Coronary Microvascular Dysfunction and Estrogen Receptor Signaling

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Review

Coronary Microvascular Dysfunction and Estrogen Receptor Signaling Elif Tunc,1 Alicia Arredondo Eve,1 and Zeynep Madak-Erdogan1,2,3,4,5,6,@,* Chest pain with non-obstructive coronary artery disease (NOCAD) occurs more frequently in women than in men and is mainly related to coronary microvascular disease (CMD). The majority of CMD patients are postmenopausal women, suggesting a role for lack of estrogens in the development and progression of CMD. Patients are often discharged without a clear treatment plan due to the limited understanding of etiology and diagnostic parameters of CMD and have significantly higher rates of future cardiovascular events. Thus, there is a need for a better understanding of the underlying biology, and CMD-specific diagnostic tests and therapies. In this article, we reviewed recent studies on CMD, estrogen action in coronary microvasculature, and diagnosis and treatment options for CMD in postmenopausal women.

Introduction In the USA, over 2 million primary care visits and more than 8 million emergency room visits are due to angina or chest pain [1,2]. Persistent chest pain is accompanied by increased morbidity and poor quality of life as readmissions for serious cardiovascular events occur in 3% of these patients [3]. Approximately 15–30% of patients have acute coronary syndrome (ACS), and more than 70% of these patients have angina and a positive cardiac stress tests without coronary artery disease (CAD), or plaque formation that blocks blood flow to the heart [4]. These patients are diagnosed to have nonobstructive coronary artery disease (NOCAD) or coronary microvascular disease (CMD) [5], which is associated with damage to the inner lining walls of the coronary artery blood vessel, increased spasms, and decreased blood flow to the heart muscle [6]. The prevalence of angina and NOCAD is higher in women than in men [7,8]. Several studies showed that the majority of female patients with NOCAD are postmenopausal women with an estrogen deficiency [9]. In the Women’s Ischemia Syndrome Evaluation (WISE) study, analysis of the data based on menopausal status illustrated that CMD is more frequent in postmenopausal women than in premenopausal women [10]. Functional coronary microvascular abnormalities are not as benign as reported in earlier studies and were found to be associated with future myocardial ischemia and adverse clinical outcomes [11,12]. A recent clinical study, which examined the impact of sex differences on the outcome after coronary angiography (CAG) in patients with angina and NOCAD, revealed that women were three times more likely to experience a cardiovascular event within the first year after the initial hospital visit compared to men [13]. The WISE study, which followed up women for 10 years after initial diagnosis, concluded that cardiovascular death or myocardial infarction (MI) occurred in 12.8% of women with NOCAD, and that the combined risk of death for MI, heart failure, and stroke was more than 2% per year [14]. Furthermore, persistence or worsening of the symptoms was common among participants. A repeat coronary angiography was performed at a 1.8-fold higher rate in women with NOCAD compared to patients with single vessel CAD. One in five women was rehospitalized for cardiac symptoms [13]. Thus, these studies revealed that CMD has a much higher prevalence in postmenopausal women. CMD is a strong predictor of major adverse cardiac events and therefore these patients have higher rates, such as heart failure, sudden cardiac death, and ACS [11]. Even though patients with CMD present with ischemia, they are prematurely discharged without a full precise diagnosis or proper medical therapy [15]. Thus, many patients with CMD are readmitted due to recurrent angina, which results in repeated exams, diagnostic testing, and high healthcare costs [16]. Despite many patients with CMD being postmenopausal women, we lack a detailed understanding of estrogens in CMD-specific

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Highlights Chest pain, in the absence of obstructive coronary artery disease (NOCAD), occurs more frequently in women than in men since changes in micro/macro-circulation are often estrogen-dependent. Despite having ischemia, patients with coronary microvascular disease (CMD) are often discharged without a clear treatment plan due to lack of a clear understanding of etiology and diagnostic parameters of this disease. The causes of CMD can be heterogeneous, and their effects on the microvascular angina are poorly understood. Currently, there is no consensus definition of CMD. CMD is more frequent in postmenopausal women than in premenopausal women and these patients are more likely to experience a cardiovascular events within the first year compared with men. Estrogens might offer a novel way to prevent and treat CVD in women without prior risk and estrogen signaling needs to be further studied in the context of CMD. 1Department of Food Science and Human Nutrition, University of Illinois, Urbana-Champaign, Urbana, IL, USA 2Division of Nutritional Sciences, University of Illinois, Urbana-Champaign, Urbana, IL, USA 3Cancer Center at Illinois, University of Illinois, Urbana-Champaign, Urbana, IL, USA 4Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, USA 5Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana-Champaign, Urbana, IL, USA 6Laboratory website: http://mel.fshn. illinois.edu @Twitter:

@zmadak

*Correspondence: [email protected]

https://doi.org/10.1016/j.tem.2019.11.001 ª 2019 Elsevier Ltd. All rights reserved.

