Cardiology & Vascular Research

Author(s): J.G. Kingma Jr^*

Faculty of Medicine, Department of Medicine, Pavillon FerdinandVandry, 1050 Avenue de la Médecine, Québec, QC, G1V 0A6.

^*Correspondence:

JG Kingma jr, Centre de Recherche de l’Institut de Cardiologie et de Pneumologie de Québec - Université Laval, 2725, Chemin SainteFoy, Québec, Qc, G1V 4G5, Canada, Fax: (418) 656-4509.

Received: 27 Jan 2021; Accepted: 26 Feb 2022; Published: 02 Mar 2022

Citation: J.G. Kingma Jr. Sex Differences: Potential Impact in Vascular Physiopathology or Ischemic Heart Disease. Cardiol Vasc Res. 2022; 6(1): 1-9.

Introduction

Biological sex differences affect progression of cardiovascular disease. In men and women microvascular disease, epicardial atherosclerosis and endothelial dysfunction stimulate vessel remodeling leading to myocardial ischemia [1,2]. While men appear to be more susceptible to typical clinical vascular changes, women generally are at greater risk for atypical vascular disease [3]. Interestingly, women with ischemic heart disease (IHD) often present with no angiographic evidence of obstructive coronary artery disease (CAD) [4-7]. Whereas «female protection» against development of cardiovascular disease has been widely researched, numerous questions remain as to why, once CAD is manifest, clinical outcomes in women are worse [8].

Multiple comorbidities display sex differences with regard to onset, frequency, morbidity and mortality [9,10]. Sex-specific relationships for cardio metabolic diseases, including obesity and diabetes, remain largely unexplored. However, recent findings suggest that differences in disease sequelae occur in both men and women with underlying cardio metabolic disease [11]. In patients with chronic kidney disease symptoms may be more pervasive in females because of greater clinical use of diuretics particularly in older females [12]. Both sex and age are important modifiers of gene expression in the mammalian heart [13,14]. Heart size differs between males and females in relation to age, which contributes to variations in overall cardiac function. In men greater absolute values for left ventricle (LV) mass, wall thickness and cavity dimensions are reported [15,16]; however, relative wall thickness of the heart is not different [17]. For women an increase in LV wall thickness [18] and concentric remodeling [19,20] is observed and is often accompanied by marked LV diastolic dysfunction [21]. Systolic torsion and circumferential LV shortening also appears to be greater in women [22] and is probably related to greater pulsatile load and differential gene expression of extracellular matrix components [23-25]. While cardiac performance is dependent on cardiac work the pressure buffering properties of elastic arteries also plays an important role. As such, a compliant arterial system (i.e. from conductance arteries to the microvasculature) is required for optimal cardiovascular performance. Differences in micro vessel function between sexes is an important area of study since modulations in oxygen exchange at the cellular level in the heart is a risk factor for progression of IHD.

Ischemic heart disease involves an imbalance between myocardial oxygen supply and demand [26] and is caused by obstructive or non-obstructive atherosclerotic CAD, or myocardial ischemia (produced by micro vessel or endothelial dysfunction, vasomotor abnormalities, etc.) [27]. Patterns of cardiac remodeling caused by adverse cardiovascular events, vary between sexes during ageing. The debate over menopause versus biological ageing and their contribution to age-related cardiovascular risk is important and ongoing. Common cardiovascular risk factors (i.e. LDL cholesterol, apo-lipoprotein B, etc.) in women change in relation to age but not with menopause [28]. Data from the Framingham study suggest that cardiovascular risk status affects age at menopause but not vice- versa. As such, risk factor levels change during menopause likely because of a combination of chronologic ageing and menopausal transition. Significant correlations between post-menopausal status, average age of menopause or clinical outcomes were not evident from a meta-analysis [29]. Intrinsic non-hormonal factors that happen during a complete lifespan may also be more important than changes that occur during midlife [16,30,31] but overall, risk factor monitoring need to be prioritized for women [32,33].

For this review, we searched basic science and clinical papers using MEDLINE, PubMed and Google Scholar with the search terms: sex differences, vascular function, myocardial infarction, cell death and ischemic conditioning. Herein, we review the current literature describing sex-specific differences and its impact on pathogenesis of acute myocardial infarction, vascular function, cellular protection strategies and outcomes. We paid particular attention to biological sex (not gender domain), but understand that while mechanisms between gender identity and cardiovascular disease risk may be important they have not been clearly established [34].

Sex Hormones

Male and female sex hormones affect regulation of vascular function; however, their actions are not uniform between sexes. Expression or abundance of sex hormone receptors in vascular smooth muscle differs between males and females causing important variations in vascular function [35]. Receptors for various sex hormones (estrogen, progesterone, testosterone) are readily found in vascular endothelium and smooth muscle [36,37]. Interactions of sex hormones with nuclear/cytosolic receptors triggers numerous genomic effects mediated by activation of signalling pathways that can stimulate or inhibit cell growth and proliferation [38]. Estrogen or testosterone effects on vasoregulation (i.e. tone, elasticity, etc.) affect progression of cardiovascular disease; however, the overall effects of testosterone – generally believed to negatively affect the heart - on cardiac physiology are less studied therefore in a review we concentrate specifically on estrogen effects. Estrogen receptors are localized in myocardium, vascular endothelium, smooth muscle and adventitial cells [39]. Estrogen-mediated gene transcription involves direct binding to receptors within the nucleus [40]. Inhibition of estrogen receptor activity adversely affects both structural and functional remodeling in females, which has the potential to worsen cardiac dysfunction. Post-menopausal estrogen replacement therapy appears to reduce the incidence of adverse coronary events and associated mortality [41].

