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1
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Chen S, Yang L, Xue J, Tian X, Hu H, Gao Q, Feng R, Hao L. Effect of estrogen on myocardial ischemia-reperfusion injury in male and female rats and related mechanism. Steroids 2025; 214:109561. [PMID: 39870188 DOI: 10.1016/j.steroids.2025.109561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 12/06/2024] [Accepted: 01/21/2025] [Indexed: 01/29/2025]
Abstract
Due to the difference of estrogen levels in different phases of estrous cycle, it is necessary to exclude the influence of endogenous estrogen when studying the cardiovascular effects of estrogen and its analogues. In this study, the ischemia/reperfusion (I/R) injury of isolated heart were investigated in female rats during different phases of estrous cycle with male rats as comparison. The results indicated that the estrogen content in blood of rats during metestrus and diestrus (MD) was lower than those during proestrus and estrous (PE). 17β-Estradiol (E2) at 10-8 M did not show significant effects on I/R injury in male rats and female rats during PE. However, E2 exerted an obviously protective effects against I/R injury on heart rate (HR), lactate dehydrogenase (LDH) and creatine kinase (CK) release in female rats during MD. Furthermore, E2 relieved I/R injury in female rats during MD by decreasing the infarct size and the expression level of p-CaMKII. The results suggested estrous cycles may influence on the extent of cardiac I/R injury due to the regulation of E2 on CaMKII expression level, providing an idea that the estrus cycle should be considered for animal model preparation and toxicity studies in estrogen and environmental hormone research.
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Affiliation(s)
- Sichong Chen
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Lijuan Yang
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Jiayao Xue
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Xinmiao Tian
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Huiyuan Hu
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Qinghua Gao
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Rui Feng
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang 110122, China.
| | - Liying Hao
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang 110122, China.
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2
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Martínez-Solano J, Martínez-Sellés M. Sudden Death in Men Versus Women with Heart Failure. Curr Heart Fail Rep 2023; 20:129-137. [PMID: 36881322 DOI: 10.1007/s11897-023-00596-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/22/2023] [Indexed: 03/08/2023]
Abstract
PURPOSE OF REVIEW Sudden cardiac death (SCD) represents the most feared complication of heart failure (HF). This review intends to provide insight on our current knowledge of sex differences in SCD mechanisms, prevention, and management in HF patients. RECENT FINDINGS Women with HF present a better prognosis than men and have a lower incidence of SCD, irrespective of the presence of ischemic heart disease and age. The influence of sex hormones, sex differences in intracellular calcium handling, and a differential myocardial remodeling may explain such a gap between men and women. Both HF drugs and ventricular arrhythmias ablation seems also useful for the management of women at risk of SCD, but special care must be taken with the use of antiarrhythmic QT-prolonging drugs. However, implantable cardioverter defibrillator (ICD) use has not been shown to be equally effective in women than men. Sex-specific recommendations regarding SCD in HF are still lacking due to the scarcity of information and the under-representation of women in clinical trials. Further investigation is required to provide specific risk stratification models in women. Cardiac magnetic resonance imaging, genetics development, and personalized medicine will probably play an increasing role in this evaluation.
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Affiliation(s)
- Jorge Martínez-Solano
- Servicio de Cardiología, Hospital General Universitario Gregorio Marañón, Calle Doctor Esquerdo, 46, 28007, Madrid, Spain
| | - Manuel Martínez-Sellés
- Servicio de Cardiología, Hospital General Universitario Gregorio Marañón, Calle Doctor Esquerdo, 46, 28007, Madrid, Spain. .,Universidad Europea, Universidad Complutense, Madrid, Spain.
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3
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Wei P, Long D, Tan Y, Xing W, Li X, Yang K, Liu H. Integrated Pharmacogenetics Analysis of the Three Fangjis Decoctions for Treating Arrhythmias Based on Molecular Network Patterns. Front Cardiovasc Med 2022; 8:726694. [PMID: 35004871 PMCID: PMC8739471 DOI: 10.3389/fcvm.2021.726694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 11/23/2021] [Indexed: 11/30/2022] Open
Abstract
Aim: To explore the diverse target distribution and variable mechanisms of different fangjis prescriptions when treating arrhythmias based on the systems pharmacology. Methods: The active ingredients and their corresponding targets were acquired from the three fangjis [Zhigancao Tang (ZT), Guizhigancao Longgumuli Tang (GLT), and Huanglian E'jiao Tang (HET)] and the arrhythmia-related genes were identified based on comprehensive database screening. Networks were constructed between the fangjis and arrhythmia and used to define arrhythmia modules. Common and differential gene targets were identified within the arrhythmia network modules and the cover rate (CR) matrix was applied to compare the contributions of the fangjis to the network and modules. Comparative pharmacogenetics analyses were then conducted to define the arrhythmia-related signaling pathways regulated by the fangjis prescriptions. Finally, the divergence and convergence points of the arrhythmia pathways were deciphered based on databases and the published literature. Results: A total of 187, 105, and 68 active ingredients and 1,139, 1,195, and 811 corresponding gene targets of the three fangjis were obtained and 102 arrhythmia-related genes were acquired. An arrhythmia network was constructed and subdivided into 4 modules. For the target distribution analysis, 65.4% of genes were regulated by the three fangjis within the arrhythmia network. ZT and GLT were more similar to each other, mainly regulated by module two, whereas HET was divided among all the modules. From the perspective of signal transduction, calcium-related pathways [calcium, cyclic guanosine 3′,5′-monophosphate (cGMP)-PKG, and cyclic adenosine 3′,5′-monophosphate (cAMP)] and endocrine system-related pathways (oxytocin signaling pathway and renin secretion pathways) were associated with all the three fangjis prescriptions. Nevertheless, heterogeneity existed between the biological processes and pathway distribution among the three prescriptions. GLT and HET were particularly inclined toward the conditions involving abnormal hormone secretion, whereas ZT tended toward renin-angiotensin-aldosterone system (RAAS) disorders. However, calcium signaling-related pathways prominently feature in the pharmacological activities of the decoctions. Experimental validation indicated that ZT, GLT, and HET significantly shortened the duration of ventricular arrhythmia (VA) and downregulated the expression of CALM2 and interleukin-6 (IL-6) messenger RNAs (mRNAs); GLT and HET downregulated the expression of CALM1 and NOS3 mRNAs; HET downregulated the expression of CRP mRNA. Conclusion: Comparing the various distributions of the three fangjis, pathways provide evidence with respect to precise applications toward individualized arrhythmia treatments.
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Affiliation(s)
- Penglu Wei
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Dehuai Long
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Yupei Tan
- Beijing University of Chinese Medicine, Beijing, China
| | - Wenlong Xing
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Xiang Li
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Kuo Yang
- School of Computer and Information Technology, Institute of Medical Intelligence, Beijing Jiaotong University, Beijing, China
| | - Hongxu Liu
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
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The Effects of Different Hormones on Supraventricular and Ventricular Premature Contractions in Healthy Premenopausal Women. Medicina (B Aires) 2021; 57:medicina57111154. [PMID: 34833372 PMCID: PMC8617862 DOI: 10.3390/medicina57111154] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 10/12/2021] [Accepted: 10/21/2021] [Indexed: 11/17/2022] Open
Abstract
Background and Objectives: The effects of gender differences on cardiac parameters have been well-established. In this study, we aimed to evaluate the possible associations of plasma levels of different sex hormones with premature atrial or ventricular contractions in premenopausal women. Materials and Methods: We conducted a prospective study which included women in late reproductive age who presented with palpitations during an eight-month period. A 12-lead electrocardiography, a transthoracic echocardiogram, blood samples, and 24-hour rhythm Holter were conducted on the third day of the menstrual cycle. Results Overall, 93 healthy premenopausal women with a median age of 42 years were enrolled. QTc interval was within normal limits in all patients. The 24 h range of premature atrial contractions (PACs) and premature ventricular contractions (PVCs) was 0–6450 and was 0–21,230, respectively. The median number of PVCs was 540 and the median number of PACs was 212, respectively. In total, 51 patients (54.8%) had a frequency of PVCs > 500/24 h and 37 patients (39.8%) had a frequency of PACs > 500/24 h, respectively. No statistically significant association was shown between any hormone and the frequency of PACs. Regarding PVCs, patients with a PVCs frequency > 500/24 h had higher estradiol levels compared to patients with PVCs less than 500/24 h (median 60 pg/mL versus 42 pg/mL, p = 0.02, OR: 1.01). No association was found between PVCs and other hormones. Conclusions: In premenopausal healthy women, higher estradiol levels are independently associated with increased PVCs. This suggests that estradiol in late reproductive stages may exert proarrhythmic effects.