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etiology, diagnosis, and treatment [17]. In this review, we will present recent studies on CMD etiology, diagnosis, and treatment in postmenopausal women and protective role of estrogen receptor signaling in microvasculature. We will further discuss future research venues addressing these unmet needs.

Definition and Symptoms CMD is the most common cause of cardiac ischemic chest pain in patients without obstructive CAD. The reasons of CMD can be heterogeneous. Microvascular angina, coronary vasospasm, and coronary slow flow, which result from multiple pathophysiologic processes were indicated among the causes of NOCAD [18,19]. The possible mechanisms include endothelial and smooth muscle dysfunction, inappropriate sympathetic tone, and microvascular atherosclerosis and inflammation, which we will describe in detail below (Table 1) [20,21]. Currently, there is no consensus in the definition of CMD. It was described as a disordered function of the smaller coronary resistance vessels [10] or an abnormal coronary microvascular resistance (MVR) due to inappropriate coronary blood flow response and impaired myocardial perfusion [22]. The Coronary Vasomotion Disorders International Study Group reported a reduced coronary flow reserve (CFR) of <2.5 in response to adenosine without obstructive CAD [23]. Reduced CFR is commonly noted in studies of patients with CMD. Even though these descriptions are used with a limited clinical success, we still need a universally accepted description of CMD for proper diagnosis and treatment of this disease.

Impact of Estrogens on Coronary Microvascular Physiology The coronary arterial system consists of three functionally distinct compartments based on diameter, resistance to flow, and biochemical regulation of function: large epicardial coronary arteries (500 mm to 2–5 mm), and small pre-arterioles (100–500 mm), and arterioles (<100 mm) (Figure 1). Epicardial arteries are mainly capacitance vessels and exert little resistance to blood flow in the healthy state. Table 1. Clinical Classification and Possible Mechanism of Coronary Microvascular Dysfunctiona

Type

Underlying clinical condition

Possible mechanism

Type 1 (Primary)

Absence of structural heart disease

Endothelial dysfunction SMC dysfunction Vascular remodeling

Type 2

Cardiomyopathies

Vascular remodeling SMC dysfunction Cardiac fibrosis and infiltration Luminal obstruction

Type 3

Obstructive CAD

Endothelial dysfunction SMC dysfunction Luminal obstruction

Type 4

Coronary interventions, such as PTCA

Endothelial dysfunction Autonomic dysfunction No reflow phenomenon/micro embolization

Type 5

Cardiac transplantation

a

Abbreviations: SMC, smooth muscle cells; CAD, coronary artery disease; PTCA, percutaneous transluminal coronary angioplasty.

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Coronary pre-arterioles and arterioles provide approximately 25% and 50% of coronary vascular resistance, respectivey, in response to stretching and metabolic stimuli (Figure 1) [24]. Myocardial perfusion is regulated by the epicardial vascular system, intramyocardial coronary vascular system, and downstream microcirculation [25]. Estrogens (E2) bind to the traditional estrogen receptors (ERs), ERa and ERb, as well as G proteincoupled ER (GPR30) [26,27]. Endogenous ligand binding to estrogen receptors activate both nuclear- and extra nuclear-initiated pathways [28,29]. In the nuclear pathway, E2 binding triggers chromatin recruitment of ERa and ERb to E2 response elements (EREs) [30], or tethering to DNA via other transcription factors, such as activator protein 1 (Ap1), specificity protein 1 (Sp1), or runt-related transcription factor 1 (RUNX1), to regulate transcription [31]. In the extra nuclearinitiated pathways, ERa, ERb and GPR30 activate acute kinase signaling pathways upon ligand binding [32]. All three receptors were shown to play a role in cardiovascular system in regulating normal and diseased physiology [33–35]. ERs were also shown to localize to mitochondria. Estrogens can improve mitochondrial function by modulating calcium influx, ATP production, apoptosis, and free radical species generation (Figure 2) [36]. Even though the in vitro effects require estrogens at micromolar range [37], in vivo studies showed E2 activity in nanomolar range relevant to physiological dose [38], suggesting an improved effect of estrogens in the presence of multiple cell types, including endothelial cells and vascular smooth muscle cells that are important for microvasculature function. Several molecular and clinical changes on microcirculation are estrogen-dependent (Figure 2).

Endothelium-Dependent Effects of E2 The coronary microvascular system plays a major role in modulating coronary blood flow depending on the myocardial requirement through vasodilator autoregulation and myogenic control. In the vasodilator autoregulation mechanism, proper capillary blood flow can be maintained despite the changes in the proximal perfusion pressure. In the myogenic control mechanism, coronary arteriolar dilation can be achieved if increased intraluminal pressure by wall receptors is detected [22]. Microcirculation

