more angina pectoris, shortness of breath, and worse quality of life, as well as more severe coronary endothelial dysfunction. Typical angina in the setting of CMD is associated with worse symptom burden and coronary endothelial dysfunction. These results indicate that TA CMD subjects represent a relatively new CAD phenotype for future study and treatment trials.
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http://dx.doi.org/10.1002/clc.22740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680106PMC
October 2017

Cardiac autonomic function and vasomotor symptoms: too much break and not enough accelerator?

Menopause 2017 07;24(7):719-721

Emory Women's Heart Center, Division of Cardiology, Emory University School of Medicine, Atlanta, GA Barbra Streisand Women's Heart Center, Cedars-Sinai Heart Institute, Los Angeles, CA.

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http://dx.doi.org/10.1097/GME.0000000000000925DOI Listing
July 2017

Menopausal symptoms and cardiovascular disease mortality in the Women's Ischemia Syndrome Evaluation (WISE).

Menopause 2017 02;24(2):126-132

1Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 2Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 3Barbra Streisand Women's Heart Center, Cedars-Sinai Heart Institute, Los Angeles, CA 4Section of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, NC 5Department of Obstetrics and Gynecology, Keck School of Medicine of University of Southern California, Los Angeles, CA 6Division of Cardiology, Department of Medicine, University of Florida, Gainesville, FL 7Division of Cardiovascular Disease, Department of Medicine, University of Alabama Birmingham, AL 8Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 9Division of Cardiology, Department of Medicine, Allegheny General Hospital, Pittsburgh, PA 10Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.

Objective: Studies have linked vasomotor symptoms (VMS) to markers of cardiovascular disease (CVD) risk, yet few have considered clinical cardiovascular events. Data suggest that associations may depend upon the age that symptoms occur. We examined associations between VMS and cardiovascular events and endothelial function, considering age of symptom onset.

Methods: The Women's Ischemia Syndrome Evaluation enrolled women referred for coronary angiography for suspected myocardial ischemia. A total of 254 women aged more than 50 years, postmenopausal, with both ovaries, not taking hormone therapy underwent a baseline evaluation, were followed annually (median = 6.0 y), and the National Death Index was searched to ascertain CVD mortality (median = 9.3 y). A subset of participants underwent brachial artery ultrasound for flow-mediated dilation (FMD). Receiver-operating curve analysis was used to determine vasomotor symptom groups (symptoms beginning < age 42 [early onset], beginning ≥42 [later onset], never) which were examined in relation to cardiovascular events and FMD in Cox proportional hazard and linear regression models.

Results: Women reporting early onset VMS (HR = 3.35, 95% CI = 1.23-7.86, P = 0.005) and women who never had VMS (HR = 2.17, 95% CI = 1.02-4.62, P = 0.05) had higher CVD mortality than women with later onset symptoms (multivariable models). Women with early onset VMS had lower FMD than women with later onset symptoms (b = -4.31, SE = 2.10, P = 0.04, multivariable).

Conclusions: Women with signs and symptoms of ischemia who had VMS beginning early in midlife had higher CVD mortality and reduced endothelial function relative to women with later onset symptoms. Future research should evaluate the vascular phenotype of women with early midlife VMS.
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http://dx.doi.org/10.1097/GME.0000000000000731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5266637PMC
February 2017

The Potential for Postrandomization Confounding in Randomized Clinical Trials.

JAMA 2016 Jun;315(21):2273-4

Departments of Biostatistics and Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.

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http://dx.doi.org/10.1001/jama.2016.3676DOI Listing
June 2016

Cardiac magnetic resonance imaging for myocardial perfusion and diastolic function-reference control values for women.