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Kim SK, Bennett R, Ingles J, Kumar S, Zaman S. Arrhythmia in Cardiomyopathy: Sex and Gender Differences. Curr Heart Fail Rep 2021; 18:274-283. [PMID: 34549379 DOI: 10.1007/s11897-021-00531-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/22/2021] [Indexed: 10/20/2022]
Abstract
PURPOSE OF REVIEW There is emerging evidence for important sex differences in cardiac arrhythmias. In this up-to-date review, we summarise the differences in incidence, aetiology, treatment and prevention of ventricular arrhythmias (VAs) and sudden cardiac death (SCD) in women versus men, in the context of ischaemic and nonischaemic cardiomyopathies. RECENT FINDINGS The incidence of ventricular tachyarrhythmia and SCD is significantly lower in women than in men with ischaemic cardiomyopathy, whereas sex differences in nonischaemic cardiomyopathy are less clear. Women who receive a primary prevention implantable cardioverter-defibrillator (ICD) are less likely to receive appropriate activations, compared to men; however, such findings are limited by under-representation of women. Women with ischaemic cardiomyopathy have significantly lower incidence of VA and SCD compared to men and may not derive the same benefit from a primary prevention ICD. However, further clinical ICD studies are needed that ensure adequate female participation, in order to examine sex differences in outcomes in both ischaemic and nonischaemic cardiomyopathies.
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Affiliation(s)
- Sul Ki Kim
- Department of Cardiology, Westmead Hospital, Sydney, Australia
| | - Richard Bennett
- Department of Cardiology, Westmead Hospital, Sydney, Australia.,Westmead Applied Research Centre, The University of Sydney, Sydney, Australia
| | - Jodie Ingles
- Cardio Genomics Program At Centenary Institute, The University of Sydney, Sydney, Australia.,Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.,Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia
| | - Saurabh Kumar
- Department of Cardiology, Westmead Hospital, Sydney, Australia.,Westmead Applied Research Centre, The University of Sydney, Sydney, Australia
| | - Sarah Zaman
- Department of Cardiology, Westmead Hospital, Sydney, Australia. .,Westmead Applied Research Centre, The University of Sydney, Sydney, Australia.
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Butters A, Arnott C, Sweeting J, Winkel BG, Semsarian C, Ingles J. Sex Disparities in Sudden Cardiac Death. Circ Arrhythm Electrophysiol 2021; 14:e009834. [PMID: 34397259 DOI: 10.1161/circep.121.009834] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The overall incidence of sudden cardiac death is considerably lower among women than men, reflecting significant and often under-recognized sex differences. Women are older at time of sudden cardiac death, less likely to have a prior cardiac diagnosis, and less likely to have coronary artery disease identified on postmortem examination. They are more likely to experience their death at home, during sleep, and less likely witnessed. Women are also more likely to present in pulseless electrical activity or systole rather than ventricular fibrillation or ventricular tachycardia. Conversely, women are less likely to receive bystander cardiopulmonary resuscitation or receive cardiac intervention post-arrest. Underpinning sex disparities in sudden cardiac death is a paucity of women recruited to clinical trials, coupled with an overall lack of prespecified sex-disaggregated evidence. Thus, predominantly male-derived data form the basis of clinical guidelines. This review outlines the critical sex differences concerning epidemiology, cause, risk factors, prevention, and outcomes. We propose 4 broad areas of importance to consider: physiological, personal, community, and professional factors.
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Affiliation(s)
- Alexandra Butters
- Cardio Genomics Program at Centenary Institute (A.B., J.I.), The University of Sydney.,Faculty of Medicine and Health (A.B., C.S., J.I.), The University of Sydney
| | - Clare Arnott
- Department of Cardiology, Royal Prince Alfred Hospital (C.A., C.S., J.I.), Sydney, Australia.,The George Institute for Global Health (C.A.), Sydney, Australia
| | | | - Bo Gregers Winkel
- Department of Cardiology, Copenhagen University Hospital, Denmark (B.G.W.)
| | - Christopher Semsarian
- Faculty of Medicine and Health (A.B., C.S., J.I.), The University of Sydney.,Agnes Ginges Centre for Molecular Cardiology at Centenary Institute (C.S.), The University of Sydney.,Department of Cardiology, Royal Prince Alfred Hospital (C.A., C.S., J.I.), Sydney, Australia
| | - Jodie Ingles
- Cardio Genomics Program at Centenary Institute (A.B., J.I.), The University of Sydney.,Faculty of Medicine and Health (A.B., C.S., J.I.), The University of Sydney.,Department of Cardiology, Royal Prince Alfred Hospital (C.A., C.S., J.I.), Sydney, Australia
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7
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Bozdogan O, Bozcaarmutlu A, Kaya ST, Sapmaz C, Ozarslan TO, Eksioglu D, Yasar S. Decreasing myocardial estrogen receptors and antioxidant activity may be responsible for increasing ischemia- and reperfusion-induced ventricular arrhythmia in older female rats. Life Sci 2021; 271:119190. [PMID: 33571518 DOI: 10.1016/j.lfs.2021.119190] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 01/21/2021] [Accepted: 02/06/2021] [Indexed: 11/18/2022]
Abstract
AIMS This study aimed to investigate the relationship between ischemia- and reperfusion-induced arrhythmia and blood serum estrogen levels, myocardial estrogen receptor levels, antioxidant enzyme activities, and the effects of the estrogen receptor blocker, fulvestrant (ICI 182 780). MAIN METHODS A total of 102 female Sprague-Dawley rats of different ages (2-3, 6-7, 14-15, and 20-21 months) were used in this study. Myocardial ischemia was produced by ligation of the descending branch of the left anterior descending coronary artery, and reperfusion was produced by releasing this artery. An electrocardiogram (ECG) and blood pressure were recorded for 6 min of ischemia and 6 min of reperfusion. The levels of superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT), estrogen receptor α (ERα), and estrogen receptor β (ERβ) in myocardial tissue and 17 beta-estradiol (E2) in blood serum were measured via enzyme-linked immunosorbent assay (ELISA). The results were compared using a Mann-Whitney U test, one-way analysis of variance (ANOVA), and a student's t-test. KEY FINDINGS It is not the changes in serum estrogen levels but the decreasing myocardial estrogen receptors and antioxidant activities that could be responsible for the occurrence of more severe arrhythmia in response to reperfusion in older female rats. SIGNIFICANCE The death rate due to a heart attack in younger men is higher than in women. However, it equalizes after the menopausal stage in women. In this study, the reason for the increasing sudden post-menopausal death rate in women was investigated experimentally.