In females, estrogen: 1- modulates vascular tone via endothelin (ET-1) [42] and multiple nitric oxide (NO)-dependent [43] and independent [44] pathways and 2- affects vessel reactivity by stimulating NO release from endothelium [45]. Biological effects of ET-1 occur via activation of ETA or ETB receptor subtypes the ratio of which, and location, varies depending on the vascular bed (arteries > arterioles) [46]. Bolus intravenous ET-1 produces a biphasic response with an initial decrease (via NO and prostacyclin synthesis in ETB-stimulated endothelium [47,48]) followed by a long-term increase (mediated by ETA receptor subtypes in smooth muscle [49]) in vascular resistance. Findings from our laboratory reported that coronary resistance vessels in males are more sensitive to ET-1 [50]; these findings have been corroborated in mesenteric arteries from rats with spontaneous hypertension [51]. Age and phase of the menstrual cycle also play an important role in endothelial function [52]. DuPont and coworkers recently reported that vascular aging phenotypes, mediated by sexually dimorphic molecular mechanisms, occur later in females [53]. Modulation of vascular responses to ET-1 depends on age, sex and vessel type. For example, vessel responses to ET-1 are lower in aorta of females and resistance arterioles in males [51,54] but are greater in larger male coronary vessels [55]. Responses to endogenous ET-1 is therefore an important determinant for regulation of organ perfusion [56]. Furthermore, myogenic responses are known to be modified by local changes in NO production when estrogen levels are modified [44,45,57,58].

Endothelial dysfunction causes an increase in peripheral resistance consequent to greater release of ET-1 or by reduced synthesis of vascular relaxation factors. Higher circulating plasma ET-1 levels correlate with heart failure and IHD [59]. Production of NO in premenopausal women is greater than in men [60]. Thus, the balance between NO and ET-1 production (regulated through autocrine feedback mechanisms [61-63]) is critical for vasoregulation [64]; for example, reduced production of NO attenuates sensitivity of vascular smooth muscle to the effects of vasoconstrictor compounds [65,66]. In female rats subject to acute myocardial ischemia, treatment with estrogen has shown variable results [67]; however, blockade of estrogen receptors worsens ischemic injury [68,69].

Administration of estrogen to males, to induce post-ischemic protection, was inconclusive [70,71]. Treatment with sex hormones has been reported to restore endothelial function [72]. In ovariectomized rabbits, treated with either 17β-estradiol or DHEA (dehydroepiandrosterone), we reported significant improvement of myocardial perfusion [73]. Positive treatment effects were attributed to normalization (particularly at the level of the microvasculature where oxygen exchange at the cellular level is crucial) of the oxygen supply-demand equilibrium due to a shift in coronary pressure-flow parameters.

Vascular Physiopathology

Arteries are classified as being elastic or muscular and comprise distinct layers each with a different cellular composition (endothelial, smooth muscle, etc.) to ensure maximum functionality [74]. Vessel wall biology and vessel size differs between men and women but cellular or molecular mechanisms responsible have not been established. Sex hormones such as estrogen or other sex-specific factors that control vessel tone and size are potential candidates [75-77]. Vascular endothelium is involved in regulation of arterial tone, platelet function and inflammatory cell interactions, coagulation and vessel growth [78] via the synthesis/ release of a plethora of vasoactive compounds [79]. Patterns of vascular remodeling over time also differ between the sexes [16] and are caused by a host of risk factors [80]. In women with CAD, arterial wall thickness is greater [81] and abnormal endothelial and non-endothelium dependent vessel function is common [6,82,83] thereby increasing the risk for adverse short-term outcomes [79,84,85].

Protection against vascular disease has been in part, attributed to levels of sex hormones. The relation between endogenous estrogen and cardiovascular disease is documented [86] and studies investigating potential associations between circulating sex steroids, sex hormone interactions and development of CAD have provided variable findings [3,87]. Progression of heart failure in females is reportedly ovarian hormone dependent [40]. A recent review suggested that sex-related differences in regulation of the renin-angiotensin-aldosterone system by estrogen might be beneficial [88]. Mechanisms responsible for protection are not easy to evaluate but have previously been discussed [25].

Potential Consequences of Vascular Dysfunction

Ageing and prevalence of cardiovascular risk factors contribute to progressive ventricular and arterial stiffening and ultimately contribute to pathogenesis of heart failure. Of interest is that ventricular-arterial stiffening appears to be exacerbated in women, moreso in older women [89].

Arterial stiffness: Vascular ageing differs between sexes and affects overt cardiovascular disease risk. Molecular mechanisms that contribute to different manifestations of cardiovascular system ageing remain poorly understood [53,90,91]. Changes in vessel function due to ageing include endothelial dysfunction, which lead to arterial stiffness and ischemic heart disease; these contribute to increases in systolic blood pressure and pulse pressure [92]. Arterial stiffness is an emerging marker for adverse cardiovascular events [89]. In pre-menopausal women (compared to men of similar age) autonomic tone and baroreceptor responses are lower but overall vascular function is preserved [93,94]; however, progression of age-related arterial dysfunction occurs more rapidly in post- menopausal women [95]. In addition, subclinical alterations in arterial structure progress differently between the sexes. For example, risk factors such as carotid intima-media thickening, arterial calcification and atherosclerosis are more prevalent in younger men (compared to women of similar age) but with advancing age levels are analogous [96,97]. Atherosclerotic plaque characteristics (i.e. thin fibrous cap, lipid rich or necrotic core, etc.) also differ substantially between the sexes rendering men more susceptible to negative consequences of cardiovascular disease [98].

Pressure buffering properties of elastic arteries are essential for optimization of cardiac work as they allow for greater transfer of blood from the heart to the periphery while at the same time regulating undue fluctuations in pressure [89]. Aortic pulse wave analysis is generally used to evaluate arterial stiffness (in pre-clinical and clinical studies) [90]. When arterial stiffness is heightened the reflected wave travels faster and returns to the heart near systole resulting in higher systolic afterload and reduced diastolic coronary perfusion pressure [99]. Sex differences contribute to variations in development of arterial stiffness and higher pulse pressure, which are considered to be an important risk factor for development of cardiovascular disease [100]. The possibility that variations in morphometric (i.e. size, shape) and vessel anatomy between sexes may be responsible has been advanced [101,102] but this has not been clearly established at a mechanistic level [90]. Increased wall stress, left ventricular diastolic dysfunction and reduced ventricular- arterial coupling affects arterial stiffness more so in women [102-106]. Ventricular-arterial stiffening increases volume sensitivity whereby small changes in volume significantly augment systolic and pulse pressures.