Cardiovasc Diagn Ther 2016 Feb;6(1):78-86

Barbra Streisand Women's Heart Center, Cedars-Sinai Heart Institute, S. Mark Taper Foundation Imaging Center, Biomedical Imaging Research Institute Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Angina, heart failure with preserved ejection fraction (HFpEF) and coronary microvascular dysfunction (CMD) in the absence of obstructive coronary artery disease (CAD) are more common in women and are associated with adverse cardiovascular prognosis. Cardiac magnetic resonance imaging (CMRI) is established for assessment of left ventricular (LV) morphology and systolic function and is increasingly used to assess myocardial perfusion and diastolic function. Indeed, stress CMRI allows measurement of myocardial perfusion reserve index (MPRI) using semi-quantitative techniques, and quantification of LV volumetric filling patterns provides valuable insight into LV diastolic function. The utility of these two techniques remains limited, because reference control values for MPRI and LV diastolic function in asymptomatic middle-aged, women have not previously been established. To address this limitation, we recruited twenty women, without clinical cardiovascular disease or cardiovascular risk factors, with normal maximal Bruce protocol exercise treadmill testing. Subjects underwent CMRI (1.5 tesla) using a standardized protocol of adenosine stress and rest perfusion and LV cinematic imaging. Commercially available with automated CMRI segmentation was used for calculation of MPRI, LV filling profiles, and ejection fraction. Mean age was 54±9 years and mean body mass index was 25±4 kg/m(3). The exercise treadmill testing results demonstrated a normotensive group with normal functional capacity and hemodynamic response. We report reference control values for semi-quantitative MPRI as well as measures of LV systolic and diastolic function including ejection fraction, stroke volume, peak filling rate (PFR), PFR adjusted for end-diastolic volume (EDV) and stroke volume, time to PFR, and EDV index. The data herein provide reference values for MPRI and diastolic function in a cohort of healthy, middle-aged of women. These reference values may be used for comparison with a variety of patient populations, including women with CMD and HFpEF.
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http://dx.doi.org/10.3978/j.issn.2223-3652.2015.09.03DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4731584PMC
February 2016

A randomized, placebo-controlled trial of late Na current inhibition (ranolazine) in coronary microvascular dysfunction (CMD): impact on angina and myocardial perfusion reserve.

Eur Heart J 2016 05 27;37(19):1504-13. Epub 2015 Nov 27.

Division of Cardiology, University of Florida, Gainesville, FL, USA.

Aims: The mechanistic basis of the symptoms and signs of myocardial ischaemia in patients without obstructive coronary artery disease (CAD) and evidence of coronary microvascular dysfunction (CMD) is unclear. The aim of this study was to mechanistically test short-term late sodium current inhibition (ranolazine) in such subjects on angina, myocardial perfusion reserve index, and diastolic filling.

Materials And Results: Randomized, double-blind, placebo-controlled, crossover, mechanistic trial in subjects with evidence of CMD [invasive coronary reactivity testing or non-invasive cardiac magnetic resonance imaging myocardial perfusion reserve index (MPRI)]. Short-term oral ranolazine 500-1000 mg twice daily for 2 weeks vs. placebo. Angina measured by Seattle Angina Questionnaire (SAQ) and SAQ-7 (co-primaries), diary angina (secondary), stress MPRI, diastolic filling, quality of life (QoL). Of 128 (96% women) subjects, no treatment differences in the outcomes were observed. Peak heart rate was lower during pharmacological stress during ranolazine (-3.55 b.p.m., P < 0.001). The change in SAQ-7 directly correlated with the change in MPRI (correlation 0.25, P = 0.005). The change in MPRI predicted the change in SAQ QoL, adjusted for body mass index (BMI), prior myocardial infarction, and site (P = 0.0032). Low coronary flow reserve (CFR <2.5) subjects improved MPRI (P < 0.0137), SAQ angina frequency (P = 0.027), and SAQ-7 (P = 0.041).

Conclusions: In this mechanistic trial among symptomatic subjects, no obstructive CAD, short-term late sodium current inhibition was not generally effective for SAQ angina. Angina and myocardial perfusion reserve changes were related, supporting the notion that strategies to improve ischaemia should be tested in these subjects.