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Affiliation(s)
- Omer Bozdogan
- Department of Biology, Faculty of Arts and Science, Bolu Abant Izzet Baysal University, Bolu, Turkey.
| | - Azra Bozcaarmutlu
- Department of Chemistry, Faculty of Arts and Science, Bolu Abant Izzet Baysal University, Bolu, Turkey
| | - Salih Tunc Kaya
- Department of Biology, Faculty of Arts and Science, Düzce University, Düzce, Turkey
| | - Canan Sapmaz
- Department of Chemistry, Faculty of Arts and Science, Bolu Abant Izzet Baysal University, Bolu, Turkey
| | - Talat Ogulcan Ozarslan
- Department of Infectious Diseases and Clinical Microbiology, Institute of Health Sciences, Bolu Abant Izzet Baysal University, Bolu, Turkey
| | - Didem Eksioglu
- Department of Biology, Faculty of Arts and Science, Bolu Abant Izzet Baysal University, Bolu, Turkey
| | - Selcuk Yasar
- Program of Medical Laboratory Techniques, Vocational School of Health Services, Istanbul Esenyurt University, Istanbul, Turkey
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8
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Wamboldt R, Haseeb S, Waddington A, Baranchuk A. Cardiac arrhythmias secondary to hormone therapy in trans women. Expert Rev Cardiovasc Ther 2019; 17:335-343. [PMID: 30987471 DOI: 10.1080/14779072.2019.1606713] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Introduction: With greater social acceptance and the evolution of transgender medicine as a specialty, more trans women are seeking hormone therapy (HT). Several studies have identified an increase in cardiovascular disease in trans women, however no studies have investigated the incidence of arrhythmias. Using two cases from the authors' clinic as examples, we propose that hormone therapy in trans women may increase the risk of cardiac arrhythmias. Areas covered: A literature search of sex hormones and cardiac arrhythmias was conducted. Using sex hormone studies completed in cis individuals and animal models we identified several similarities to trans women on HT. In cis men, low levels of testosterone are associated with increased rates of atrial fibrillation and right ventricular outflow tract arrhythmias. The role of estradiol remains less clear but there is evidence to suggest that the administration of exogenous estrogen may increase the rates of cardiac arrhythmias in cis women. Expert opinion: Research in the field of transgender medicine is expanding. As more trans women initiate HT, we will have a larger database from which to collect information regarding the benefits and risks of treatment, including the potential side effect of arrhythmias.
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Affiliation(s)
- Rachel Wamboldt
- a Division of Internal Medicine, Kingston Health Science Center , Queen's University , Kingston , Ontario , Canada
| | - Sohaib Haseeb
- b Division of Cardiology, Kingston Health Science Center , Queen's University , Kingston , Ontario , Canada
| | - Ashley Waddington
- c Department of Obstetrics & Gynecology, Kingston Health Science Center , Queen's University , Kingston , Ontario , Canada
| | - Adrian Baranchuk
- b Division of Cardiology, Kingston Health Science Center , Queen's University , Kingston , Ontario , Canada
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9
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Increased cardiac and stroke death risk in the first year after discontinuation of postmenopausal hormone therapy. Menopause 2018; 25:375-379. [DOI: 10.1097/gme.0000000000001023] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
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10
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Iorga A, Cunningham CM, Moazeni S, Ruffenach G, Umar S, Eghbali M. The protective role of estrogen and estrogen receptors in cardiovascular disease and the controversial use of estrogen therapy. Biol Sex Differ 2017; 8:33. [PMID: 29065927 PMCID: PMC5655818 DOI: 10.1186/s13293-017-0152-8] [Citation(s) in RCA: 522] [Impact Index Per Article: 65.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Accepted: 10/04/2017] [Indexed: 12/15/2022] Open
Abstract
Epidemiologic studies have previously suggested that premenopausal females have reduced incidence of cardiovascular disease (CVD) when compared to age-matched males, and the incidence and severity of CVD increases postmenopause. The lower incidence of cardiovascular disease in women during reproductive age is attributed at least in part to estrogen (E2). E2 binds to the traditional E2 receptors (ERs), estrogen receptor alpha (ERα), and estrogen receptor beta (ERβ), as well as the more recently identified G-protein-coupled ER (GPR30), and can exert both genomic and non-genomic actions. This review summarizes the protective role of E2 and its receptors in the cardiovascular system and discusses its underlying mechanisms with an emphasis on oxidative stress, fibrosis, angiogenesis, and vascular function. This review also presents the sexual dimorphic role of ERs in modulating E2 action in cardiovascular disease. The controversies surrounding the clinical use of exogenous E2 as a therapeutic agent for cardiovascular disease in women due to the possible risks of thrombotic events, cancers, and arrhythmia are also discussed. Endogenous local E2 biosynthesis from the conversion of testosterone to E2 via aromatase enzyme offers a novel therapeutic paradigm. Targeting specific ERs in the cardiovascular system may result in novel and possibly safer therapeutic options for cardiovascular protection.
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Affiliation(s)
- Andrea Iorga
- Present address: Department of Medicine, Division of Gastroenterology/Liver, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA
| | - Christine M Cunningham
- Department of Anesthesiology, Division of Molecular Medicine, David Geffen School of Medicine at University of California, Los Angeles, BH-160CHS, Los Angeles, CA, 90095-7115, USA
| | - Shayan Moazeni
- Department of Anesthesiology, Division of Molecular Medicine, David Geffen School of Medicine at University of California, Los Angeles, BH-160CHS, Los Angeles, CA, 90095-7115, USA
| | - Gregoire Ruffenach
- Department of Anesthesiology, Division of Molecular Medicine, David Geffen School of Medicine at University of California, Los Angeles, BH-160CHS, Los Angeles, CA, 90095-7115, USA
| | - Soban Umar
- Department of Anesthesiology, Division of Molecular Medicine, David Geffen School of Medicine at University of California, Los Angeles, BH-160CHS, Los Angeles, CA, 90095-7115, USA
| | - Mansoureh Eghbali
- Department of Anesthesiology, Division of Molecular Medicine, David Geffen School of Medicine at University of California, Los Angeles, BH-160CHS, Los Angeles, CA, 90095-7115, USA.
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11
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Blakemore J, Naftolin F. Aromatase: Contributions to Physiology and Disease in Women and Men. Physiology (Bethesda) 2017; 31:258-69. [PMID: 27252161 DOI: 10.1152/physiol.00054.2015] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Aromatase (estrogen synthetase; EC 1.14.14.1) catalyzes the demethylation of androgens' carbon 19, producing phenolic 18-carbon estrogens. Aromatase is most widely known for its roles in reproduction and reproductive system diseases, and as a target for inhibitor therapy in estrogen-sensitive diseases including cancer, endometriosis, and leiomyoma (141, 143). However, all tissues contain estrogen receptor-expressing cells, the majority of genes have a complete or partial estrogen response element that regulates their expression (61), and there are plentiful nonreceptor effects of estrogens (79); therefore, the effect of aromatase through the provision of estrogen is almost universal in terms of health and disease. This review will provide a brief but comprehensive overview of the enzyme, its role in steroidogenesis, the problems that arise with its functional mutations and mishaps, the roles in human physiology of aromatase and its product estrogens, its current clinical roles, and the effects of aromatase inhibitors. While much of the story is that of the consequences of the formation of its product estrogens, we also will address alternative enzymatic roles of aromatase as a demethylase or nonenzymatic actions of this versatile molecule. Although this short review is meant to be thorough, it is by no means exhaustive; rather, it is meant to reflect the cutting-edge, exciting properties and possibilities of this ancient enzyme and its products.
