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J Am Coll Cardiol, 2006; 47:30-35, doi:10.1016/j.jacc.2005.09.023
© 2006 by the American College of Cardiology Foundation
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STATE-OF-THE-ART PAPER

Some Thoughts on the Vasculopathy of Women With Ischemic Heart Disease

Carl J. Pepine, MD, MACC*,*, Richard A. Kerensky, MD, FACC*, Charles R. Lambert, MD, PhD, FACC*, Karen M. Smith, MD, FACC*, Gregory O. von Mering, MD, FACC*, George Sopko, MD{dagger} and C. Noel Bairey Merz, MD, FACC{ddagger}

* Division of Cardiovascular Medicine, Department of Medicine, University of Florida College of Medicine, Gainesville, Florida
{dagger} National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
{ddagger} Division of Cardiology, Department of Medicine, Cedars-Sinai Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.

Manuscript received September 21, 2005; accepted September 29, 2005.

* Reprint requests and correspondence: Dr. Carl J. Pepine, Division of Cardiovascular Medicine, University of Florida College of Medicine, Gainesville, Florida 32610. (Email: pepincj{at}medicine.ufl.edu).


   Abstract
Top
 Abstract
Vascular disease risk conditions
 Alterations in vascular...
 Vascular function
 References
 
Considerable experimental and clinical data indicate that sex has an important influence on cardiovascular physiology and pathology. This report integrates selected literature with new data from the Women’s Ischemia Syndrome Evaluation (WISE) on vascular findings in women with ischemic heart disease (IHD) and how these findings differ from those in men. A number of common vascular disease-related conditions are either unique to (e.g., hypertensive disorders of pregnancy, gestational diabetes, peripartum dissection, polycystic ovarian syndrome, etc.) or more frequent (e.g., migraine, coronary spasm, lupus, vasculitis, Raynaud’s phenomenon, etc.) in women than men. Post-menopausal women more frequently have many traditional vascular disease risk conditions (e.g., hypertension, diabetes, obesity, inactivity, and so on), and these conditions cluster more frequently in them than men. Considerable evidence supports the notion that, with these requisite conditions, women develop a more severe or somewhat different form of vascular disease than men. Structurally, women’s coronary vessels are smaller in size and appear to contain more diffuse atherosclerosis, their aortas are stiffer (fibrosis, remodeling, and so on), and their microvessels appear to be more frequently dysfunctional compared with men. Functionally, women’s vessels frequently show impaired vasodilator responses. Limitations of existing data and higher risks in women with acute myocardial infarction, need for revascularization, or heart failure create uncertainty about management. A better understanding of these findings should provide direction for new algorithms to improve management of the vasculopathy underlying IHD in women.

Abbreviations and Acronyms
  ACS = acute coronary syndrome
  CAD = coronary artery disease
  CV = cardiovascular
  EPC = endothelial progenitor cell
  IHD = ischemic heart disease
  WISE = Women’s Ischemia Syndrome Evaluation

Considerable data indicate that sex has an important influence on cardiovascular (CV) physiology and pathology (1,2). The purpose of this report is to critically review selected clinical and experimental data, while integrating new findings from the Women’s Ischemia Syndrome Evaluation (WISE), on vascular findings related to ischemic heart disease (IHD) in women and how these findings differ from those in men. The hypothesis is that women with IHD have evidence for a more severe or different form of vascular disease compared with men. These data should help to better define the vasculopathy underlying IHD as it occurs in women and suggest direction for new algorithms to improve detection and management at an early stage.


   Vascular disease risk conditions
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 Abstract
 Vascular disease risk conditions
Alterations in vascular...
 Vascular function
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Gender-related differences in clinical findings linked to vascular disease are best illustrated by risk conditions unique to women (Table 1). In the peripartum period, some examples include the hypertensive disorders of pregnancy (e.g., preeclampsia and eclampsia), proximal coronary artery and aortic root dissection, as well as gestational diabetes and delivering a thin baby. For example, the relatively common (~5% to 10% of term pregnancies) hypertensive disorders of pregnancy are associated with significant increase in IHD later in the mother’s life (3,4). For the relatively rare coronary or aortic dissection, the IHD risk is obvious. But gestational diabetes, occurring in 2% to 9% of pregnancies, results in sustained glucose intolerance or diabetes in most cases and implications for vascular disease that are not as obvious (5,6). Mothers who once gave birth to thin babies are also at increased risk for IHD (7). It has been suggested that these mothers, like their children, have impaired vascular function, which was already present during the process of implantation interfering with placental function leading to low birth weight. Many of these conditions have been linked with oxidative stress, endothelial dysfunction, inflammation, insulin resistance, defective angiogenesis, and dyslipidemia (8–11). Perhaps these conditions explain, at least in part, some non-genetic factors in a family history of CV disease that play a role in the lifelong risk for IHD in women.