Macrocirculation

CFR FFR

IMR

Segment and size

Epicardial arteries

Small arteries

Arterioles

Capillaries

Main stimulus for vasomotion

Flow

Pressure

Metabolites

Metabolites

Transport

Regulation

Regulation

Exchange

Percentage of total resistance to flow

Low

Moderate

High

Low

Estrogen effect

LDL↓ HDL↑ Adhesion molecules↓ Monocyte adhesion↓

ROS↓ Inflammatory cytokines↓

ROS↓ Inflammatory cytokines↓

NO↑ Relaxation ↑ Flow induced arterial Dilatation↑

Structural abnormality

Focal epicardial stenosis myocardial bridging, anomalous coronary origin

Diffuse atheroma decreasing of vasodilatory capacity

Abnormal vascular remodeling microvascular constriction

Extrinsic vascular compression

Microvascular spasm

Microvascular spasm

Endothelial dysfunction

Main function

Functional abnormality

Vascular smooth muscle dysfunction and vasospasm

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Figure 1. Summary of the Coronary Vascular System and Estrogen Effect. Abbreviations: CFR, coronary flow reserve; FFR, fractional flow reserve; IMR, index of microcirculatory resistance.

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GPER1 PI3K MAPK

ER

↑ENOS

Mitochondria

ER

↓ROS Produc on ↑Cell survival

EREs ↑VEGF

↑Vasodila on ↑Angiogenesis

TF Nucleus N l

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Figure 2. Genomic and Nongenomic Actions of Estrogens (E2) on an Endothelial Cell. In the genomic pathway, E2 binds and activates the estrogen receptor (ER) resulting in direct binding to E2 response elements (EREs) or tethering through other transcription factors (TFs), induce chromatin remodeling, and change gene transcription in the nucleus. In the nongenomic pathway, E2 binds to ERs and G proteincoupled ER (GPR30) at the plasma membrane and leads to activation of phosphoinositide 3-kinase (PI3K) and mitogen activated protein kinase (MAPK) signaling cascade. ERs in mitochondria cause changes in gene expression and decrease reactive oxygen species (ROS) production to increase cell survival.

Studies reported that most of the CMD patients are in peri- or postmenopausal stage, suggesting that the level of estrogen changes during this phase plays an important role in CMD progression [39,40]. These studies show that estrogen plays a protective role by regulating endothelial and smooth muscle cell factors in the coronary arterial wall [39]. In CMD patients, CFR is impaired in the absence of epicardial coronary artery obstruction. Decreasing estrogen levels during perimenopausal transition initiate impairment in endothelial function due to decreased NO production, increased oxidative stress and proinflammatory cytokines (Figure 1). Previous studies showed that 17-b E2 rapidly and selectively induced vasodilation in both epicardial coronary arteries and coronary microvascular arteries of postmenopausal women [31]. Estrogens modulate production and release of the endothelium-derived hyperpolarizing factors (EDHFs), which are critical factors that regulate vascular relaxation. Ovariectomy produces a notable reduction in acetylcholine-induced hyperpolarization in female mouse arteries; however, 17-b E2 therapy reversed this arterial effect [41]. Estrogen improves nitric oxide (NO) production and coronary arterial relaxation [42,43]. In endothelial cells, E2 activates endothelial nitric oxide synthase (eNOS) via rapid signaling by the PI3K/Akt pathway (Figure 2) [42,44]. Previous studies have showed that estrogen replacement therapy increases coronary blood flow and decreases coronary resistance [45]. In addition to the NO production, the nongenomic ER signaling pathway also regulates intracellular calcium homeostasis that occurs rapidly after estrogen administration [46]. Reactive oxygen species (ROS) play a significant role in the pathogenesis of myocardial ischemia/ reperfusion injury, leading to cardiac apoptosis and ventricular dysfunction. E2 decreases ROS

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generation in cultured neonatal rat cardio myocytes (Figures 1 and 2) [47]. Consistent with these protective effects of estrogens, the Women’s Health Initiative (WHI) ancillary study showed that women who received conjugated equine estrogens had a lower coronary plaque burden and a lower prevalence of subclinical coronary artery disease after completion of the estrogen treatment than did women taking the placebo [48].

Endothelium-Independent E2 Effects Vascular smooth muscle cells (VSMC) also play an important role in atherosclerotic cardiovascular diseases. For example, upon estrogen treatment, VSMCs secrete factors that inhibit migration of adventitial fibroblast, which promotes neointima formation, to the endothelial injury site [49]. Estrogens reduce the arterial stiffness and arterial enlargement in response to a chronic increase in blood flow, decrease basal coronary vasomotor tone, and vascular resistance [50]. These effects can explain the cardiovascular protective effects of estrogen on the coronary vascular system in postmenopausal women (Figure 1).