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12
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Regitz-Zagrosek V, Kararigas G. Mechanistic Pathways of Sex Differences in Cardiovascular Disease. Physiol Rev 2017; 97:1-37. [PMID: 27807199 DOI: 10.1152/physrev.00021.2015] [Citation(s) in RCA: 458] [Impact Index Per Article: 57.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Major differences between men and women exist in epidemiology, manifestation, pathophysiology, treatment, and outcome of cardiovascular diseases (CVD), such as coronary artery disease, pressure overload, hypertension, cardiomyopathy, and heart failure. Corresponding sex differences have been studied in a number of animal models, and mechanistic investigations have been undertaken to analyze the observed sex differences. We summarize the biological mechanisms of sex differences in CVD focusing on three main areas, i.e., genetic mechanisms, epigenetic mechanisms, as well as sex hormones and their receptors. We discuss relevant subtypes of sex hormone receptors, as well as genomic and nongenomic, activational and organizational effects of sex hormones. We describe the interaction of sex hormones with intracellular signaling relevant for cardiovascular cells and the cardiovascular system. Sex, sex hormones, and their receptors may affect a number of cellular processes by their synergistic action on multiple targets. We discuss in detail sex differences in organelle function and in biological processes. We conclude that there is a need for a more detailed understanding of sex differences and their underlying mechanisms, which holds the potential to design new drugs that target sex-specific cardiovascular mechanisms and affect phenotypes. The comparison of both sexes may lead to the identification of protective or maladaptive mechanisms in one sex that could serve as a novel therapeutic target in one sex or in both.
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Affiliation(s)
- Vera Regitz-Zagrosek
- Institute of Gender in Medicine & Center for Cardiovascular Research, Charite University Hospital, and DZHK (German Centre for Cardiovascular Research), Berlin, Germany
| | - Georgios Kararigas
- Institute of Gender in Medicine & Center for Cardiovascular Research, Charite University Hospital, and DZHK (German Centre for Cardiovascular Research), Berlin, Germany
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13
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Avula UMR, Noonavath M, Wan E. Gender Differences in Atrial Fibrillation. GENDER AND THE GENOME 2017. [DOI: 10.1089/gg.2016.0002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Affiliation(s)
- Uma Mahesh R. Avula
- Department of Medicine, Division of Cardiology, Columbia University, New York, New York
| | - Meghana Noonavath
- Department of Medicine, Division of Cardiology, Columbia University, New York, New York
| | - Elaine Wan
- Department of Medicine, Division of Cardiology, Columbia University, New York, New York
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14
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Avula U, Noonavath M, Wan E. Review Article: Gender Differences in Atrial Fibrillation. GENDER AND THE GENOME 2017. [DOI: 10.1177/247028971700100101] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
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15
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Shore R, Björne H, Omoto Y, Siemiatkowska A, Gustafsson JÅ, Lindblad M, Holm L. Sex differences and effects of oestrogen in rat gastric mucosal defence. World J Gastroenterol 2017; 23:426-436. [PMID: 28210078 PMCID: PMC5291847 DOI: 10.3748/wjg.v23.i3.426] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 10/05/2016] [Accepted: 10/19/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate sex differences and the effects of oestrogen administration in rat gastric mucosal defence.
METHODS Sex differences in gastric mucus thickness and accumulation rate, absolute gastric mucosal blood flow using microspheres, the integrity of the gastric mucosal epithelium in response to a chemical irritant and the effects of oestrogen administration on relative gastric mucosal blood flow in an acute setting was assessed in an in vivo rat experimental model. Subsequently, sex differences in the distribution of oestrogen receptors and calcitonin gene related peptide in the gastric mucosa of animals exposed to oestrogen in the above experiments was evaluated using immunohistochemistry.
RESULTS The absolute blood flow in the GI-tract was generally higher in males, but only significantly different in the corpus part of the stomach (1.12 ± 0.12 mL/min•g in males and 0.51 ± 0.03 mL/min•g in females) (P = 0.002). After removal of the loosely adherent mucus layer the thickness of the firmly adherent mucus layer in males and females was 79 ± 1 µm and 80 ± 3 µm respectively. After 60 min the mucus thickness increased to 113 ± 3 µm in males and 121 ± 3 µm in females with no statistically significant difference seen between the sexes. Following oestrogen administration (0.1 followed by 1 µg/kg•min), mean blood flow in the gastric mucosa decreased by 31% [68 ± 13 perfusion units (PFU)] in males which was significantly different compared to baseline (P = 0.02). In females however, mean blood flow remained largely unchanged with a 4% (5 ± 33 PFU) reduction. The permeability of the gastric mucosa increased to a higher level in females than in males (P = 0.01) after taurocholate challenge. However, the calculated mean clearance increase did not significantly differ between the sexes [0.1 ± 0.04 to 1.1 ± 0.1 mL/min•100 g in males and 0.4 ± 0.3 to 2.1 ± 0.3 mL/min•100 g in females (P = 0.065)]. There were no significant differences between 17β-Estradiol treated males (mean ratio of positive staining ± SEM) (0.06 ± 0.07) and females (0.11 ± 0.11) in the staining of ERα (P = 0.24). Also, there were no significant differences between 17β-Estradiol treated males (0.18 ± 0.21) and females (0.06 ± 0.12) in the staining of ERβ (P = 0.11). Finally, there were no significant differences between 17β-Estradiol treated males (0.04 ± 0.05) and females (0.11 ± 0.10) in the staining of CGRP (P = 0.14).
CONCLUSION Gastric mucosal blood flow is higher in male than in female rats and is reduced in male rats by oestrogen administration.
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G-protein coupled estrogen receptor-mediated non-genomic facilitatory effect of estrogen on cooling-induced reduction of skin blood flow in mice. Eur J Pharmacol 2017; 797:26-31. [PMID: 28089920 DOI: 10.1016/j.ejphar.2017.01.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Revised: 12/15/2016] [Accepted: 01/12/2017] [Indexed: 12/31/2022]
Abstract
An enhanced vasoconstrictor activity of cutaneous arteries participates in the reduction of skin blood flow induced by cooling stimulation. Raynaud's phenomenon, which is characterized by intense cooling-induced constriction of cutaneous arteries, is more common in women during the period from menarche to menopause. We thus investigated the effect of 17β-estradiol (E2) on cooling-induced reduction of plantar skin blood flow (PSBF) in mouse in vivo. Ovariectomized female ddY mice, anaesthetized with pentobarbital, were treated with tetrodotoxin for eliminating the sympathetic nerve tone and artificially ventilated. The PSBF was measured by laser Doppler flowmetry. Cooling air temperature around the foot from 25 to 20, 15, or 10°C decreased the PSBF in a temperature-dependent manner, which was suppressed by the specific α2C-adrenoceptor antagonist MK-912. When E2 was intravenously administered as a bolus followed by a constant infusion for 10min just before the cooling stimulation, the cooling-induced reduction of PSBF was facilitated by E2 in a dose-dependent manner. The facilitatory effect of E2 was not induced after the treatment with MK-912. Similar facilitatory effect was induced by an intravenous application of G-1, an agonist of G protein-coupled estrogen receptor (GPER, also termed GPR30). Moreover, the facilitatory effect of E2 was abolished by the GPER antagonist G15. These results suggest that acute administration of E2 leads to the facilitation of cooling-induced, α2C-adrenoceptor-mediated reduction of skin blood flow via the activation of the non-genomic estrogen receptor GPER.