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  		Table 1. The Vasculopathy of Women With IHD: Risk Conditions Versus Men
 
Examples of risk conditions unique to women unrelated to the peripartum period but linked to hypertension, obesity, insulin resistance, and IHD include polycystic ovarian syndrome, hypoestrogenemia of central origin, and estrogen replacement, which are reviewed elsewhere in this supplement (12) (Table 1). Additionally, women have higher frequencies of vasculitis (e.g., Takayasu’s arteritis, temporal arteritis, rheumatoid vasculitis, lupus vasculitis, polymyalgia rheumatica, etc.) compared with men.

Women also have somewhat different clinical findings that relate to pathophysiology of IHD than male counterparts. The woman with IHD often is older, has a greater risk factor burden, and more functional disability (12,13). Aging attenuates many estrogen-related potentially beneficial vascular responses (2) including endothelial progenitor cells (EPCs) (14) and coronary microvascular function in the WISE (15). Experimental models have linked sex hormones and other risk conditions (e.g., hypertension, diabetes, and so on) to IHD in women (2). Briefly, high estrogen levels before menopause and decreasing estrogen and progesterone levels after menopause are believed to influence IHD in women. Estrogen exerts effects via receptors abundant in vascular tissue to transduce signals regulating expression of many genes, and it also has non-genomic actions. Variations in plasma sex hormones and receptor genes, acting with endothelial and vascular smooth muscle factors, are potential links to the differences in vascular structure and function that contribute to both heterogeneity among women and gender differences in IHD.


   Alterations in vascular structure
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Large artery structure appears different in women (Table 2), illustrated by the fact that their coronary arteries are smaller than men independent of body size (16). Changes in artery size (e.g., remodeling) occur in response to physiologic (e.g., exercise) or pathologic conditions (e.g., atherosclerosis, hypertension, and so on). Female vessels uniquely undergo remodeling during and after pregnancy. Traditionally, this has been considered physiologic remodeling, but, in the presence of peripartum conditions linked with IHD (e.g., coronary dissection, thin babies, gestational diabetes, and so on), this may not be the case. Recently, potentially pathologic gender-related differences in remodeling have been described in cardiac transplant recipients and transgender patients.


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  		Table 2. The Vasculopathy of Women With IHD: Coronary Structure and Function Versus Men
 
Female hearts transplanted to women show little change in coronary artery size over time, but, when transplanted to men, they show progressive coronary enlargement independent of body size and left ventricular hypertrophy (17). A link between arterial size and sex hormones is supported by studies of transsexuals where brachial artery size in genetic men taking estrogens is smaller compared with control men (18,19). Genetic women taking androgens have larger arteries than control women (20). Androgen-deprivation therapy in genetic men is associated with smaller artery size compared with control men (21). These findings imply that sex hormones have different effects on arterial remodeling with androgens causing enlargement (e.g., positive remodeling). Positive remodeling may be a marker of vascular injury (22–24), and perhaps such injury could explain the high event rate observed among women with non-obstructive coronary angiographic findings in the WISE (25). Also, larger brachial artery size was associated with more angiographic evidence of coronary artery disease (CAD) (26). Brachial artery size, readily measured non-invasively by ultrasound, may be helpful to identify women with early atherosclerosis.