Diagnostic Tests of CMD The coronary microcirculation cannot be directly visualized in vivo. Hemodynamic assessment of the coronary microcirculation system can be done via functional measurement. Echocardiography, single photon emission computed tomography (SPECT), positron emission tomography (PET), cardiovascular magnetic resonance (CMR), and coronary angiography with invasive functional assessment of coronary microvascular function are the major diagnostic tests for CMD (Table 2). The current parameters for the clinical determination of the microvascular function are CFR and index of microcirculatory resistance (IMR) (Figure 1). CFR is assessed as the ratio of the maximal blood flow after a hyperemic stimulus to the resting blood flow [51] and IMR is assessed as the distal coronary pressure divided by coronary flow [52]. Yet, even when CFR or IMR has been used as the primary diagnostic criterion for CMD, the threshold for defining dysfunction has considerably differed between studies. The present literature suggests that variable CFR and IMR cut-off levels have varying specificities and sensitivities. Current diagnostic tests have disadvantages and most of them are not routinely used in the clinic for CMD diagnosis due to cost and access (Table 2). There are no specific clinical indicators for CMD in postmenopausal women and we lack specific biomarkers for CMD in this population. Since, postmenopausal women comprise the majority of CMD patients, CMD-specific diagnostic tests should be developed along with universally accepted clinical criteria to identify these patients early, when they might still benefit from protective effects of HRT (Figure 3).

Therapeutic Strategies Only a few studies on drug effectiveness have been performed in patients with CMD. According to guidelines, pain relief is the first line of treatment. As secondary prevention, antiplatelet agents, statins, and beta-blockers and/or calcium channel blockers are prescribed unless contraindicated. In patients with CMD, symptoms often persist despite the full classic regimen of anti-ischemic therapy. Traditional treatment options of the CMD include heart rate reducing drugs, drugs that reduce coronary microvascular tone, drugs with positive effect on vascular remodeling, drugs acting on myocytes, dyslipidemia/antiplatelet/atherosclerosis/raised inflammatory markers (Figure 3) [53,54]. Based on epidemiological data supporting a role for the loss of estrogens during menopause, HRT use for women who recently had menopause onset might provide a means to prevent or even treat CMD. Several previous large prospective studies (e.g., the WHI study and the Heart and Estrogen/ progestin Replacement Study), showed that HRT was not beneficial on cardiovascular system. In these trials, HRT has shown to affect lipid profile and type 2 diabetes, but did not improve cardiovascular outcomes. By contrast, data obtained from the WHI review [55] and previous guidelines [56,57], suggested that decreased risk of CAD in women who initiate HRT when aged younger than 60 years and/or who are within 10 years of menopause onset had reduced risk of CAD. Absolute risks of cardiovascular disease events and all-cause mortality rates were found to be significantly lower in

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Table 2. Advantages and Disadvantages of Diagnostic Tests

Diagnostic tests Transthoracic echocardiography

Advantages

Disadvantages

Easy access

Echo contrast needed in suboptimal images

Considered very safe

Difficulties with image interpretation

Noninvasive

Dependent on the expertise and training of the

Real-time results and interpretation

operator

Inexpensive Single photon emission computed tomography

Standardized protocols Increased spatial resolution 3D imaging

Exposure the ionizing radiation Difficulties with image interpretation High cost and long scan time Suboptimal identification of multivessel coronary disease

Cardiovascular magnetic resonance

High spatial resolution Three-dimensional capabilities that enable imaging in any plane No ionizing radiation

Not yet widely available Not applicable to everyone (contrast related contra-indications or inability to image most patients with metal implants due to safety concerns) Limited functional determination in some clinical conditions A specific cut-off weight for patients High cost

Positron emission tomography

Flow quantitation Show activity within the body on a cellular level

Exposure the ionizing radiation Not yet widely available resolution of the scans is lower High cost

Coronary angiography(acetylcholine test and

Precise diagnose

adenosine test)

Gold standard

Complex and time consuming procedure Reduction of patient quality of life Require of trained personnel Exposure the ionizing radiation Carries procedural risk High cost

younger women than in older women. Timing hypothesis suggested that these women were postmenopausal for a number of years before estrogen was administered, and later estrogen therapy increased the risk of cardiovascular events and stroke due to negative impact of estrogen signaling on already formed atherosclerosis. Continuous treatment with estrogen might have a different cardiovascular outcome than readmission of estrogen after it reduces during the menopause period [58,59]. In addition to the timing hypothesis, it has been suggested that the effects of estrogens might depend on the age [60], as aging-related changes in the cardiovascular system may reduce the protective effects of estrogens [61]. Estrogens affect vascular smooth muscle cells and endothelial cells. Cardiovascular protective actions of estrogens can directly be observed on the vessel wall. The WISE study showed an improvement in clinical symptoms with low-dose estrogen treatment but there was no improvement in

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Patients with chest pain YES

ACS NO

Cardiac Stress Test Specific biomarker of CMD

CAG

YES

Obstructive CAD

Abnormal

YES

NO

NO

CFR IMR

Consider MBF AND CBF YES

Revascularization Medical Therapy Optimal CV risk factor therapy

Abnormal

Abnormal NO

Optimal management of CV risk factor Nonischemic noncardiac chest pain

YES

Microvascular disease subtyping Therapy of concomitant disease Optimal CV risk factor therapy