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Salem JE, Alexandre J, Bachelot A, Funck-Brentano C. Influence of steroid hormones on ventricular repolarization. Pharmacol Ther 2016; 167:38-47. [PMID: 27452340 DOI: 10.1016/j.pharmthera.2016.07.005] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Accepted: 07/11/2016] [Indexed: 12/19/2022]
Abstract
QT interval prolongation, corrected for heart rate (QTc), either spontaneous or drug-induced, is associated with an increased risk of torsades de pointes and sudden death. Women have longer QTc than men and are at higher risk of torsades de pointes, particularly during post-partum and the follicular phase. Men with peripheral hypogonadism have longer QTc than healthy controls. The role of the main sex steroid hormones has been extensively studied with inconsistent findings. Overall, estradiol is considered to promote QTc lengthening while progesterone and testosterone shorten QTc. New findings suggest more complex regulation of QTc by sex steroid hormones involving gonadotropins (i.e. follicle-stimulating hormone), the relative concentrations of sex steroid hormones (which depends on gender, i.e., progesterone/estradiol ratio in women). Aldosterone, another structurally related steroid hormone, can also prolong ventricular repolarization in both sex. Better understanding of pathophysiological hormonal processes which may lead to increased susceptibility of women (and possibly hypogonadic men) to drug-induced arrhythmia may foster preventive treatments (e.g. progesterone in women). Exogenous hormonal intake might offer new therapeutic opportunities or, alternatively, increase the risk of torsades de pointes. Some exogenous sex steroids may also have paradoxical effects on ventricular repolarization. Lastly, variations of QTc in women linked to the menstrual cycle and sex hormone fluctuations are generally ignored in regulatory thorough QT studies. Investigators and regulatory agencies promoting inclusion of women in thorough QT studies should be aware of this source of variability especially when studying drugs over several days of administration.
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Affiliation(s)
- Joe-Elie Salem
- INSERM, CIC-1421 and UMR ICAN 1166, France; AP-HP, Pitié-Salpêtrière Hospital, Department of Pharmacology and CIC-1421, France; Sorbonne Universités, UPMC Univ Paris 06, Faculty of Medicine, France; Institute of Cardiometabolism and Nutrition (ICAN), F-75013 Paris, France
| | - Joachim Alexandre
- Normandie Université, France; EA 4650, Signalisation, Electrophysiologie et Imagerie des Lésions d'Ischémie-reperfusion Myocardique, France; Pharmacology Department, CHU Caen, F-14032 Caen, France
| | - Anne Bachelot
- AP-HP, Pitié-Salpêtrière Hospital, IE3M, Department of Endocrinology and Reproductive Medicine, and Centre de Référence des Maladies Endocriniennes Rares de la croissance et Centre des Pathologies gynécologiques Rares, and CIC-1421, F-75013 Paris, France
| | - Christian Funck-Brentano
- INSERM, CIC-1421 and UMR ICAN 1166, France; AP-HP, Pitié-Salpêtrière Hospital, Department of Pharmacology and CIC-1421, France; Sorbonne Universités, UPMC Univ Paris 06, Faculty of Medicine, France; Institute of Cardiometabolism and Nutrition (ICAN), F-75013 Paris, France.
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Dogan M, Yiginer O, Uz O, Kucuk U, Degirmencioglu G, Isilak Z, Uzun M, Davulcu E. The Effects of Female Sex Hormones on Ventricular Premature Beats and Repolarization Parameters in Physiological Menstrual Cycle. PACING AND CLINICAL ELECTROPHYSIOLOGY: PACE 2016; 39:418-26. [PMID: 26842421 DOI: 10.1111/pace.12821] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Revised: 01/11/2016] [Accepted: 01/11/2016] [Indexed: 11/30/2022]
Abstract
BACKGROUND The effects of gender difference on cardiac electrophysiology have been well studied. In this study, we aimed to evaluate the effects of estradiol and progesteron changes occuring in physiological menstrual cycle on ventricular premature beats (VPBs) and cardiac repolarization parameters. METHODS Women of reproductive age with VPBs were included into the study group and healthy women were recruited as the control group. During the menstruation period, a 12-lead electrocardiography, blood samples, and 24-hour rhythm Holter were applied to the study group. Similarly, all tests were repeated in the estimated ovulation period (12-14 days before menstruation) by all cases. RESULTS The study group consisted of 20 women patients with VPB, and the control group of 18 healthy women. While the number of VPB in the menstruation period was 210 beats/day (interquartile range [IQR]: 1,144), it decreased to 86 beats/day (IQR: 251) in the ovulation period with statistical significance (P < 0.05). Average heart rate in the menstruation period was 81.4 ± 10 beats/min and it significantly increased to 84.6 ± 8 beats/min in the ovulation period (P < 0.05). There were no differences in cardiac repolarization parameters in both menstruation and ovulation periods between the study and control groups. Comparing the menstruation and the ovulation periods, J-Tpeak interval, which reflects early repolarization, was shorter in the ovulation period (193 ± 27.7 ms and 201.1 ± 28.6 ms, respectively; P < 0.05). Other repolarization parameters did not show any significant difference. CONCLUSION VPB frequency decreases with estradiol peak in the ovulation period. This suggests that estrogen may have protective effects against ventricular arrhythmias.
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Affiliation(s)
- Mehmet Dogan
- Ankara Mevki Military Hospital, Department of Cardiology, Ankara, Turkey
| | - Omer Yiginer
- Haydarpasa Training Hospital, Department of Cardiology, Istanbul, Turkey
| | - Omer Uz
- Haydarpasa Training Hospital, Department of Cardiology, Istanbul, Turkey
| | - Ugur Kucuk
- Haydarpasa Training Hospital, Department of Cardiology, Istanbul, Turkey
| | | | - Zafer Isilak
- Haydarpasa Training Hospital, Department of Cardiology, Istanbul, Turkey
| | - Mehmet Uzun
- Haydarpasa Training Hospital, Department of Cardiology, Istanbul, Turkey
| | - Ezgi Davulcu
- Haydarpasa Training Hospital, Department of Cardiology, Istanbul, Turkey
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Efficacy of female rat models in translational cardiovascular aging research. J Aging Res 2014; 2014:153127. [PMID: 25610649 PMCID: PMC4294461 DOI: 10.1155/2014/153127] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Revised: 12/05/2014] [Accepted: 12/05/2014] [Indexed: 01/11/2023] Open
Abstract
Cardiovascular disease is the leading cause of death in women in the United States. Aging is a primary risk factor for the development of cardiovascular disease as well as cardiovascular-related morbidity and mortality. Aging is a universal process that all humans undergo; however, research in aging is limited by cost and time constraints. Therefore, most research in aging has been done in primates and rodents; however it is unknown how well the effects of aging in rat models translate into humans. To compound the complication of aging gender has also been indicated as a risk factor for various cardiovascular diseases. This review addresses the systemic pathophysiology of the cardiovascular system associated with aging and gender for aging research with regard to the applicability of rat derived data for translational application to human aging.
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Bell JR, Bernasochi GB, Varma U, Boon WC, Ellem SJ, Risbridger GP, Delbridge LMD. Aromatase transgenic upregulation modulates basal cardiac performance and the response to ischemic stress in male mice. Am J Physiol Heart Circ Physiol 2014; 306:H1265-74. [DOI: 10.1152/ajpheart.00012.2014] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Estrogen in females is conventionally considered a cardioprotective influence, but a role for estrogen in male cardioprotection has yet to be defined. Estrogen biosynthesis from testosterone is regulated by aromatase. Aromatase has recently been shown to be expressed in the adult heart, although little is known about its involvement in the regulation of myocardial function and stress responses. The goal of this study was to determine whether upregulation of tissue aromatase expression could improve ischemic resilience in male hearts. Isolated hearts from male transgenic aromatase-overexpressing (AROM+; high estrogen, low testosterone) mice and wild-type (WT) mice (12 wk) were Langendorff perfused and subjected to ischemia-reperfusion (25 min ischemia and 60 min of reperfusion). Basal systolic function was lower in AROM+ hearts (dP/d tmax: 4,121 ± 255 vs. 4,992 ± 283 mmHg/s, P < 0.05) and associated with augmented Akt phosphorylation, consistent with a suppressor action of estrogen on contractility. Ischemic contracture was attenuated in AROM+ hearts (43 ± 3 vs. 55 ± 4 mmHg, P < 0.05), yet AROM+ hearts were more arrhythmic in early reperfusion. At the end of 60 min of reperfusion, AROM+ systolic functional recovery was lower (left ventricular developed pressure: 39 ± 6 vs. 56 ± 5 %basal, P < 0.05) and diastolic dysfunction was accentuated (36 ± 4 vs. 24 ± 2 mmHg, P < 0.05). This is the first study to show that in vivo aromatase upregulation modulates basal cardiac performance and the response to ischemic stress. These data suggest that while chronic exposure to enhanced estrogenic influence may have benefits in limiting ischemic contracture severity, acute functional recovery in reperfusion is compromised. A temporally targeted, tissue-specific intervention combining aromatase treatment with inotropic support may offer therapeutic potential for men and women.