Postmenopausal women more frequently have atherosclerosis risk conditions (e.g., hypertension, diabetes, metabolic syndrome, obesity, and so on) than men, and these conditions more frequently cluster in women. Adding the risk conditions unique to women noted previously would predict more atheroma burden in their smaller coronary arteries. Even with apparently "normal" coronary angiography, diffuse atherosclerosis may result in abnormal resistance limiting myocardial flow (27) with deleterious consequences for revascularization (28,29). Study of transplant donor hearts suggest coronary atherosclerosis without apparent flow limiting stenoses has a similar prevalence comparing men and women (30). These findings support the notion that severe coronary atherosclerosis may alter structure in many of these women without recognition by angiography.

Structural changes in large arteries from aging and atherosclerosis increase arterial stiffness (31). In diabetic women, but not men, age-related stiffening of the aorta occurs (32). Alterations in large artery stiffness were observed in a sample of women from the WISE compared with age- and body mass index-matched control women (33). In other postmenopausal women with CAD, brachial pulse pressure, another measure of arterial stiffness, was associated with CAD progression, independent of risk factors or hormone replacement (34). In the WISE, pulse pressure was an independent predictor of CAD severity and clinical outcomes (35). Non-invasive measures of arterial stiffness may be useful to estimate the structural consequences of atherosclerosis in post-menopausal women and may provide insight into the effect of therapies on stiffness and adverse outcomes.

Microvascular structural damage secondary to aging, hypertension, diabetes, left ventricular hypertrophy, and other processes is also likely to be important in women. To this end, retinal microvascular abnormalities have been linked to past blood pressure (36), inflammation, and endothelial dysfunction (37). Such microvascular abnormalities predict IHD outcomes in women but not men (38). Thus, retinal microvascular structural alterations allow non-invasive investigation of systemic vascular pathology.


   Vascular function
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Functional alterations as changes in vascular reactivity also suggest a more severe disease in women implicating both endothelium and smooth muscle (Table 2). Sex hormones exert effects on vascular reactivity via endothelium and also directly on smooth muscle (2). Various mechanisms are involved, ranging from gender-specific influences on nitric oxide synthase gene (39) to sex-hormone–related differences in L-type voltage-gated Ca2+-activated K+ channels (2,40) and also include effects on vascular repair (41). Because women’s vessels spend considerable time under widely varying hormonal influences (e.g., puberty, pregnancy, peripartum, and menopause), their vessels may be programmed for more severe functional alterations compared with men.

Role of coronary endothelial dysfunction.   More than half the women tested with acetylcholine in the WISE had coronary endothelial dysfunction, which independently predicted adverse outcomes (42). The risk conditions present in women, alone or in clusters, increase oxidative stress to injure endothelium of both large and small vessels in varying degrees (43,44). In large arteries of women presenting with chest discomfort, endothelial dysfunction is a marker for early atherosclerosis before structural changes to the vessel wall are appreciated by angiography (45). Vascular injury resulting in endothelial dysfunction has been linked to positive remodeling of large coronary arteries without flow-limiting lesions (22). Endothelial dysfunction of the microvasculature has the potential to limit myocardial perfusion (45,46).

Normal endothelial repair processes may be adequate for this injury, but over time, repair processes may become inadequate for many reasons (e.g., loss of estrogen, overwhelming oxidative stress as associated with metabolic syndrome, hypertension, obesity, aging, and so on). Recent evidence indicates that bone-marrow–derived EPCs are important in vascular repair, and estrogen increases circulating EPCs by antiapoptotic effects (41). Circulating EPCs become depleted in individuals with multiple risk conditions and aging (41). Considering the density of risk conditions among women presenting with suspected IHD in the WISE, a reasonable hypothesis would be that such women are more vulnerable to continuing injury leading to more atherosclerosis than those without high densities of risk factor conditions. Some female unique conditions (e.g., pregnancy-associated hypertension or metabolic disorders, and so on) are also associated with endothelial dysfunction and make such women more vulnerable to develop IHD. Finally, because clinical manifestations of IHD in women present 10 or more years later in life than men, this occurs at time when aging likely has powerful effects on supply and quality of EPCs. Thus women, at this later stage of life, would be less capable of vascular repair, which could contribute to poor outcomes compared with men whose coronary vessels were preconditioned at an age when they were more capable of vascular repair.