Stability and compliance of the arterial wall requires a balance between extracellular matrix proteins such as elastin and collagen. Disruptions of this balance, which leads to arterial stiffening are exacerbated in the presence of cardiovascular risk factors [107]. Potential mechanisms of arterial stiffness include 1- alterations to extracellular matrix (i.e. augmented collagen deposition, increased elastin breakdown, etc.), 2- alterations to vascular smooth muscle cytoskeleton and 3- altered integrin and extracellular matrix interactions [108-110]. Various studies have described a role for vascular oxidative stress and increased production of oxygen radicals along with activation of angiotensin receptor mediated intracellular signalling. Unfortunately, most preclinical studies on age-related pathogenesis of arterial stiffness are limited to male subjects. Further studies to elucidate potential sex differences at the mechanistic level are essential; this might also be important for development and modification of treatment stratagems for women [111-113].

Ischemic heart disease: Ischemic heart disease continues to claim a disproportionate number of lives worldwide compared to other diseases. The incidence of acute myocardial infarction is significantly lower in pre-menopausal women (compared to age-matched men). As a result, clinical treatment for women with acute myocardial infarction is often less aggressive which might help to explain the higher mortality risk [114-116] and worse clinical outcome (compared to age-matched men) following acute myocardial infarction. Sex is independently associated with a higher risk of mortality [117,118] but its influence on prognosis in patients with IHD remains largely unexplored.

Acute myocardial ischemia (classified on the basis of electrocardiographic presentation) influences regional ST- segment profiles [119,120]; for instance, ST-segment elevation myocardial infarction (STEMI) is characterized by a ≥ 2 mm ST segment elevation and prominent T waves) while non-ST- segment elevation myocardial infarction (NSTEMI) consists of ST- segment depression with T wave inversion. STEMI is life threatening and time sensitive and requires rapid intervention to alleviate symptoms. European Society of Cardiology Guidelines for management of STEMI advise that females comprise a distinct subset and therefore require particular attention with regard to diagnosis and treatment [121]. A greater risk for net adverse clinical events has been reported in females with STEMI; however, these patients are often older and present with more comorbidities (i.e. hypertension, diabetes, chronic kidney disease, vascular disease, etc.) [122]. Thus, it is not clear that differences are real; they could be related to other factors including symptom-to-door or door-to-balloon times that are generally longer in women [123- 125]. A recent study from China, reported that long-term outcomes in female patients with STEMI were worse (compared to short- term data) [126]. Reasons for poorer outcomes in females with STEMI are multifactorial and include psychological stressors, intrinsic variations in angiogenesis, physiopathology of ischemic heart disease and sex hormone deficiency [126,127]. Finally, a prospective observational cohort study of females with STEMI from Sweden reported that sex was independently associated with reduced eGFR, a strong independent risk factor for short as well as long-term mortality.

Animal studies with acute myocardial infarction: In situ experimental findings from diverse animal species regarding effects of sex and myocardial infarction in relation to sex are equivocal [128-130] with some studies reporting reduced susceptibility to ischemic injury in females [128,131,132]. Indeed, post-ischemic incidence of cardiac arrhythmias, ventricular contractile dysfunction and necrosis are all reportedly mitigated in studies comparing females versus males [133-135].

Acute cellular injury caused by arterial obstruction stimulates release of a host of inflammatory mediators that participate in the development of organ dysfunction and post- ischemic remodeling. In both animal and human studies, production of pro-inflammatory cytokines varies between the sexes in response to cellular injury [136,137]. For example, post-ischemic activation of myocardial p38 MAPK (mitogen-activated protein kinase) differs in females and results in significantly decreased cytokine production [135]. Thus, subtle biochemical differences between sexes could affect ischemia-induced alterations at the cellular level. These differences in cardio protection might be related to release of other humoral factors that are known to activate intracellular signalling pathways.

Potential cardio protective strategies

Activation of endogenous cellular protection mechanisms post- injury have been under intense scrutiny since Murry et al published their paper on reduction of ischemic injury by preconditioning [138]. Exercise training (potential candidate for preconditioning) also has infarct-sparing effects; however, protection is variable between sexes [131,139-141]. For ischemic preconditioning, application of multiple, brief cycles of non-lethal ischemia followed by restoration of blood flow to the same vascular bed prior to a prolonged ischemic event significantly delays progression of cell death [138,142,143]. Conditioning-mediated protection, reported in all species studied including humans, may also be influenced by sex. In animal studies that compared the level of protection by ischemic conditioning between males and females infarct size was reduced less in the female heart [144-146]; however, recent findings suggest that sex may not be a determinant for conditioning mediated protection [147]. Multiple pathways that lead to reduced cellular injury may involve sex hormones. For instance, in mice, subject to global ischemia preceded by ischemic preconditioning, post-ischemic contractile function was only improved in older animals. However, this was not observed for males suggesting that both age and sex could be critical determinants of ischemic conditioning-mediated cytoprotection [132]. In clinical studies of remote conditioning, no differences between sexes with regard to biomarker release or infarct size have been reported to date [148- 151].

Conclusions

Activation of specific physiological mechanisms or intracellular signalling pathways that are involved in the pathogenesis of cellular injury in relation to sex have not been established. Regulation of blood perfusion, within the microvasculature, probably differs between the sexes and may contribute to early limitation, and later worsening of myocardial function with ageing. Improved understanding of these differences could be important for clinical diagnosis and treatment of women with vascular or ischemic heart disease. While female hearts are initially believed to be more resistant to ischemia-reperfusion injury compared to males, current data show that protection is age-dependent. Further studies need to address risk factors to understand how they may be responsible for increased morbidity and mortality particularly in older women. New clinical stratagems that tailor to the needs of women with acute myocardial infarction and its consequences are also required.