Male

Female

Premenopause

Drugs

Postmenopause

Standard of Care +HRT? Trends in Endocrinology & Metabolism

Figure 3. Modified Chest Pain Evaluation Diagram. Abbreviations: ACS, acute coronary syndrome; CAD, coronary artery disease; CAG, coronary angiography; CBF, cerebral blood flow; CFR, coronary flow reserve; CMD, coronary microvascular disease; IMR, index of microcirculatory resistance; MBF, myocardial blood flow.

measures of myocardial ischemia [62]. One of the recent clinical trials, 17-b-E2 and progestin combination resulted in the reduction of angina episodes and improved myocardial perfusion reserve [63]. Another study has showed that long-term HRT improved endothelial function of the coronary arteriolar vessels in postmenopausal women without coronary risk factors [64]. A recent prospective

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observational study showed that HRT with estrogen alone or in combination with a progesterone addition to standard management of cardiovascular risk factors may provide a beneficial effect on the vascular endothelium of the coronary microcirculation [65]. Another recent study reported that long-term HRT shows a strong association with lower coronary calcium score in comparison with women who had never used HRT [66]. E2 decreases production, vascular accumulation, and oxidation of low-density lipoprotein as well as the process of inflammation, which might affect microvasculature [67–69]. In addition to E2, tissue selective estrogen receptor modulators (SERMs) such as tamoxifen, raloxifene, and bazedoxifene, with estrogen-like activity were shown to have positive effects on flow-mediated dilation, metabolic function (glucose, insulin, and lipid homeostasis) and metabolic parameters [70–74]. Thus, HRT shows promise as a treatment for perimenopausal women or women who are a couple of years into menopause to manage cardiovascular disease.

Where Do We Go from Here? The studies that we reviewed in this article suggests a strong connection between estrogens (or lack thereof) and CMD. To our knowledge, there are no specific recent studies addressing the impact of estrogen receptor ligands or HRT on CMD. This is mainly due to the lack of specific preclinical models and insufficient knowledge of the molecular basis of CMD. Numerous studies addressed the impact of E2 on micro- and macrovascular systems as well as angiogenesis, suggesting that estrogen treatment might be a novel therapeutic modality in the management of arterial insufficiency once we stratify patients based on sex and menopausal status (Figure 3). Moreover, discovery of novel biomarkers of CMD could increase precision of patient selection for treatment decision and further follow up, improving quality of life and health outcomes for postmenopausal women with CMD. Thus, future studies are required to identify better diagnostic biomarkers for postmenopausal women with CMD and to delineate the role of estrogens and ER-dependent pathways in the etiology of CMD.

Concluding Remarks As life expectancy increases, the number of postmenopausal women is increasing and is estimated to be 1.1 billion by 2020. CMD is seen more frequently in postmenopausal women and prognosis is substantially poor. In clinical practice, there are numerous knowledge gaps for the evaluation, diagnosis, and treatment of these patients. There are no currently available biochemical testing methods. For this reason, patients cannot be diagnosed early, or are diagnosed with inconvenient and risky tests. Once diagnosed, patients are treated with nonspecific medications or are not treated at all. Advances in metabolomics and proteomics led to identification of circulating biomarkers for various chronic disease and in combination with preclinical models, these biomarkers hold promise in stratifying patients that would benefit from estrogen therapy. New knowledge that will be gained from preclinical or in vitro studies pave the path for novel therapeutic options. Future research is needed for identification of circulating CMD biomarkers that can guide diagnosis and therapy decisions (see Outstanding Questions). Moreover, the impact of estrogens and the role of estrogen receptor signaling in CMD prevention needs to be further studied to harness the therapeutic potential of HRT prescription to treat postmenopausal CMD patients (Figure 3) [75]. Overall, there is a clinical need for a better understanding of the underlying microvascular pathology to develop targeted, CMD-specific therapies and standardized methods of CMD diagnostic assessment for personalized medicine.

Acknowledgments This work was supported by grants from the University of Illinois, Office of the Vice Chancellor for Research, College of ACES FIRE grant (to Z.M-E.), National Institute of Food and Agriculture, US Department of Agriculture, award ILLU-698-909 (to Z.M-E.) and TUBITAK 2219 Post Doctorate Research Scholarship Program-1059B191601914 (to E.T.). We would like to thank Dr Mehmet Tokac, Eylem Kulkoyluoglu Cotul, and Brandi Smith for the critically reading of our manuscript.

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Outstanding Questions Are estrogen and estrogen signaling pathways important in the etiology of CMD? Can any biomarker be identified for use in the early diagnosis of the CMD? According to the most recent data and results, can estrogen or SERMs be added to the therapy options of postmenopausal CMD patients? Are estrogen and estrogen signaling pathways important in the etiology of CMD?