Role of vascular smooth muscle dysfunction.   Manifestations suggesting alterations of vascular smooth muscle function are more frequent in women than men (e.g., coronary artery spasm, Raynaud’s phenomenon, and migraine), and both coronary spasm and migraine have been linked with IHD. Impaired smooth muscle relaxation has also been suggested as a marker for atherosclerosis (47). Coronary flow reserve attenuation, as observed in many of the WISE women with intracoronary adenosine (15,48–50), suggests impaired microvascular smooth muscle relaxation. Positron emission tomographic scanning results in a WISE subgroup without epicardial CAD suggest that the distribution of this microvascular defect is heterogenous (51), and P31 cardiac magnetic spectroscopy results document high-energy phosphate depletion as seen with ischemia (52). Hypertension, diabetes, obesity, and other conditions found more frequently in postmenopausal women than men are associated with microvascular dysfunction. But atherosclerosis risk conditions account for <20% of the variability in coronary flow reserve, indicating that other factors, as yet to be identified, influence microvascular function (15).

Previous studies have also documented gender-related differences in skin flow responses to provocative maneuvers (43) and in endothelial nitric oxide production in skin microvasculature (44). Estrogen improves endothelial function, but menopause is associated with abnormal endothelial function in coronary microvessels. Estrogens, but not progestogens, antagonize the effect of menopause (53). So women are primed to have microvascular dysfunction, which has been suggested as a cause for ischemia without flow-limiting epicardial stenoses. Also, microvascular spasm may cause ischemia, and most of these patients are women (54–56). Recently, it has been suggested that endothelial-independent microvascular dysfunction to adenosine is an independent predictor of adverse outcomes in angina patients (57). These examples indicate that microvascular dysfunction has the potential to evoke angina-like symptoms and cardiac ischemia and is linked with adverse outcomes.

Relative roles of endothelial versus smooth muscle dysfunction and large vessels versus microvessels.   Considerable evidence implicates the coronary microcirculation, along with large vessel atheroma, to explain findings in IHD (58). This includes wide variability in effort tolerance over time (a frequent finding in women), large scatter between stenosis severity and flow reserve (59), reduced flow responses to stress in regions perfused by non-stenotic vessels (60), variability in outcome after successful percutaneous intervention (61), the 25% of women with acute coronary syndrome (ACS) who have no flow-limiting stenosis (62), the predictive value of brain natriuretic peptide and C-reactive protein for adverse outcomes in women with ACS (63), and pathologic findings of plaque erosion with microvascular embolization in women dying with ACS (64).

In summary, considerable evidence indicates that the large and small coronary vessels of women with IHD may be more diseased compared to men (Tables 1 and 2). Under these circumstances, the consequences of a given ischemic episode would be expected to be altered in an unfavorable manner. In such women, an area of ischemic injury may not be limited because usual vasorelaxation required for collateral function is abnormal. This theory could help explain why women tolerate ACS poorly compared with men and why subsequent heart failure, for example, is not only more frequent but also more lethal in women than men. The foregoing should help the reader place the vascular findings from the WISE and other studies into a meaningful clinical perspective (Tables 1 and 2).


   Footnotes
 
This work was supported by contracts from the National Heart, Lung, and Blood Institute, nos. N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164, grants U0164829, U01 HL649141, U01 HL649241, a GCRC grant MO1-RR00425 from the National Center for Research Resources, and grants from the Gustavus and Louis Pfeiffer Research Foundation, Denville, New Jersey, Women’s Guild of Cedars-Sinai Medical Center, Los Angeles, California, Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, Pennsylvania, and QMED, Inc., Laurence Harbor, New Jersey.


   References
Top
 Abstract
 Vascular disease risk conditions
 Alterations in vascular...
 Vascular function
 References
 