Trial Registration: clinicaltrials.gov Identifier: NCT01342029.
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http://dx.doi.org/10.1093/eurheartj/ehv647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872284PMC
May 2016

Gender, Cardiovascular Disease, and the Sexism of Obesity.

J Am Coll Cardiol 2015 Nov;66(18):1958-1960

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

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http://dx.doi.org/10.1016/j.jacc.2015.08.860DOI Listing
November 2015

Hormone therapy in menopause: An update on cardiovascular disease considerations.

Trends Cardiovasc Med 2015 Aug 12;25(6):540-9. Epub 2015 Feb 12.

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

Cardiovascular disease (CVD) remains the number one cause of death and morbidity worldwide, and while overall CVD incidence rates declined in both genders between 1999 and 2007, age-specific data suggest that coronary risk factors in women are on the rise. While early observational data favored menopausal hormone therapy's (MHT's) role in primary CVD prevention, the initial interventional study data from the WHI did not. Further detailed analyses of both observational and interventional data have pointed to the possibility that MHT may play a role in primary CVD prevention if initiated within 10 years of menopause and less than 60 years of age (the timing hypothesis). Unanswered questions remain regarding the optimal route and dosage of estrogen in MHT. Data so far, favor transdermal estradiol over conventional-dose CEE with respect to CVD risk and oral estradiol over conventional-dose CEE with respect to stroke risk. Low-dose oral CEE may similarly have benefit over conventional-dose oral CEE for some CVD events. In addition, the transdermal route of delivery may avoid the excess risk of certain CVD events associated with MHT and lower doses of estrogen may have fewer adverse effects than the doses previously tested in WHI. Because questions regarding benefits versus risks remain, MHT is yet to be recommended for CVD prevention. However, it is indicated for menopausal symptom management in women within 10 years of menopause and under the age of 60 years, in whom it does not appear to carry increased cardiovascular risk. Additional research is ongoing and needed to confirm or refute the comparative safety of the various MHT options.
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http://dx.doi.org/10.1016/j.tcm.2015.01.008DOI Listing
August 2015

Statin therapy in women.

Menopause 2014 Aug;21(8):896-8

From the 1Barbra Streisand Women's Heart Center, Cedars-Sinai Heart Institute, Los Angeles, CA; and 2Brigham & Women's Hospital, Harvard Medical School, Boston, MA.

The 2013 American College of Cardiology/American Heart Association guidelines on the treatment of cholesterol recommend therapy for patients with (1) known cardiovascular disease (CVD); (2) low-density lipoprotein cholesterol (LDL-C) of 190 mg/dL or higher; (3) type 1 or type 2 diabetes mellitus and LDL-C between 70 mg/dL and 189 mg/dL (for ages 40-75); and 4) LDL-C between 70 mg/dL and 189 mg/dL and an estimated 10-year cardiovascular risk ≥7.5% (for ages 40-75), using their new risk calculator. Although statin therapy is indicated for women at elevated risk of CVD, safety concerns related to glucose elevations and myalgias may outweigh benefits for women at low absolute risk of CVD.
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http://dx.doi.org/10.1097/GME.0000000000000317DOI Listing
August 2014

Cardiac magnetic resonance imaging myocardial perfusion reserve index assessment in women with microvascular coronary dysfunction and reference controls.

Cardiovasc Diagn Ther 2013 Sep;3(3):153-60

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

Objective: We sought to comparatively assess cardiac magnetic resonance imaging (CMRI) myocardial perfusion reserve index (MPRI) in women with confirmed microvascular coronary dysfunction (MCD) cases and reference control women.

Background: Women with signs or symptoms of myocardial ischemia in the absence of obstructive coronary artery disease (CAD) frequently have MCD which carries an adverse prognosis. Diagnosis involves invasive coronary reactivity testing (CRT). Adenosine CMRI is a non-invasive test that may be useful for the detection of MCD.