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References 1. Amsterdam, E.A. et al. (2014) 2014 AHA/ACC guideline for the management of patients with nonST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. J. Am. Coll. Cardiol. 64, e139–e228 2. Benjamin, E.J. et al. (2018) Heart disease and stroke statistics – 2018 update: a report from the American Heart Association. Circulation 137, e67– e492 3. Kwok, C.S. et al. (2019) Non-specific chest pain and subsequent serious cardiovascular readmissions. Int. J. Cardiol. 291, 1–7 4. Natsui, S. et al. (2019) Evaluation of outpatient cardiac stress testing after emergency department encounters for suspected acute coronary syndrome. Ann. Emerg. Med. 74, 216–223 5. Hoffmann, U. et al. (2017) Prognostic value of noninvasive cardiovascular testing in patients with stable chest pain: insights from the PROMISE trial (prospective multicenter imaging study for evaluation of chest pain). Circulation 135, 2320–2332 6. Safdar, B. and D’Onofrio, G. (2016) Women and chest pain: recognizing the different faces of angina in the emergency department. Yale J. Biol. Med. 89, 227–238 7. Fihn, S.D. et al. (2014) 2014 ACC/AHA/AATS/PCNA/ SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J. Ame. Coll. Cardiol. 64, 1929–1949 8. Mommersteeg, P.M.C. et al. (2017) Impaired health status, psychological distress, and personality in women and men with nonobstructive coronary artery disease: sex and gender differences: the TWIST (Tweesteden Mild Stenosis) Study. Circ. Cardiovasc. Qual. Outcomes 10, e003387 9. Sara, J.D. et al. (2015) Prevalence of coronary microvascular dysfunction among patients with chest pain and nonobstructive coronary artery disease. JACC Cardiovasc. Interv. 8, 1445–1453 10. Reis, S.E. et al. (2001) Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: results from the NHLBI WISE study. Am. Heart J. 141, 735–741 11. Murthy, V.L. et al. (2014) Effects of sex on coronary microvascular dysfunction and cardiac outcomes. Circulation 129, 2518–2527 12. Brainin, P. et al. (2018) The prognostic value of coronary endothelial and microvascular dysfunction in subjects with normal or non-obstructive coronary artery disease: a systematic review and metaanalysis. Int. J. Cardiol. 254, 1–9 13. Sedlak, T.L. et al. (2013) Sex differences in clinical outcomes in patients with stable angina and no obstructive coronary artery disease. Am. Heart J. 166, 38–44 14. Sharaf, B. et al. (2013) Adverse outcomes among women presenting with signs and symptoms of ischemia and no obstructive coronary artery disease: findings from the National Heart, Lung, and Blood Institute–sponsored Women’s Ischemia Syndrome Evaluation (WISE) angiographic core laboratory. Am. Heart J. 166, 134–141 15. Radico, F. et al. (2014) Angina pectoris and myocardial ischemia in the absence of obstructive

16. 17.

18. 19.

20.

21. 22. 23. 24. 25.

26.

27. 28.

29.

30.

31.

32. 33.

34. 35.

coronary artery disease: practical considerations for diagnostic tests. JACC Cardiovasc. Interv. 7, 453–463 Lee, B.K. et al. (2015) Invasive evaluation of patients with angina in the absence of obstructive coronary artery disease. Circulation 131, 1054–1060 Safdar, B. et al. (2018) Prevalence and characteristics of coronary microvascular dysfunction among chest pain patients in the emergency department. Eur. Heart J. Acute Cardiovasc. Care, 2048872618764418. Haasenritter, J. et al. (2015) Causes of chest pain in primary care – a systematic review and meta-analysis. Croat. Med. J. 56, 422–430 Laureano-Phillips, J. et al. (2019) HEART score risk stratification of low-risk chest pain patients in the emergency department: a systematic review and meta-analysis. Ann. Emerg. Med. 74, 187–203 Corcoran, D. et al. (2018) Coronary microvascular dysfunction in patients with stable coronary artery disease: the CE-MARC 2 coronary physiology substudy. Int. J. Cardiol. 266, 7–14 Crea, F. et al. (2014) Coronary microvascular dysfunction: an update. Eur. Heart J. 35, 1101–1111 Beltrame, J.F. et al. (2009) Advances in coronary microvascular dysfunction. Heart Lung Circ. 18, 19–27 Ong, P. et al. (2018) International standardization of diagnostic criteria for microvascular angina. Int. J. Cardiol. 250, 16–20 Duncker, D.J. et al. (2015) Regulation of coronary blood flow in health and ischemic heart disease. Prog. Cardiovasc. Dis. 57, 409–422 Feher, A. and Sinusas, A.J. (2017) Quantitative assessment of coronary microvascular function: dynamic single-photon emission computed tomography, positron emission tomography, ultrasound, computed tomography, and magnetic resonance imaging. Circ. Cardiovasc. Imaging 10, e006427 Barton, M. et al. (2018) Twenty years of the G proteincoupled estrogen receptor GPER: historical and personal perspectives. J. Steroid Biochem. Mol. Biol. 176, 4–15 Burns, K.A. and Korach, K.S. (2012) Estrogen receptors and human disease: an update. Arch. Toxicol. 86, 1491–1504 Madak-Erdogan, Z. et al. (2011) Genomic collaboration of estrogen receptor alpha and extracellular signal-regulated kinase 2 in regulating gene and proliferation programs. Mol. Cell. Biol. 31, 226–236 Madak-Erdogan, Z. et al. (2008) Nuclear and extranuclear pathway inputs in the regulation of global gene expression by estrogen receptors. Mol. Endocrinol. 22, 2116–2127 Madak-Erdogan, Z. et al. (2013) Integrative genomics of gene and metabolic regulation by estrogen receptors a and b, and their coregulators. Mol. Syst. Biol. 9, 676 Stender, J.D. et al. (2010) Genome-wide analysis of estrogen receptor alpha DNA binding and tethering mechanisms identifies Runx1 as a novel tethering factor in receptor-mediated transcriptional activation. Mol. Cell. Biol. 30, 3943–3955 Bologa, C.G. et al. (2006) Virtual and biomolecular screening converge on a selective agonist for GPR30. Nat. Chem. Biol. 2, 207 Deschamps, A.M. et al. (2010) Estrogen receptor activation and cardioprotection in ischemia reperfusion injury. Trends Cardiovasc. Med. 20, 73–78 Knowlton, A.A. and Lee, A.R. (2012) Estrogen and the cardiovascular system. Pharmacol. Ther. 135, 54–70 Chambliss, K.L. et al. (2010) Non-nuclear estrogen receptor a signaling promotes cardiovascular