  1. Pepine CJ. Ischemic heart disease in womenfacts and wishful thinking. J Am Coll Cardiol 2004;43:1727-1730.[Free Full Text]
  2. Orshal JM, Khalil RA. Gender, sex hormones, and vascular tone Am J Physiol Regul Integr Comp Physiol 2004;286:R233-R249.[Abstract/Free Full Text]
  3. Irgens HU, Reisaeter L, Irgens LM, Lie RT. Long term mortality of mothers and fathers after pre-eclampsiapopulation based cohort study. BMJ 2001;323:1213-1217.[Abstract/Free Full Text]
  4. Haukkamaa L, Salminen M, Laivuori H, Leinonen H, Hiilesmaa V, Kaaja R. Risk for subsequent coronary artery disease after preeclampsia Am J Cardiol 2004;93:805-808.[CrossRef][ISI][Medline]
  5. Silverman B, Metzger BE, Cho NH, Loeb CA. Impaired glucose tolerance in adolescent offspring of diabetic mothersrelationship to fetal hyperinsulinism. Diabetes Care 1995;18:611-617.[Abstract]
  6. O’Sullivan J. Carbohydrate metabolism in pregnancy and the newbornIn: Sutherland HW, Stowers JM, Pearson DWM, editors. The Boston Gestational Diabetes Studies. London: Springer-Verlag; 1989. pp. 287-294.
  7. Smith GCS, Pell JP, Walsh D. Pregnancy complications and maternal risk of ischemic heart diseasea retrospective cohort study of 129,290 births. Lancet 2001;357:2002-2006.[CrossRef][ISI][Medline]
  8. Raijmakers MTM, Dechend R, Poston L. Oxidative stress and preeclampsiarationale for antioxidant clinical trials. Hypertension 2004;44:374-380.[Abstract/Free Full Text]
  9. Norman M, Martin H. Preterm birth attenuates association between low birth weight and endothelial dysfunction Circulation 2003;108:996-1001.[CrossRef][ISI][Medline]
  10. Granger JP, Alexander BT, Llinas MT, Bennett WA, Khalil RA. Pathophysiology of hypertension during preeclampsia linking placental ischemia with endothelial dysfunction Hypertension 2001;38:718-722.[Abstract/Free Full Text]
  11. Thadhani R, Ecker JL, Mutter WP, et al. Insulin resistance and alterations in angiogenesisadditive insults that may lead to preeclampsia. Hypertension 2004;43:988-992.[Abstract/Free Full Text]
  12. Bairy Merz CN, Shaw LJ, Reis SE, et al. Insights from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) study. Part II: gender differences in presentation, diagnosis, and outcome with regard to gender-based pathophysiology of atherosclerosis, macro-, and microvascular coronary disease J Am Coll Cardiol Suppl 2006;47(Suppl A):21A-29A.
  13. Shaw LJ, Bairey Merz CN, Pepine CJ, et al. Insights from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study. Part I: gender differences in traditional and novel risk factors, symptom evaluation, and gender-optimized diagnostic strategies J Am Coll Cardiol 2006;47(Suppl A):4A-20A.
  14. Hill JM, Zalos G, Halcox JPJ, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk N Engl J Med 2003;348:593-600.[Abstract/Free Full Text]
  15. Wessel TR, Arant CB, McGorray SP, et al. Coronary vascular dysfunction is only partially predicted by traditional cardiovascular risk factors in women undergoing evaluation for suspected ischemiaresults from the NHLBI Women’s Ischemia Syndrome Evaluation (WISE) study. J Am Coll Cardiol 2004;43(Suppl A):484A(abstr).
  16. 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.[ISI][Medline]
  17. Herity NA, Lo S, Lee DP, et al. Effect of a change in gender on coronary arterial sizea longitudinal intravascular ultrasound study in transplanted hearts. J Am Coll Cardiol 2003;41:1539-1546.[Abstract/Free Full Text]
  18. New G, Timmins KL, Duffy SJ, et al. Long-term estrogen therapy improves vascular function in male to female transsexuals J Am Coll Cardiol 1997;29:1437-1444.[Abstract]
  19. McCrohon JA, Walters WAW, Robinson JTC, et al. Arterial reactivity is enhanced in genetic males taking high dose estrogens J Am Coll Cardiol 1997;29:1432-1436.[Abstract]