Methods: Fifty-three women with MCD confirmed by CRT and 12 age- and estrogen-use matched reference controls underwent adenosine CMRI. CMRI was assessed for MPRI, calculated using the ratio of myocardial blood flow at hyperemia/rest for the whole myocardium and separately for the 16 segments as defined by the American Heart Association. Statistical analysis was performed using repeated measures ANOVA models.

Results: Compared to reference controls, MCD cases had lower MPRI values globally and in subendocardial and subepicardial regions (1.63±0.39 vs. 1.98±0.38, P=0.007, 1.51±0.35 vs. 1.84±0.34, P=0.0045, 1.68±0.38 vs. 2.04±0.41, P=0.005, respectively). A perfusion gradient across the myocardium with lower MPRI in the subendocardium compared to the subepicardium was observed for both groups.

Conclusions: Women with MCD have lower MPRI measured by perfusion CMRI compared to reference controls. CMRI may be a useful diagnostic modality for MCD. Prospective validation of a diagnostic threshold for MPRI in patients with MCD is needed.
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http://dx.doi.org/10.3978/j.issn.2223-3652.2013.08.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3839208PMC
September 2013

Hormone therapy dose, formulation, route of delivery, and risk of cardiovascular events in women: findings from the Women's Health Initiative Observational Study.

Menopause 2014 Mar;21(3):260-6

From the 1Barbra Streisand Women's Heart Center, Cedars-Sinai Heart Institute, Los Angeles, CA; 2Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA; 3National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD; 4MedStar Health Research Institute, Hyattsville, MD; 5University of Florida College of Medicine-Jacksonville, Jacksonville, FL; 6Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN; 7George Washington University School of Medicine and Health Sciences, Washington, DC; 8Atlanta VA Medical Center, Decatur, GA; 9Division of Endocrinology and Metabolism, Department of Medicine, Emory University School of Medicine, Atlanta, GA; and 10Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Objective: Research comparing hormone therapy (HT) doses, regimens, and routes of delivery in relation to cardiovascular disease (CVD) outcomes has been limited. This study directly compared different estrogen doses, routes of delivery, and HT formulations in postmenopausal women in relation to the risk of coronary heart disease (CHD), stroke, CVD mortality, total CVD, and all-cause mortality.

Methods: The Women's Health Initiative Observational Study is a multicenter prospective cohort study that was conducted at 40 US sites. Analyses included 93,676 postmenopausal women aged 50 to 79 years at study entry who were recruited from September 1994 to December 1998, with annual follow-up through August 14, 2009.

Results: The mean follow-up was 10.4 years. In direct comparisons, oral estradiol was associated with lower hazard ratios (HRs) for stroke than oral conjugated equine estrogens (CEE; HR, 0.64; 95% CI, 0.40-1.02), but statistical power was limited. Similarly, transdermal estradiol was associated with a moderate but nonsignificantly lower risk of CHD compared with oral CEE (HR, 0.63; 95% CI, 0.37-1.06). For other outcomes, comparisons revealed no appreciable differences by estrogen doses, formulations, or routes of delivery. Absolute risks of CVD events and all-cause mortality were markedly lower in younger women compared with older women.

Conclusions: In direct comparisons, various HT doses and regimens are associated with similar rates of cardiovascular events and all-cause mortality. However, oral estradiol may be associated with a lower risk of stroke, and transdermal estradiol may be associated with a lower risk of CHD, compared with conventional-dose oral CEE. Additional research is needed to confirm these hypotheses.
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http://dx.doi.org/10.1097/GME.0b013e31829a64f9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872264PMC
March 2014

Maternal recall of hypertensive disorders in pregnancy: a systematic review.

J Womens Health (Larchmt) 2013 Jan 6;22(1):37-47. Epub 2012 Dec 6.

Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

Background: Hypertensive disorders in pregnancy are risk markers for future maternal coronary heart disease (CHD). Clinical assessment of a woman's history of pregnancy complications relies on self-report, but the predictive value of maternal recall is unclear. A systematic review was conducted to comprehensively review and critically assess the available literature on maternal recall of hypertensive disorders in pregnancy.

Methods: The PubMed, EMBASE, and Web of Science databases were searched through August 2012. We included original research articles comparing maternal recall of hypertensive disorders in pregnancy with medical records.

Results: Ten studies met eligibility criteria for qualitative analysis and were independently reviewed by two investigators. Recall periods ranged from 48 hours to 30 years. Length of recall did not appear to uniformly affect recall quality. Sensitivity was generally lower and less consistent for gestational hypertension than for preeclampsia. Specificity was >90% for all hypertensive disorders. Determinants of recall accuracy included maternal education and parity.

Conclusions: Although maternal recall of hypertensive disorders of pregnancy is specific, low sensitivity and predictive values may limit the clinical utility of asking mothers to recall their history of hypertensive pregnancy complications. Future research on maternal recall of pregnancy complications should be designed to yield predictive values and test recall of disorder subtypes, recurrent complications, and changing recall over time in the same population. The utility of gestation length and offspring birth weight for clinical identification of women whose pregnancy history puts them at increased CHD risk should also be explored.
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http://dx.doi.org/10.1089/jwh.2012.3740DOI Listing
January 2013

A pilot randomized, single-blind, placebo-controlled trial of traditional acupuncture for vasomotor symptoms and mechanistic pathways of menopause.

Menopause 2012 Jan;19(1):54-61

Department of Medicine, Cedars-Sinai Heart Institute, Los Angeles, CA 90048, USA.

Objective: The aim of this study was to conduct a pilot study for the feasibility of planning a definitive clinical trial comparing traditional acupuncture (TA) with sham acupuncture (SA) and waiting control (WC) on menopause-related vasomotor symptoms (VMS), quality of life, and the hypothalamic-pituitary-adrenal axis in perimenopausal and postmenopausal women.

Methods: Thirty-three perimenopausal and postmenopausal women with at least seven VMS daily were randomized to TA, SA, or WC. The TA and SA groups were given three treatments per week for 12 weeks. Outcomes included the number and severity of VMS, Menopause-Specific Quality of Life Questionnaire, Beck Depression Inventory, Spielberg State-Trait Anxiety Instrument, Pittsburgh Quality Sleep Index, 24-hour urine cortisol and metabolites, and adrenocorticotropic hormone stimulation testing.

Results: Both the TA and SA groups demonstrated improved VMS trends compared with the WC group (Δ -3.5 ± 3.00 vs -4.1 ± 3.79 vs -1.2 ± 2.4, respectively; P = 20) and significantly improved Menopause-Specific Quality of Life Questionnaire vasomotor scores (Δ -1.5 ± 2.02 vs -1.8 ± 1.52 vs -0.3 ± 0.64, respectively; P = 0.04). There were no psychosocial group differences. Exit 24-hour urinary measures were lower in the TA versus the SA or WC group in total cortisol metabolites (4,658.9 ± 1,670.9 vs 7,735.8 ± 3,747.9 vs 5,166.0 ± 2,234.5, P = 0.03; respectively) and dehydroepiandrosterone (41.4 ± 27.46, 161.2 ± 222.77, and 252.4 ± 385.40, respectively; P = 0.05). The response data on adrenocorticotropic hormone stimulation cortisol also trended in the hypothesized direction (P = 0.17).

Conclusions: Both TA and SA reduce VMS frequency and severity and improve VMS-related quality of life compared with WC; however, TA alone may impact the hypothalamic-pituitary-adrenal axis. This association is viewed as preliminary and hypothesis generating and should be explored in a large clinical trial.
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http://dx.doi.org/10.1097/gme.0b013e31821f9171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3246091PMC
January 2012