1. Pepine CJ, Ferdinand KC, Shaw LJ, et Emergence of Nonobstructive Coronary Artery Disease: A Woman's Problem and Need for Change in Definition on Angiography. J Am Coll Cardiol. 2015; 66: 1918-1933.
2. Mehta LS, Beckie TM, DeVon HA, et al. Acute Myocardial Infarction in Women: A Scientific Statement From the American Heart Circulation. 2016; 133: 916-947.
3. Wilmot KA, O'Flaherty M, Capewell S, et al. Coronary Heart Disease Mortality Declines in the United States From 1979 Through 2011: Evidence for Stagnation in Young Adults, Especially Women. Circulation. 2015; 132: 997-1002.
4. Groepenhoff F, Bots SH, Kessler EL, et Sex-Specific Aspects in the Pathophysiology and Imaging of Coronary Macro and Microvascular Disease. J Cardiovasc Transl Res. 2020; 13: 39- 46.
5. Parvand M, Rayner-Hartley E, Sedlak T. Recent Developments in Sex-Related Differences in Presentation, Prognosis, and Management of Coronary Artery Disease. Can J Cardiol. 2018; 34: 390-399.
6. Reis SE, Holubkov R, Conrad Smith AJ, et 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. 2001; 141: 735-741.
7. Jespersen L, Hvelplund A, Abildstrom SZ, et al. Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events. Eur Heart J. 2012; 33: 734-744.
8. Vaccarino V, Krumholz HM, Berkman LF, et Sex differences in mortality after myocardial infarction. Is there evidence for an increased risk for women?. Circulation. 1995; 91: 1861-1871.
9. Arnetz L, Ekberg NR, Alvarsson M. Sex differences in type 2 diabetes: focus on disease course and outcomes. Diabetes Metab Syndr Obes. 2014; 7: 409-420.
10. Bucholz EM, Butala NM, Rathore SS, et al. Sex differences in long-term mortality after myocardial infarction: a systematic Circulation. 2014; 130: 757-767.
11. Censin JC, Peters SAE, Bovijn J, et al. Causal relationships between obesity and the leading causes of death in women and PLoS Genet. 2019; 15: e1008405.
12. Russo G, Rea F, Barbati G, et al. Sex-related differences in chronic heart failure: a community-based study. J Cardiovasc 2021; 22: 36-44.
13. Isensee J, Witt H, Pregla R, et al. Sexually dimorphic gene expression in the heart of mice and men. J Mol Med (Berl). 2008; 86: 61-74.
14. Queiros AM, Eschen C, Fliegner D, et al. Sex- and estrogen- dependent regulation of a miRNA network in the healthy and hypertrophied Int J Cardiol. 2013; 169: 331-338.
15. Cheng S, Fernandes VR, Bluemke DA, et al. Age-related left ventricular remodeling and associated risk for cardiovascular outcomes: the Multi-Ethnic Study of Circ Cardiovasc Imaging. 2009; 2: 191-198.
16. Merz AA, Cheng S. Sex differences in cardiovascular ageing. 2016; 102: 825-831.
17. de Simone G, Devereux RB, Daniels SR, et Gender differences in left ventricular growth. Hypertension. 1995; 26: 979-983.
18. Cheng S, Xanthakis V, Sullivan LM, et Correlates of echocardiographic indices of cardiac remodeling over the adult life course: longitudinal observations from the Framingham Heart Study. Circulation. 2010; 122: 570-578.
19. Krumholz HM, Larson M, Levy D. Sex differences in cardiac adaptation to isolated systolic Am J Cardiol. 1993; 72: 310-313.
20. Lieb W, Xanthakis V, Sullivan LM, et al. Longitudinal tracking of left ventricular mass over the adult life course: clinical correlates of short- and long-term change in the framingham offspring study. Circulation. 2009; 119: 3085-3092.
21. Gori M, Lam CS, Gupta DK, et al. Sex-specific cardiovascular structure and function in heart failure with preserved ejection Eur J Heart Fail. 2014; 16: 535-542.
22. Yoneyama K, Gjesdal O, Choi EY, et Age, sex, and hypertension-related remodeling influences left ventricular torsion assessed by tagged cardiac magnetic resonance in asymptomatic individuals: the multi-ethnic study of atherosclerosis. Circulation. 2012; 126: 2481-2490.
23. Hayward CS, Kelly Gender-related differences in the central arterial pressure waveform. J Am Coll Cardiol. 1997; 30: 1863- 1871.
24. Gerdts E, Okin PM, de Simone G, et al. Gender differences in left ventricular structure and function during antihypertensive treatment: the Losartan Intervention for Endpoint Reduction in Hypertension Hypertension. 2008; 51: 1109-1114.
25. Regitz-Zagrosek V, Kararigas G. Mechanistic Pathways of Sex Differences in Cardiovascular Disease. Physiol Rev. 2017; 97: 1-37.
26. Bugiardini R, Bairey Merz CN. Angina with "normal" coronary arteries: a changing JAMA. 2005; 293: 477-484.
27. Shaw LJ, Bugiardini R, Merz CN. Women and ischemic heart disease: evolving J Am Coll Cardiol. 2009; 54: 1561-1575.
28. Matthews KA, Crawford SL, Chae CU, et al. Are changes in cardiovascular disease risk factors in midlife women due to chronological aging or to the menopausal transition?. J Am Coll 2009; 54: 2366-2373.
29. Atsma F, Bartelink ML, Grobbee DE, et al. Postmenopausal status and early menopause as independent risk factors for cardiovascular disease: a meta analysis. Menopause. 2006; 13: 265-279.
30. Guillaume M, Lapidus L, Lambert Differences in associations of familial and nutritional factors with serum lipids between boys and girls: the Luxembourg Child Study. Am J Clin Nutr. 2000; 72: 384-388.
31. Bohm B, Hartmann K, Buck M, et al. Sex differences of carotid intima media thickness in healthy children and Atherosclerosis. 2009; 206: 458-463.