  20. McCredie RJ, McCrohon JA, Turner L, Griffiths KA, Handelsman DJ, Celermajer DS. Vascular reactivity is impaired in genetic females taking high-dose androgens J Am Coll Cardiol 1998;32:1331-1335.[Abstract/Free Full Text]
  21. Herman SM, Robinson JTC, McCredie RJ, Adams MR, Boyer MJ, Celermajer DS. Androgen deprivation is associated with enhanced endothelium-dependent dilatation in adult men Arterioscler Thromb Vasc Biol 1997;17:2004-2009.[Abstract/Free Full Text]
  22. Lerman A, Cannan CR, Higano SH, Nishimura RA, Holmes Jr. DR. Coronary vascular remodeling in association with endothelial dysfunction Am J Cardiol 1998;81:1105-1109.[CrossRef][ISI][Medline]
  23. Hermiller JB, Tenaglia AN, Kisslo KB, et al. In vivo validation of compensatory enlargement of atherosclerotic coronary arteries Am J Cardiol 1993;71:665-668.[CrossRef][ISI][Medline]
  24. Steinke W, Els T, Hennerici M. Compensatory carotid artery dilatation in early atherosclerosis Circulation 1994;89:2578-2581.[ISI][Medline]
  25. Sharaf BL, Shaw L, Johnson BD, et al. Any measurable coronary artery disease identified in women presenting with ischemic chest pain is associated with an adverse outcomefindings from the NIH-NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) study angiographic core laboratory. J Am Coll Cardiol 2004;43:292A(abstr).
  26. Holubkov R, Karas RH, Pepine CJ, et al. Large brachial artery diameter is associated with angiographic coronary artery disease in women Am Heart J 2002;143:802-807.[CrossRef][ISI][Medline]
  27. De Bruyne B, Hersbach F, Pijls NHJ, et al. Abnormal epicardial coronary resistance in patients with diffuse atherosclerosis but "normal" coronary angiography Circulation 2001;104:2401-2406.[Abstract/Free Full Text]
  28. O’Connor GT, Morton JR, Diehl MJ, et al. Differences between men and women in hospital mortality associated with coronary artery bypass graft surgery Circulation 1993;88:2104-2110.[ISI][Medline]
  29. Blankstein R, Parker Ward RP, Arnsdorf M, Jones B, Lou YB, Pine M. Female gender is an independent predictor of operative mortality after coronary artery bypass graft surgerycontemporary analysis of 31 Midwestern hospitals. Circulation 2005;112:I323-I327.
  30. Tuzcu EM, Kapadia SR, Tutar E, et al. High prevalence of coronary atherosclerosis in asymptomatic teenagers and young adultsevidence from intravascular ultrasound. Circulation 2001;103:2705-2710.[ISI][Medline]
  31. Herrington DM, Brown WV, Mosca L, et al. Relationship between arterial stiffness and subclinical aortic atherosclerosis Circulation 2004;110:432-437.[CrossRef][Medline]
  32. De Angelis L, Millasseau SC, Smith A, et al. Sex differences in age-related stiffening of the aorta in subjects with type 2 diabetes Hypertension 2004;44:67-71.[Abstract/Free Full Text]
  33. von Mering GO, Nichols WW, Kerensky RA, Wessel TR, Arant CB, Pepine CJ. Women with chest pain and normal coronary arteries have increased arterial stiffness by radial artery tonometrya report from the Women’s Ischemia Syndrome Evaluation (WISE). Circulation 2004;110:III522(abstr).
  34. Nair GV, Waters D, Rogers W, Kowalchuk GJ, Stuckey TD, Herrington DM. Pulse pressure and coronary atherosclerosis progression in postmenopausal women Hypertension 2005;45:53-57.[Abstract/Free Full Text]
  35. Sizemore BC, Barrow G, Johnson BD, et al. Pulse pressure is a stronger predictor of mortality and cardiovascular events than systolic blood pressure in womena report from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) study (abstr). Circulation 2005;112:II678.
  36. Wong TY, Klein R, Sharrett AR, et al. Retinal arteriolar diameter and risk for hypertension Ann Intern Med 2004;140:248-255.[Abstract/Free Full Text]
  37. Klein R, Sharrett AR, Klein BEK, et al. Are retinal arteriolar abnormalities related to atherosclerosis? The Atherosclerosis Risk in Communities study Arterioscler Thromb Vasc Biol 2000;20:1644-1650.[Abstract/Free Full Text]