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Affiliation(s)
- James R. Bell
- Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia
| | | | - Upasna Varma
- Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia
| | - Wah Chin Boon
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia; and
| | - Stuart J. Ellem
- Prostate Cancer Research Program, Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia
| | - Gail P. Risbridger
- Prostate Cancer Research Program, Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia
| | - Lea M. D. Delbridge
- Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia
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DI FUSCO STEFANIAANGELA, PALAZZO STEFANO, COLIVICCHI FURIO, SANTINI MASSIMO. The Influence of Gender on Heart Rhythm Disease. PACING AND CLINICAL ELECTROPHYSIOLOGY: PACE 2014; 37:650-7. [DOI: 10.1111/pace.12369] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2013] [Revised: 01/11/2014] [Accepted: 01/17/2014] [Indexed: 01/08/2023]
Affiliation(s)
| | - STEFANO PALAZZO
- Cardiovascular Department; San Filippo Neri Hospital; Rome Italy
| | - FURIO COLIVICCHI
- Cardiovascular Department; San Filippo Neri Hospital; Rome Italy
| | - MASSIMO SANTINI
- Cardiovascular Department; San Filippo Neri Hospital; Rome Italy
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Bell JR, Bernasochi GB, Varma U, Raaijmakers AJA, Delbridge LMD. Sex and sex hormones in cardiac stress--mechanistic insights. J Steroid Biochem Mol Biol 2013; 137:124-35. [PMID: 23770428 DOI: 10.1016/j.jsbmb.2013.05.015] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2013] [Revised: 05/28/2013] [Accepted: 05/29/2013] [Indexed: 01/14/2023]
Abstract
Important sex differences in the onset and characteristics of cardiovascular disease are evident, yet the mechanistic details remain unresolved. Men are more susceptible to cardiovascular disease earlier in life, though younger women who have a cardiovascular event are more likely to experience adverse outcomes. Emerging evidence is prompting a re-examination of the conventional view that estrogen is protective and testosterone a liability. The heart expresses both androgen and estrogen receptors and is functionally responsive to circulating sex steroids. New evidence of cardiac aromatase expression indicates local estrogen production may also exert autocrine/paracrine actions in the heart. Cardiomyocyte contractility studies suggest testosterone and estrogen have contrasting inotropic actions, and modulate Ca(2+) handling and transient characteristics. Experimentally, sex differences are also evident in cardiac stress responses. Female hearts are generally less susceptible to acute ischemic damage and associated arrhythmias, and generally are more resistant to stress-induced hypertrophy and heart failure, attributed to the cardioprotective actions of estrogen. However, more recent data show that testosterone can also improve acute post-ischemic outcomes and facilitate myocardial function and survival in chronic post-infarction. The myocardial actions of sex steroids are complex and context dependent. A greater mechanistic understanding of the specific actions of systemic/local sex steroids in different cardiovascular disease states has potential to lead to the development of cardiac therapies targeted specifically for men and women.
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Affiliation(s)
- James R Bell
- Department of Physiology, University of Melbourne, Victoria, Australia.
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Hatcher AS, Clements-Jewery H. Susceptibility to ischemia-induced ventricular fibrillation in isolated female rat hearts varies moderately with estrous cycle stage. J Pharmacol Toxicol Methods 2013; 67:134-9. [DOI: 10.1016/j.vascn.2013.01.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2012] [Revised: 12/11/2012] [Accepted: 01/17/2013] [Indexed: 11/26/2022]
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Canpolat U, Tokgözoğlu L, Yorgun H, Bariş Kaya E, Murat Gürses K, Şahiner L, Bozdağ G, Kabakçi G, Oto A, Aytemir K. The association of premature ovarian failure with ventricular repolarization dynamics evaluated by QT dynamicity. Europace 2013; 15:1657-63. [PMID: 23592757 DOI: 10.1093/europace/eut093] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
AIMS The association between premature ovarian failure (POF) and cardiovascular diseases has been investigated in a few studies, but none have looked at ventricular repolarization abnormalities in these patients. In this study, we aimed to evaluate the ventricular repolarization by QT dynamicity in patients with POF. METHODS AND RESULTS We enrolled 26 female patients (mean age 37.5 ± 10.1 years) with primary POF and 31 healthy female subjects (mean age 37.5 ± 9.0 years). The linear regression slopes of the QT interval measured to the apex and to the end of the T-wave plotted against RR intervals (QTapex/RR and QTend/RR slopes, respectively) were calculated from 24 h Holter recordings using a standard algorithm. QTapex/RR and QTend/RR slopes were more steeper in the POF patients in contrary to healthy control subjects (QTapex/RR = 0.184 ± 0.022 vs. 0.131 ± 0.019, P < 0.001; QTend/RR = 0.164 ± 0.021 vs. 0.128 ± 0.018, P < 0.001). Pearson's correlation analyses revealed a stronger negative correlation between oestradiol (E2) and QTapex/RR (r = -0.715, P < 0.001). There was also a moderate negative correlation between E2 and QTend/RR (r = -0.537, P < 0.001). Serum follicle-stimulating hormone level was positively correlated with QTapex/RR (r = 0.681, P < 0.001) and QTend/RR (r = 0.531, P < 0.001). CONCLUSIONS Our study results suggest that QT dynamicity is impaired in patients with POF despite the absence of overt cardiovascular involvement. Further studies are needed to elucidate the prognostic significance and clinical implications of impaired ventricular repolarization in patients with POF.
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Affiliation(s)
- Uğur Canpolat
- Department of Cardiology, Faculty of Medicine, Hacettepe University, 06100 Sihhiye, Ankara, Turkey
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Fukumoto T, Tawa M, Yamashita N, Ohkita M, Matsumura Y. Protective effects of 17beta-estradiol on post-ischemic cardiac dysfunction and norepinephrine overflow through the non-genomic estrogen receptor/nitric oxide-mediated pathway in the rat heart. Eur J Pharmacol 2012; 699:74-80. [PMID: 23219795 DOI: 10.1016/j.ejphar.2012.11.042] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2012] [Revised: 11/15/2012] [Accepted: 11/23/2012] [Indexed: 11/27/2022]
Abstract
The present study was undertaken to examine the effect of acute treatment with 17β-estradiol on post-ischemic cardiac dysfunction and norepinephrine overflow and its possible mechanisms. Male rat hearts were perfused with the Langendorff method and subjected to 40 min of global ischemia followed by 30 min of reperfusion. Each drug was perfused from 15 min before ischemia to 5 min after reperfusion. During reperfusion, 17β-estradiol treatment showed significantly greater functional recovery of left ventricular developed pressure (LVDP), left ventricular end diastolic pressure (LVEDP), and dP/dt(max). Excessive norepinephrine release in coronary effluent from the post-ischemic heart was notably suppressed by treatment with 17β-estradiol. These beneficial effects of 17β-estradiol were not observed in the presence of the nitric oxide synthase inhibitor N(G)-nitro-l-arginine and estrogen receptor antagonist ICI 182,780 ((7α, 17β)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol), respectively. When NO(2)/NO(3) levels in coronary effluents after the onset of reperfusion were measured, reverse-correlation relationships between NO(2)/NO(3) production and ischemia/reperfusion-induced cardiac dysfunction, as well as norepinephrine overflow were observed. These findings suggest that 17β-estradiol exerts cardioprotective effects against ischemia/reperfusion-induced cardiac dysfunction, at least in part, by suppressing norepinephrine overflow, and that nitric oxide production via estrogen receptor activation plays a key role in this process.