32. Kok HS, van Asselt KM, van der Schouw YT, et Heart disease risk determines menopausal age rather than the reverse. J Am Coll Cardiol. 2006; 47: 1976-1983.
33. Mikkola TS, Gissler M, Merikukka M, et Sex differences in age-related cardiovascular mortality. PLoS One. 2013; 8: e63347.
34. Connelly PJ, Azizi Z, Alipour P, et The Importance of Gender to Understand Sex Differences in Cardiovascular Disease. Can J Cardiol. 2021; 37: 699-710.
35. Tamaya T, Wada K, Nakagawa M, et al. Sexual dimorphism of binding sites of testosterone and dihydrotestosterone in rabbit Comp Biochem Physiol Comp Physiol. 1993; 105: 745- 749.
36. Kim-Schulze S, McGowan KA, Hubchak SC, et al. Expression of an estrogen receptor by human coronary artery and umbilical vein endothelial Circulation. 1996; 94: 1402-1407.
37. Thompson J, Khalil Gender differences in the regulation of vascular tone. Clin Exp Pharmacol Physiol. 2003; 30: 1-15.
38. Orshal JM, Khalil Gender, sex hormones, and vascular tone. Am J Physiol Regul Integr Comp Physiol. 2004; 286: 233- 249.
39. Vitale C, Fini M, Speziale G, et Gender differences in the cardiovascular effects of sex hormones. Fundam Clin Pharmacol. 2010; 24: 675-685.
40. El Hajj MC, Ninh VK, El Hajj EC, et al. Estrogen receptor antagonism exacerbates cardiac structural and functional remodeling in female rats. Am J Physiol Heart Circ Physiol. 2017; 312: 98-105.
41. Ettinger B, Friedman GD, Bush T, et Reduced mortality associated with long-term postmenopausal estrogen therapy. Obstet Gynecol. 1996; 87: 6-12.
42. Leblanc AJ, Chen B, Dougherty PJ, et al. Divergent effects of aging and sex on vasoconstriction to endothelin in coronary 19 Microcirculation. 2013; 20: 365-376.
43. Lam CS, McEntegart M, Claggett B, et al. Sex differences in clinical characteristics and outcomes after myocardial infarction: insights from the Valsartan in Acute Myocardial Infarction Trial (VALIANT). Eur J Heart 2015; 17: 301-312.
44. Huang A, Sun D, Koller A, et al. Gender difference in myogenic tone of rat arterioles is due to estrogen-induced, enhanced release of American Journal of Physiology. 1997; 272: 1804-1809.
45. Moien-Afshari F, Kenyon E, Choy JC, et Long term effects of ovariectomy and estrogen replacement treatment on endothelial function in mature rats. Maturitas. 2003; 45: 213-223.
46. Wang Y, Kanatsuka H, Akai K, et Effects of low doses of endothelin-1 on basal vascular tone and autoregulatory vasodilation in canine coronary microcirculation in vivo. Jpn Circ J. 1999; 63: 617-623.
47. Berti F, Rossoni G, Della BD, et Nitric oxide and prostacyclin influence coronary vasomotor tone in perfused rabbit heart and modulate endothelin-1 activity. J CardiovascPharmacol. 1993; 22: 321-326.
48. Bird JE, Waldron TL, Dorso CR, et al. Effects of the endothelin (ET) receptor antagonist BQ 123 on initial and delayed vascular responses induced by ET-1 in conscious, normotensive rats. J 1993; 22: 69-73.
49. Brunner F, Bras-Silva C, Cerdeira AS, et Cardiovascular endothelins: essential regulators of cardiovascular homeostasis. Pharmacol Ther. 2006; 111: 508-531.
50. Kingma JG Jr, Laher I. Effect of endothelin on sex-dependent regulation of tone in coronary resistance Biochem Biophys Res Commun. 2021; 540: 56-60.
51. Gohar EY, Cook AK, Pollock DM, et Afferent arteriole responsiveness to endothelin receptor activation: does sex matter?. Biol Sex Differ. 2019; 10.
52. Hashimoto M, Akishita M, Eto M, et Modulation of endothelium-dependent flow-mediated dilatation of the brachial artery by sex and menstrual cycle. Circulation. 1995; 92: 3431- 3435.
53. DuPont JJ, Kim SK, Kenney RM, et al. Sex differences in the time course and mechanisms of vascular and cardiac aging in mice: role of the smooth muscle cell mineralocorticoid receptor. Am J Physiol Heart Circ 2021; 320: 169-180.
54. Shipley RD, Muller-Delp JM. Aging decreases vasoconstrictor responses of coronary resistance arterioles through endothelium- dependent Cardiovasc Res. 2005; 66: 374-383.
55. Korzick DH, Muller-Delp JM, Dougherty P, et al. Exaggerated coronary vasoreactivity to endothelin-1 in aged rats: role of protein kinase Cardiovasc Res. 2005; 66: 384-392.
56. Kelly RF, Hursey TL, Schaer GL, et Cardiac endothelin release and infarct size, myocardial blood flow, and ventricular function in canine infarction and reperfusion. J Investig Med. 1996; 44: 575-582.
57. Wellman GC, Bonev AD, Nelson MT, et al. Gender differences in coronary artery diameter involve estrogen, nitric oxide, and Ca 2+ -dependent K + Circulation Research. 1996; 79: 1024-1030.
58. Wu Y, Huang A, Sun D, et Gender-specific compensation for the lack of NO in the mediation of flow-induced arteriolar dilation. Am J Physiol Heart Circ Physiol. 2001; 280: 2456- 2461.
59. Fraccarollo D, Hu K, Galuppo P, et Chronic endothelin receptor blockade attenuates progressive ventricular dilation and improves cardiac function in rats with myocardial infarction: possible involvement of myocardial endothelin system in ventricular remodeling. Circulation. 1997; 96: 3963-3973.
60. Forte P, Kneale BJ, Milne E, et Evidence for a difference in nitric oxide biosynthesis between healthy women and men. Hypertension. 1998; 32: 730-734.
61. Nguyen A, Thorin-Trescases N, Thorin Working under pressure: coronary arteries and the endothelin system. Am J Physiol Regul Integr Comp Physiol. 2010; 298: 1188-1194.