Trends in Endocrinology & Metabolism, --, Vol. --, No. --

9

Please cite this article in press as: Tunc et al., Coronary Microvascular Dysfunction and Estrogen Receptor Signaling, Trends in Endocrinology & Metabolism (2019), https://doi.org/10.1016/j.tem.2019.11.001

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36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48. 49.

50. 51. 52.

53.

10

protection but not uterine or breast cancer growth in mice. J. Clin. Invest. 120, 2319–2330 Mattingly, K.A. et al. (2008) Estradiol stimulates transcription of nuclear respiratory factor-1 and increases mitochondrial biogenesis. Mol. Endocrinol. 22, 609–622 Yen, C.H. et al. (2001) 17b-Estradiol inhibits oxidized low density lipoprotein-induced generation of reactive oxygen species in endothelial cells. Life Sci. 70, 403–413 Collins, P. et al. (1994) Nitric oxide accounts for dosedependent estrogen-mediated coronary relaxation after acute estrogen withdrawal. Circulation 90, 1964–1968 Pepine, C.J. et al. (2010) Coronary microvascular reactivity to adenosine predicts adverse outcome in women evaluated for suspected ischemia: results from the National Heart, Lung and Blood Institute WISE (Women’s Ischemia Syndrome Evaluation) Study. J. Am. Coll. Cardiol. 55, 2825–2832 Shaw, L.J. et al. (2006) Insights from the NHLBISponsored Women’s Ischemia Syndrome Evaluation (WISE) Study: part I: gender differences in traditional and novel risk factors, symptom evaluation, and gender-optimized diagnostic strategies. J. Am. Coll. Cardiol. 47, S4–S20 Tarhouni, K. et al. (2016) Estrogens are needed for the improvement in endothelium-mediated dilation induced by a chronic increase in blood flow in rat mesenteric arteries. Vasc. Pharmacol. 80, 35–42 Chen, Z. et al. (1999) Estrogen receptor alpha mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. J. Clin. Invest. 103, 401–406 Darkow, D.J. et al. (1997) Estrogen relaxation of coronary artery smooth muscle is mediated by nitric oxide and cGMP. Am. J. Physiol. Heart Circ. Physiol. 272, H2765–H2773 Li, L. et al. (2003) Plasma membrane localization and function of the estrogen receptor alpha variant (ER46) in human endothelial cells. Proc. Natl. Acad. Sci. U. S. A. 100, 4807–4812 Hill, B.J.F. et al. (2017) 17b-estradiol reduces Cav1.2 channel abundance and attenuates Ca2+dependent contractions in coronary arteries. Pharmacol. Res. Perspect. 5, e00358 Mazzuca, M.Q. et al. (2015) Estrogen receptor subtypes mediate distinct microvascular dilation and reduction in [Ca2+]I in mesenteric microvessels of female rat. J. Pharmacol. Exp. Therap. 352, 291–304 Kim, J.K. et al. (2006) Estrogen prevents cardiomyocyte apoptosis through inhibition of reactive oxygen species and differential regulation of p38 kinase isoforms. J. Biol. Chem. 281, 6760–6767 Manson, J.E. et al. (2007) Estrogen therapy and coronary-artery calcification. N. Engl. J. Med. 356, 2591–2602 Li, G. et al. (2000) Estrogen attenuates integrin-b3– dependent adventitial fibroblast migration after inhibition of osteopontin production in vascular smooth muscle cells. Circulation 101, 2949–2955 Scuteri, A. et al. (2001) Effect of estrogen and progestin replacement on arterial stiffness indices in postmenopausal women. Aging (Milano) 13, 122–130 Kato, S. et al. (2017) Stress perfusion coronary flow reserve versus cardiac magnetic resonance for known or suspected CAD. J. Am. Coll. Cardiol. 70, 869–879 Yong, A.S. et al. (2013) Calculation of the index of microcirculatory resistance without coronary wedge pressure measurement in the presence of epicardial stenosis. JACC Cardiovasc. Interv. 6, 53–58 Athanasiadis, A. et al. (2015) Pharmacotherapy for coronary microvascular dysfunction. Eur. Heart J. 1, 65–71