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Affiliation(s)
- Taiki Fukumoto
- Laboratory of Pathological and Molecular Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka 569-1094, Japan
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Savergnini SQ, Reis AM, Santos RAS, Santos PEB, Ferreira AJ, Almeida AP. Effects of short-term administration of estradiol on reperfusion arrhythmias in rats of different ages. Braz J Med Biol Res 2012; 45:1248-54. [PMID: 23108785 PMCID: PMC3854225 DOI: 10.1590/s0100-879x2012007500169] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2012] [Accepted: 08/22/2012] [Indexed: 11/22/2022] Open
Abstract
Little is known about age-related differences in short-term effects of estradiol on ischemia-reperfusion (I/R) insults. The present study was designed to evaluate the effects of short-term treatment with estradiol on reperfusion arrhythmias in isolated hearts of 6-7-week-old and 12-14-month-old female rats. Wistar rats were sham-operated, ovariectomized and treated with vehicle or ovariectomized and treated with 17β-estradiol (E2; 5 µg·100 g−1·day−1) for 4 days. Hearts were perfused by the Langendorff technique. Reperfusion arrhythmias, i.e., ventricular tachycardia and/or ventricular fibrillation, were induced by 15 min of left coronary artery ligation and 30 min of reperfusion. The duration and incidence of I/R arrhythmias were significantly higher in young rats compared to middle-aged rats (arrhythmia severity index: 9.4 ± 1.0 vs 3.0 ± 0.3 arbitrary units, respectively, P < 0.05). In addition, middle-aged rats showed lower heart rate, systolic tension and coronary flow. Four-day E2 treatment caused an increase in uterine weight. Although E2 administration had no significant effect on the duration of I/R arrhythmias in middle-aged rats, it induced a marked reduction in the rhythm disturbances of young rats accompanied by a decrease in heart rate of isolated hearts. Also, this reduction was associated with an increase in QT interval. No significant changes were observed in the QT interval of middle-aged E2-treated rats. These data demonstrate that short-term estradiol treatment protects against I/R arrhythmias in hearts of young female rats. The anti-arrhythmogenic effect of estradiol might be related to a lengthening of the QT interval.
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Affiliation(s)
- S Q Savergnini
- Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil
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Jiang H, Hu X, Wang J. Estrogen replacement therapy for idiopathic outflow tract ventricular arrhythmias: a potential therapeutic approach. Med Hypotheses 2011; 78:144-5. [PMID: 22047984 DOI: 10.1016/j.mehy.2011.10.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2011] [Accepted: 10/11/2011] [Indexed: 11/26/2022]
Abstract
Idiopathic outflow tract ventricular arrhythmias (IOTVA), including left and right ventricular outflow tract, are dued to cyclic adenosine monophosphate (cAMP)-mediated calcium-dependent delayed after depolarizations. A growing body of evidence suggests that the changes of sex hormone levels and gender differences may affect ventricular repolarization and be associated with the occurrence of ventricular arrhythmias. Recent studies showed that the level of estradiol in the IOTVA male patients decreased significantly and the count of ventricular arrhythmias was significantly negatively correlated with the level of estradiol in male patients with IOTVA. Meanwhile, estrogen replacement therapy could inhibit significantly the count of ventricular arrhythmias in the postmenopausal patients with IOTVA. In conclusion, estrogen replacement therapy may be a potential therapeutic approach for IOTVA besides postmenopausal patients.
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Affiliation(s)
- Hong Jiang
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University, Wuhan, China.
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Druzin M, Malinina E, Grimsholm O, Johansson S. Mechanism of estradiol-induced block of voltage-gated K+ currents in rat medial preoptic neurons. PLoS One 2011; 6:e20213. [PMID: 21625454 PMCID: PMC3098870 DOI: 10.1371/journal.pone.0020213] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2011] [Accepted: 04/15/2011] [Indexed: 12/24/2022] Open
Abstract
The present study was conducted to characterize possible rapid effects of 17-β-estradiol on voltage-gated K+ channels in preoptic neurons and, in particular, to identify the mechanisms by which 17-β-estradiol affects the K+ channels. Whole-cell currents from dissociated rat preoptic neurons were studied by perforated-patch recording. 17-β-estradiol rapidly (within seconds) and reversibly reduced the K+ currents, showing an EC50 value of 9.7 µM. The effect was slightly voltage dependent, but independent of external Ca2+, and not sensitive to an estrogen-receptor blocker. Although 17-α-estradiol also significantly reduced the K+ currents, membrane-impermeant forms of estradiol did not reduce the K+ currents and other estrogens, testosterone and cholesterol were considerably less effective. The reduction induced by estradiol was overlapping with that of the KV-2-channel blocker r-stromatoxin-1. The time course of K+ current in 17-β-estradiol, with a time-dependent inhibition and a slight dependence on external K+, suggested an open-channel block mechanism. The properties of block were predicted from a computational model where 17-β-estradiol binds to open K+ channels. It was concluded that 17-β-estradiol rapidly reduces voltage-gated K+ currents in a way consistent with an open-channel block mechanism. This suggests a new mechanism for steroid action on ion channels.
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Affiliation(s)
- Michael Druzin
- Department of Integrative Medical Biology, Section for Physiology, Umeå University, Umeå, Sweden
| | - Evgenya Malinina
- Department of Integrative Medical Biology, Section for Physiology, Umeå University, Umeå, Sweden
| | - Ola Grimsholm
- Department of Integrative Medical Biology, Section for Physiology, Umeå University, Umeå, Sweden
| | - Staffan Johansson
- Department of Integrative Medical Biology, Section for Physiology, Umeå University, Umeå, Sweden
- * E-mail:
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Hu X, Wang J, Xu C, He B, Lu Z, Jiang H. Effect of oestrogen replacement therapy on idiopathic outflow tract ventricular arrhythmias in postmenopausal women. Arch Cardiovasc Dis 2011; 104:84-8. [DOI: 10.1016/j.acvd.2010.11.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2010] [Revised: 11/21/2010] [Accepted: 11/24/2010] [Indexed: 11/30/2022]
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Yang PC, Kurokawa J, Furukawa T, Clancy CE. Acute effects of sex steroid hormones on susceptibility to cardiac arrhythmias: a simulation study. PLoS Comput Biol 2010; 6:e1000658. [PMID: 20126530 PMCID: PMC2813260 DOI: 10.1371/journal.pcbi.1000658] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2009] [Accepted: 12/22/2009] [Indexed: 01/08/2023] Open
Abstract
Acute effects of sex steroid hormones likely contribute to the observation that post-pubescent males have shorter QT intervals than females. However, the specific role for hormones in modulating cardiac electrophysiological parameters and arrhythmia vulnerability is unclear. Here we use a computational modeling approach to incorporate experimentally measured effects of physiological concentrations of testosterone, estrogen and progesterone on cardiac ion channel targets. We then study the hormone effects on ventricular cell and tissue dynamics comprised of Faber-Rudy computational models. The “female” model predicts changes in action potential duration (APD) at different stages of the menstrual cycle that are consistent with clinically observed QT interval fluctuations. The “male” model predicts shortening of APD and QT interval at physiological testosterone concentrations. The model suggests increased susceptibility to drug-induced arrhythmia when estradiol levels are high, while testosterone and progesterone are apparently protective. Simulations predict the effects of sex steroid hormones on clinically observed QT intervals and reveal mechanisms of estrogen-mediated susceptibility to prolongation of QT interval. The simulations also indicate that acute effects of estrogen are not alone sufficient to cause arrhythmia triggers and explain the increased risk of females to Torsades de Pointes. Our results suggest that acute effects of sex steroid hormones on cardiac ion channels are sufficient to account for some aspects of gender specific susceptibility to long-QT linked arrhythmias. It is well known that female gender is an independent risk factor for some types of cardiac arrhythmias. However, it has been difficult to determine how much of a role physiological concentrations of circulating sex steroid hormones play in gender linked arrhythmia susceptibility because the cardiac system is so extraordinarily complex. Here we employ a computational strategy, based on experimental measurements, to tease out the individual contributions of estrogen, progesterone and testosterone on cardiac electrical behavior and then make predictions about their effects in combination and in the presence of drugs. The computational models convincingly reproduce observed fluctuations of QT intervals (as recorded on the ECG (electrocardiogram), the QT interval reflects the time period between ventricular excitation and relaxation) through the menstrual cycle in females and effects of testosterone on ECG parameters. Our simulations also predict that testosterone and progesterone are protective against drug-induced arrhythmias, while estrogen likely exacerbates the breakdown of normal cardiac electrical activity in the presence of QT-prolonging drugs.