62. Boulanger C, Luscher Release of endothelin from the porcine aorta. Inhibition by endothelium- derived nitric oxide. J Clin Invest. 1990; 85: 587-590.
63. Mitsutomi N, Akashi C, Odagiri J, et al. Effects of endogenous and exogenous nitric oxide on endothelin-1 production in cultured vascular endothelial cells. Eur J Pharmacol. 1999; 364: 65-73.
64. Warner TD. Relationships between the endothelin and nitric oxide pathways. Clin Exp Pharmacol Physiol. 1999; 26: 247-
65. Verma S, Skarsgard P, Bhanot S, et al. Reactivity of mesenteric arteries from fructose hypertensive rats to Am J Hypertens. 1997; 10: 1010-1019.
66. Flores-Monroy J, Ramirez-Hernandez D, Samano-Hernandez C, et Sex Differences in Vascular Reactivity to Angiotensin II During the Evolution of Myocardial Infarction. J Cardiovasc Pharmacol. 2018; 71: 19-25.
67. Gardner JD, Brower GL, Voloshenyuk TG, et Cardioprotection in female rats subjected to chronic volume overload: synergistic interaction of estrogen and 21 phytoestrogens. Am J Physiol Heart Circ Physiol. 2008; 294: 198-204.
68. Kolodgie FD, Farb A, Litovsky SH, et al. Myocardial protection of contractile function after global ischemia by physiologic estrogen replacement in the ovariectomized J Mol Cell Cardiol. 1997; 29: 2403-2414.
69. Sbarouni E, Iliodromitis EK, Bofilis E, et Short-term estrogen reduces myocardial infarct size in oophorectomized female rabbits in a dose-dependent manner. Cardiovasc Drugs Ther. 1998; 12: 457-462.
70. Hale SL, Birnbaum Y, Kloner B-estradiol, but not a-estradiol, reduces myocardial necrosis in rabbits after ischemia and reperfusion. Am Heart J. 1996; 132: 258-262.
71. Kim YD, Chen B, Beauregard J, et al. 17 beta Estradiol prevents dysfunction of canine coronary endothelium and myocardium and reperfusion arrhythmias after brief ischemia/reperfusion. 1996; 94: 2901-2908.
72. Treasure CB, Klein JL, Weintraub WS, et al. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med. 1995; 332: 481-487.
73. Rouleau JR, Dagnault A, Simard D, et al. Effect of estrogen replacement therapy on distribution of myocardial blood flow in female anesthetized rabbits. Am J Physiol Heart Circ Physiol. 2001; 281: 1407-1412.
74. Wilting J. Integrated vascular anatomy. Lanzer PT, E.J., editor. Berlin, Heidelberg: 2002.
75. Bailey AL, Scantlebury DC, Smyth Thrombosis and antithrombotic therapy in women. Arterioscler Thromb Vasc Biol. 2009; 29: 284-288.
76. Sheifer SE, Canos MR, Weinfurt KP, et al. Sex differences in coronary artery size assessed by intravascular ultrasound. Am Heart J. 2000; 139: 649-653.
77. Gilligan DM, Quyyumi AA, Cannon RO, Effects of physiological levels of estrogen on coronary vasomotor function in postmenopausal women. Circulation. 1994; 89: 2545-2551.
78. Celermajer DS. Endothelial dysfunction: does it matter? Is it reversible?. J Am Coll 1997; 30: 325-333.
79. Sader MA, Celermajer Endothelial function, vascular reactivity and gender differences in the cardiovascular system. Cardiovasc Res. 2002; 53: 597-604.
80. Kardys I, Vliegenthart R, Oudkerk M, et The female advantage in cardiovascular disease: do vascular beds contribute equally?. Am J Epidemiol. 2007; 166: 403-412.
81. Campbell DJ, Somaratne JB, Jenkins AJ, et al. Differences in myocardial structure and coronary microvasculature between men and women with coronary artery disease. Hypertension. 2011; 57: 186-192.
82. von Mering GO, Arant CB, Wessel TR, et Abnormal coronary vasomotion as a prognostic indicator of cardiovascular events in women: results from the National Heart, Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE). Circulation. 2004; 109: 722-725.
83. AlBadri A, Bairey Merz CN, Johnson BD, et Impact of Abnormal Coronary Reactivity on Long-Term Clinical Outcomes in Women. J Am Coll Cardiol. 2019; 73: 684-693.
84. Khuddus MA, Pepine CJ, Handberg EM, et al. An intravascular ultrasound analysis in women experiencing chest pain in the absence of obstructive coronary artery disease: a substudy from the National Heart, Lung and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE). J Interv 2010; 23: 511-519.
85. Braith RW, Conti CR, Nichols WW, et al. Enhanced external counterpulsation improves peripheral artery flow-mediated dilation in patients with chronic angina: a randomized sham- controlled Circulation. 2010; 122: 1612-1620.
86. Crandall CJ, Barrett-Connor E. Endogenous sex steroid levels and cardiovascular disease in relation to the menopause: a systematic review. Endocrinol Metab Clin North Am. 2013; 42: 227-253.
87. Barrett-Connor E, Goodman-Gruen Prospective study of endogenous sex hormones and fatal cardiovascular disease in postmenopausal women. BMJ. 1995; 311: 1193-1196.
88. Nicolaou Sex differences in heart failure medications targeting the renin angiotensin-aldosterone system. Eur J Pharmacol. 2021; 897: 173961.
89. Coutinho T. Arterial stiffness and its clinical implications in Can J Cardiol. 2014; 30: 756-764.
90. DuPont JJ, Kenney RM, Patel AR, et al. Sex differences in mechanisms of arterial stiffness. Br J Pharmacol. 2019; 176: 4208-4225.
91. Keller KM, Howlett SE. Sex Differences in the Biology and Pathology of the Aging Heart. Can J Cardiol. 2016; 32: 1065-
92. Lakatta EG, Levy Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part I: aging arteries: a "set up" for vascular disease. Circulation. 2003; 107: 139-146.