54. Task Force, M. et al. (2013) 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur. Heart J. 34, 2949–3003 55. Cobin, R.H. and Goodman, N.F. (2017) American Association of Clinical Endocrinologists and American College of Endocrinology Position Statement on Menopause – 2017 update. Endocr. Pract. 23, 869–880 56. The NAMS 2017 Hormone Therapy Position Statement Advisory Panel (2017) The 2017 hormone therapy position statement of The North American Menopause Society. Menopause 24, 728–753 57. Gompel, A. et al. (2015) Treatment of symptoms of the menopause: an Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 100, 3975–4011 58. Hodis, H.N. et al. (2015) Methods and baseline cardiovascular data from the Early versus Late Intervention Trial with estradiol testing the menopausal hormone timing hypothesis. Menopause (New York, N.Y.) 22, 391–401 59. Giordano, S. et al. (2015) Estrogen and cardiovascular disease: is timing everything? Am. J. Med. Sci. 350, 27–35 60. Bowling, M.R. et al. (2014) Estrogen effects on vascular inflammation are age dependent: role of estrogen receptors. Arteriosc. Thromb. Vasc. Biol. 34, 1477–1485 61. Nicholson, C.J. et al. (2017) Estrogenic vascular effects are diminished by chronological aging. Sci. Rep. 7, 12153 62. Bairey Merz, C.N. et al. (2010) A randomized controlled trial of low dose hormone therapy on myocardial ischemia in postmenopausal women with no obstructive coronary artery disease: results from the National Institutes of Health – National Heart, Lung, and Blood Institute (NHLBI) – Sponsored Women’s Ischemia Syndrome Evaluation (WISE). Am. Heart J. 159, 987.e1–987.e7 63. Knuuti, J. et al. (2007) Effect of estradioldrospirenone hormone treatment on myocardial perfusion reserve in postmenopausal women with angina pectoris. Am. J. Cardiol. 99, 1648–1652 64. Campisi, R. et al. (2002) Noninvasive assessment of coronary microcirculatory function in postmenopausal women and effects of short-term and long-term estrogen administration. Circulation 105, 425–430 65. Schindler, T.H. et al. (2009) Effect of hormone replacement therapy on vasomotor function of the coronary microcirculation in post-menopausal women with medically treated cardiovascular risk factors. Eur. Heart J. 30, 978–986 66. Gudmundsson, A. et al. (2017) Long-term hormone replacement therapy is associated with low coronary artery calcium levels in a cohort of older women: the Age, Gene/Environment Susceptibility-Reykjavik Study. J. Am. Geriatr. Soc. 65, 200–206 67. Kim, J.H. et al. (2014) Tissue-selective estrogen complexes with bazedoxifene prevent metabolic dysfunction in female mice. Mol. Metab. 3, 177–190 68. Mauvais-Jarvis, F. et al. (2013) The role of estrogens in control of energy balance and glucose homeostasis. Endocr. Rev. 34, 309–338 69. Gordon, F.K. et al. (2014) Research resource: aortaand liver-specific ERa-binding patterns and gene regulation by estrogen. Mol. Endocrinol. 28, 1337– 1351 70. Xu, B. et al. (2017) The effect of selective estrogen receptor modulators on type 2 diabetes onset in women: basic and clinical insights. J. Diabetes Complications 31, 773–779

Trends in Endocrinology & Metabolism, --, Vol. --, No. --

Please cite this article in press as: Tunc et al., Coronary Microvascular Dysfunction and Estrogen Receptor Signaling, Trends in Endocrinology & Metabolism (2019), https://doi.org/10.1016/j.tem.2019.11.001

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71. Xu, B. et al. (2016) Effect of selective estrogen receptor modulators on metabolic homeostasis. Biochimie 124, 92–97 72. Kim, J.H. et al. (2014) Tissue-selective estrogen complexes with bazedoxifene prevent metabolic dysfunction in female mice. Mol. Metab. 3, 177–190 73. Arnal, J.-F. et al. (2017) Membrane and nuclear estrogen receptor alpha actions: from tissue specificity to medical implications. Physiol. Rev. 97, 1045–1087

74. Barrera, J. et al. (2014) Bazedoxifene and conjugated estrogen prevent diet-induced obesity, hepatic steatosis, and type 2 diabetes in mice without impacting the reproductive tract. Am. J. Physiol. Endocrinol. Metab. 307, E345–E354 75. Lerman, A. et al. (2012) Coronary microvascular dysfunction in the clinical setting: from mystery to reality. Eur. Heart J. 33, 2771–2783

Trends in Endocrinology & Metabolism, --, Vol. --, No. --

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