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Affiliation(s)
- Pei-Chi Yang
- Department of Pharmacology, University of California, Davis, Davis, California, United States of America
| | - Junko Kurokawa
- Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tetsushi Furukawa
- Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Colleen E. Clancy
- Department of Pharmacology, University of California, Davis, Davis, California, United States of America
- * E-mail:
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Hu X, Jiang H, Xu C, Zhou X, Cui B, Lu Z. Relationship between sex hormones and idiopathic outflow tract ventricular arrhythmias in adult male patients. Transl Res 2009; 154:265-8. [PMID: 19840768 DOI: 10.1016/j.trsl.2009.07.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2009] [Revised: 06/22/2009] [Accepted: 07/20/2009] [Indexed: 11/18/2022]
Abstract
Sex hormones and gender differences have been reported to be associated with the occurrences of ventricular arrhythmias. This study investigated the relationship between sex hormones and idiopathic outflow tract ventricular arrhythmias (IOTVA) in adult male patients. Serum sex hormonal levels, which include testosterone, estradiol, and progestogen, were measured by using commercially prepared immunoassay kits. The average count of premature ventricular contractions (PVCs) (number/24h) was assessed by 72h electrocardiographic monitoring. No differences were found in the levels of testosterone and progestogen between the IOTVA male patients and the control males (both P>0.05). However, the level of estradiol in the IOTVA male patients was significantly lower than that in the control males (P<0.05). A significant negative correlation was observed between the number of PVCs and the level of estradiol in the IOTVA male patients (r=0.702, P<0.05). The current study suggested that IOTVA might be associated with the reduction of estradiol level in adult male patients.
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Affiliation(s)
- Xiaorong Hu
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University, Wuhan, China
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Mitochondrial benzodiazepine receptors mediate cardioprotection of estrogen against ischemic ventricular fibrillation. Pharmacol Res 2009; 60:61-7. [PMID: 19427588 DOI: 10.1016/j.phrs.2009.03.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2008] [Revised: 03/04/2009] [Accepted: 03/04/2009] [Indexed: 11/24/2022]
Abstract
The cardioprotective effects of estrogen remain controversial in clinical practice. Previous reports have shown that cardioprotective mechanisms converge on the mitochondria, but the role of mitochondria in estrogen's actions on cardiac arrhythmias is unclear. Here, we report that stimulation or inhibition of mitochondrial benzodiazepine receptors (mBzR) affected ventricular fibrillation (VF) almost in an "all-or-none" manner in an in vitro rat heart model of ischemic VF. Low concentrations of estrogen did not provide antiarrhythmic effects; however, the combination of mBzR activator and estrogen reduced VF incidence in hearts from either gender. Such synergistic actions also enabled cardiomyocytes to resist metabolic stress-induced intracellular [Ca(2+)](i) overload. Ligand binding experiments revealed that estrogen itself did not affect mBzR activity under basal conditions but promoted its up-regulation under myocardial ischemia. Our results suggest that mBzR may be an important molecule for ischemic arrhythmia and may act as a molecular switch for estrogen's antiarrhythmic effects. This finding provides a clue for elucidating the conflicting results regarding estrogen's cardiac effects in clinical studies and also suggests potential new strategies for hormone treatment in the female population.
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Drugs for men and women — How important is gender as a risk factor for TdP? Pharmacol Ther 2008; 119:186-94. [DOI: 10.1016/j.pharmthera.2008.03.005] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2008] [Accepted: 03/14/2008] [Indexed: 11/19/2022]
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Philp KL, Hart G, Coker SJ. A gender-independent proarrhythmic action of 17β-estradiol in anaesthetized rabbits. Eur J Pharmacol 2007; 575:113-21. [PMID: 17692839 DOI: 10.1016/j.ejphar.2007.07.035] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2007] [Revised: 06/27/2007] [Accepted: 07/04/2007] [Indexed: 11/16/2022]
Abstract
Women are at increased risk of having drug-induced arrhythmias such as torsade de pointes but less susceptible to arrhythmias associated with myocardial ischaemia. We have shown previously that 17beta-estradiol had greater antiarrhythmic activity in female rats than in male rats subject to myocardial ischaemia. The aim of this work was to investigate the effects of acute administration of 17beta-estradiol in both sexes in an established in vivo model of drug-induced arrhythmias. In alpha(1)-adrenoceptor-stimulated, pentobarbital-anaesthetized rabbits, 17beta-estradiol (100, 300 or 1000 ng/kg bolus followed by 10, 30 or 100 ng/kg/min infusion) tended to increase the incidence of torsade de pointes, induced by clofilium, in both sexes: from 50% in controls to 80%, 70% and 80% in females; from 40% in controls to 60%, 70% and 80% in males with increasing doses of 17beta-estradiol (n=10 per group). The total duration of all episodes of torsade de pointes was increased significantly by the highest dose of 17beta-estradiol compared to vehicle in both female and male rabbits: from 9+/-4 s to 93+/-26 s in females; from 26+/-14 s to 96+/-20 s in males. There were no baseline differences between the sexes in heart rate, QTc interval or epicardial monophasic action potential duration. The proarrhythmic effect of acute administration of 17beta-estradiol in the alpha(1)-adrenoceptor-stimulated anaesthetized rabbit model was independent of gender. This indicates that the underlying mechanism differs from that involved in the gender-selective reduction of ischaemia-induced arrhythmias by 17beta-estradiol.
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Affiliation(s)
- Karen L Philp
- Department of Pharmacology and Therapeutics, The University of Liverpool, Liverpool, UK
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Abstract
The mechanisms by which gender affects cardiac electrophysiological parameters and alters the predisposition to certain arrhythmias are not well understood, although differences in the expression and function of ion channels and in the activation of the autonomic nervous system may contribute. In their study Philp and coworkers address the issue of the effect of 17beta-estradiol on ventricular vulnerability in a rat model of ischemia. Their data show that there is a dose-dependent antiarrhythmic activity of 17beta-estradiol administration with suppression ventricular premature beats, ventricular tachycardia and ventricular fibrillation during ischemia. Furthermore they show a dose-dependent blockage of I(CaL) by 17beta-estradiol which is again stronger in female than in male mice. They postulate that the shown gender-selective, concentration-dependent inhibition of I(CaL) is sufficient to account for the reduction in ischaemia-induced arrhythmia. With this data they have added important information on the influence of sex hormones on cardiac electrophysiology under pathophysiological conditions.
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Affiliation(s)
- T Korte
- Department of Cardiology, Medical School Hannover, Hannover, Germany.
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