93. Barnett SR, Morin RJ, Kiely DK, et Effects of age and gender on autonomic control of blood pressure dynamics. Hypertension. 1999; 33: 1195-1200.
94. Christou DD, Jones PP, Jordan J, et al. Women have lower tonic autonomic support of arterial blood pressure and less effective baroreflex buffering than Circulation. 2005; 111: 494-498.
95. Zaydun G, Tomiyama H, Hashimoto H, et Menopause is an independent factor augmenting the age-related increase in arterial stiffness in the early postmenopausal phase. Atherosclerosis. 2006; 184: 137-42.
96. Prati P, Vanuzzo D, Casaroli M, et Prevalence and determinants of carotid atherosclerosis in a general population. Stroke. 1992; 23: 1705-1711.
97. Janowitz WR, Agatston AS, Kaplan G, et al. Differences in prevalence and extent of coronary artery calcium detected by ultrafast computed tomography in asymptomatic men and Am J Cardiol. 1993; 72: 247-254.
98. Ota H, Reeves MJ, Zhu DC, et al. Sex differences in patients with asymptomatic carotid atherosclerotic plaque: in vivo 3.0-T magnetic resonance Stroke. 2010; 41: 1630-1635.
99. Luft Molecular mechanisms of arterial stiffness: new insights. J Am Soc Hypertens. 2012; 6: 436-438.
100. Mitchell Arterial Stiffness and Wave Reflection: Biomarkers of Cardiovascular Risk. Artery Res. 2009; 3: 56-64.
101. Dart AM, Kingwell BA, Gatzka CD, et Smaller aortic dimensions do not fully account for the greater pulse pressure in elderly female hypertensives. Hypertension. 2008; 51: 1129- 1134.
102. Coutinho T, Borlaug BA, Pellikka PA, et al. Sex differences in arterial stiffness and ventricular-arterial interactions. J Am Coll 2013; 61: 96-103.
103. Mitchell GF, Lacourciere Y, Ouellet JP, et al. Determinants of elevated pulse pressure in middle-aged and older subjects with uncomplicated systolic hypertension: the role of proximal aortic diameter and the aortic pressure-flow relationship. Circulation. 2003; 108: 1592-1598.
104. Shim CY, Park S, Choi D, et Sex differences in central hemodynamics and their relationship to left ventricular diastolic function. J Am Coll Cardiol. 2011; 57: 1226-1233.
105. Goto T, Ohte N, Fukuta H, et al. Relationship between effective arterial elastance, total vascular resistance, and augmentation index at the ascending aorta and left ventricular diastolic function in older women. Circ J. 2013; 77: 123-129.
106. Regnault V, Thomas F, Safar ME, et Sex difference in cardiovascular risk: role of pulse pressure amplification. J Am Coll Cardiol. 2012; 59: 1771-1777.
107. Zieman SJ, Melenovsky V, Kass Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol. 2005; 25: 932-943.
108. Lacolley P, Regnault V, Avolio AP. Smooth muscle cell and arterial aging: basic and clinical aspects. Cardiovasc Res. 2018; 114: 513-528.
109. Qiu H, Zhu Y, Sun Z, et al. Short communication: vascular smooth muscle cell stiffness as a mechanism for increased aortic stiffness with Circ Res. 2010; 107: 615-619.
110. Sehgel NL, Zhu Y, Sun Z, et al. Increased vascular smooth muscle cell stiffness: a novel mechanism for aortic stiffness in hypertension. Am J Physiol Heart Circ Physiol. 2013; 305: 1281-1287.
111. Fleenor BS, Sindler AL, Marvi NK, et al. Curcumin ameliorates arterial dysfunction and oxidative stress with Exp Gerontol. 2013; 48: 269-276.
112. Rossman MJ, Santos-Parker JR, Steward CAC, et al. Chronic Supplementation With a Mitochondrial Antioxidant (MitoQ) Improves Vascular Function in Healthy Older Hypertension. 2018; 71: 1056-1063.
113. Gioscia-Ryan RA, Battson ML, Cuevas LM, et Mitochondria- targeted antioxidant therapy with MitoQ ameliorates aortic stiffening in old mice. J Appl Physiol (1985). 2018; 124: 1194- 1202.
114. Canto JG, Rogers WJ, Goldberg RJ, et Association of age and sex with myocardial infarction symptom presentation and in-hospital mortality. JAMA. 2012; 307: 813-822.
115. Vaccarino V, Horwitz RI, Meehan TP, et al. Sex differences in mortality after myocardial infarction: evidence for a sex-age Arch Intern Med. 1998; 158: 2054-2062.
116. Vaccarino V, Krumholz HM, Yarzebski J, et al. Sex differences in 2-year mortality after hospital discharge for myocardial Ann Intern Med. 2001; 134: 173-181.
117. Hochman JS, Tamis JE, Thompson TD, et Clinical presentation, and outcome in patients with acute coronary syndromes. Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes IIb Investigators. N Engl J Med. 1999; 341: 226-232.
118. Champney KP, Frederick PD, Bueno H, et The joint contribution of sex, age and type of myocardial infarction on hospital mortality following acute myocardial infarction. Heart. 2009; 95: 895-899.
119. Ishida M, Kato S, Sakuma H. Cardiac MRI in ischemic heart Circ J. 2009; 73: 1577-1588.
120. Gregg RE, Babaeizadeh S. Detection of culprit coronary lesion location in pre hospital 12-lead J Electrocardiol. 2014; 47: 890-894.
121. Perk J, De Backer G, Gohlke H, et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other 26 Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart 2012; 33: 1635-1701.
122. D'Onofrio G, Safdar B, Lichtman JH, et Sex differences in reperfusion in young patients with ST-segment-elevation myocardial infarction: results from the VIRGO study. Circulation. 2015; 131: 1324-1332.
123. Stehli J, Martin C, Brennan A, et Sex Differences Persist in Time to Presentation, Revascularization, and Mortality in Myocardial Infarction Treated With Percutaneous Coronary Intervention. J Am Heart Assoc. 2019; 8: e012161.
124. Roswell RO, Kunkes J, Chen AY, et al. Impact of Sex and Contact-to-Device Time on Clinical Outcomes in Acute ST- Segment Elevation Myocardial Infarction-Findings From the National Cardiovascular Data J Am Heart Assoc. 2017; 6.
125. Sederholm Lawesson S, Isaksson RM, Ericsson M, et al. Gender disparities in first medical contact and delay in ST-elevation myocardial infarction: a prospective multicentre Swedish survey study. BMJ 2018; 8: e020211.
126. Fu WX, Zhou TN, Wang XZ, et Sex-Related Differences in Short- and Long-Term Outcome among Young and Middle- Aged Patients for ST-Segment Elevation Myocardial Infarction Underwent Percutaneous Coronary Intervention. Chin Med J (Engl). 2018; 131: 1420-1429.
127. Lidegaard Hormonal contraception, thrombosis and age. Expert Opin Drug Saf. 2014; 13: 1353-1360.
128. Li Y, Kloner RA. Is There a Gender Difference in Infarct Size and Arrhythmias Following Experimental Coronary Occlusion and Reperfusion?. J Thromb 1995; 2: 221-225.
129. Przyklenk K, Ovize M, Bauer B, et Gender does not influence acute myocardial infarction in adult dogs. Am Heart J. 1995; 129: 1108-1113.
130. Lee TM, Su SF, Tsai CC, et al. Cardioprotective effects of 17 beta estradiol produced by activation ofmitochondrial ATP- sensitive K(+)Channels in canine hearts. J Mol Cell Cardiol. 2000; 32: 1147-1158.
131. Brown DA, Lynch JM, Armstrong CJ, et Susceptibility of the heart to ischaemia-reperfusion injury and exercise-induced cardioprotection are sex-dependent in the rat. J Physiol. 2005; 564: 619-630.
132. Turcato S, Turnbull L, Wang GY, et Ischemic preconditioning depends on age and gender. Basic Res Cardiol. 2006; 101: 235- 243.
133. Humphreys RA, Kane KA, Parratt The influence of maturation and gender on the anti-arrhythmic effect of ischaemic preconditioning in rats. Basic Res Cardiol. 1999; 94: 1-8.
134. Song X, Li G, Vaage J, et Effects of sex, gonadectomy, and oestrogen substitution on ischaemic preconditioning and ischaemia-reperfusion injury in mice. Acta Physiol Scand. 2003; 177: 459-466.
135. Wang M, Baker L, Tsai BM, et Sex differences in the myocardial inflammatory response to ischemia-reperfusion injury. Am J Physiol Endocrinol Metab. 2005; 288: 321-326.
136. Dougherty CJ, Kubasiak LA, Prentice H, et al. Activation of c-Jun N-terminal kinase promotes survival of cardiac myocytes after oxidative Biochem J. 2002; 362: 561-571.
137. Salituro FG, Germann UA, Wilson KP, et al. Inhibitors of p38 MAP kinase: therapeutic intervention in cytokine-mediated Curr Med Chem. 1999; 6: 807-823.
138. Murry CE, Jennings RB, Reimer Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circ. 1986; 74: 1124-1136.
139. Brown DA, Jew KN, Sparagna GC, et Exercise training preserves coronary flow and reduces infarct size after ischemia- reperfusion in rat heart. J Appl Physiol (1985). 2003; 95: 2510- 2518.
140. Yamashita N, Baxter GF, Yellon Exercise directly enhances myocardial tolerance to ischaemia-reperfusion injury in the rat through a protein kinase C mediated mechanism. Heart. 2001; 85: 331-336.
141. Hamilton KL, Staib JL, Phillips T, et al. Exercise, antioxidants, and HSP72: protection against myocardial ischemia/reperfusion. Free Radic Biol 2003; 34: 800-809.
142. Heusch Cardioprotection: chances and challenges of its translation to the clinic. Lancet. 2013; 381: 166-175.
143. Kloner RA, Rezkalla Preconditioning, postconditioning and their application to clinical cardiology. Cardiovasc Res. 2006; 70: 297-307.
144. Penna C, Tullio F, Merlino A, et Postconditioning cardioprotection against infarct size and post-ischemic systolic dysfunction is influenced by gender. Basic Res Cardiol. 2009; 104: 390-402.
145. Ciocci Pardo A, Scuri S, Gonzalez Arbelaez LF, et al. Survival kinase-dependent pathways contribute to gender difference in the response to myocardial ischemia-reperfusion and ischemic post-conditioning. Cardiovasc 2018; 33: 19-26.
146. Litwin SE, Katz SE, Litwin CM, et al. Gender differences in postinfarction left ventricular Cardiology. 1999; 91: 173-183.
147. Lieder HR, Irmert A, Kamler M, et Sex is no determinant of cardioprotection by ischemic preconditioning in rats, but ischemic/reperfused tissue mass is for remote ischemic preconditioning. Physiol Rep. 2019; 7: e14146.
148. Kleinbongard P, Neuhauser M, Thielmann M, et Confounders of Cardioprotection by Remote Ischemic Preconditioning in Patients Undergoing Coronary Artery Bypass Grafting. Cardiology. 2016; 133: 128-133.
149. Crimi G, Pica S, Raineri C, et Remote ischemic post- conditioning of the lower limb during primary percutaneous coronary intervention safely reduces enzymatic infarct size in anterior myocardial infarction: a randomized controlled trial. JACC Cardiovasc Interv. 2013; 6: 1055-1063.
150. Sloth AD, Schmidt MR, Munk K, et Impact of cardiovascular risk factors and medication use on the efficacy of remote ischaemic conditioning: post hoc subgroup analysis of a randomised controlled trial. BMJ Open. 2015; 5: e006923.
151. Eitel I, Stiermaier T, Rommel KP, et al. Cardioprotection by combined intrahospital remote ischaemic perconditioning and postconditioning in ST-elevation myocardial infarction: the randomized LIPSIA CONDITIONING trial. Eur Heart J. 2015; 36: 3049-3057.