  38. Wong TY, Klein R, Sharrett AR, et al. Retinal arteriolar narrowing and risk of coronary heart disease in men and womenthe Atherosclerosis Risk in Communities study. JAMA 2002;287:1153-1159.[Abstract/Free Full Text]
  39. Chen W, Srinivasan SR, Li S, Boerwinkle E, Berenson GS. Gender-specific influence of NO synthase gene on blood pressure since childhoodthe Bogalusa Heart study. Hypertension 2004;44:668-673.[Abstract/Free Full Text]
  40. Bowles DK, Maddali KK, Ganjam VK, et al. Endogenous testosterone increases L-type Ca2+ channel expression in porcine coronary smooth muscle Am J Physiol Heart Circl Physiol 2004;287:H2091-H2098.
  41. Rauscher FM, Goldschmidt-Clermont PJ, Davis BH, et al. Aging, progenitor cell exhaustion, and atherosclerosis Circulation 2003;108:457-463.[CrossRef][ISI][Medline]
  42. von Mering GO, Arant CB, Wessel TR, et al. Abnormal coronary vasomotion as a prognostic indicator of cardiovascular events in womenresults from the National Heart, Lung, and Blood Institute-sponsored Women’s Ischemia Syndrome Evaluation (WISE). Circulation 2004;109:722-725.[CrossRef][ISI][Medline]
  43. Cankar K, Finderle Z, Strucl M. Gender differences in cutaneous laser Doppler flow response to local direct and contralateral cooling J Vasc Res 2000;37:183-188.[CrossRef][Medline]
  44. Algotsson A, Nordberg A, Winblad B. Influence of age and gender on skin vessel reactivity to endothelium-dependent and endothelium-independent vasodilators tested with iontophoresis and a laser Doppler perfusion imager J Gerontol A Biol Sci Med Sci 1995;50:M121-M127.[Abstract]
  45. Bugiardini R, Bairey Merz CN. Angina with "normal" coronary arteriesa changing philosophy. JAMA 2005;293:477-484.[Abstract/Free Full Text]
  46. Bøttcher M, Bøtker HE, Sonne H, Nielsen TT, Czernin J. Endothelium-dependent and -independent perfusion reserve and the effect of L-arginine on myocardial perfusion in patients with syndrome X Circulation 1999;99:1795-1801.[Medline]
  47. Clarkson P, Celermajer DS, Donald AE, et al. Impaired vascular reactivity in insulin-dependent diabetes mellitus is related to disease duration and low density lipoprotein cholesterol levels J Am Coll Cardiol 1996;28:573-579.[Abstract]
  48. Pepine CJ. Ischemic heart disease in womenthe role of coronary microvascular dysfunction. Trans Am Clin Climatol Assoc 1999;110:107-116.[Medline]
  49. Reis SE, Holubkov R, Lee JS, et al. Coronary flow velocity response to adenosine characterizes coronary microvascular function in women with chest pain and no obstructive coronary disease—results from the pilot phase of the Women’s Ischemia Syndrome Evaluation (WISE) study J Am Coll Cardiol 1999;33:1469-1475.[Abstract/Free Full Text]
  50. Reis SE, Holubkov R, Conrad Smith AJ, et al. Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery diseaseresults from the NHLBI WISE study. Am Heart J 2001;141:735-741.[CrossRef][ISI][Medline]
  51. Marroquin OC, Holubkov R, Edmundowicz D, et al. Heterogeneity of microvascular dysfunction in women with chest pain not attributable to coronary artery diseaseimplications for clinical practice. Am Heart J 2003;145:628-635.[Medline]
  52. Johnson BD, Shaw LJ, Buchthal SD, et al. Prognosis in women with myocardial ischemia in the absence of obstructive coronary diseaseresults from the National Institutes of Health–National Heart, Lung, and Blood Institute-sponsored Women’s Ischemia Syndromes Evaluation (WISE). Circulation 2004;109:2993-2999.[CrossRef][ISI][Medline]
  53. Campisi R, Nathan L, Hernandez Pampaloni MH, et al. Noninvasive assessment of coronary microcirculatory function in postmenopausal women and effects of short-term and long-term estrogen administration Circulation 2002;105:425-430.[Abstract/Free Full Text]
  54. Mohri M, Koyanagi M, Egashira K, et al. Angina pectoris caused by coronary microvascular spasm Lancet 1998;351:1165-1169.[CrossRef][ISI][Medline]
  55. Sun H, Mohri M, Shimokawa H, Usui M, Urakami L, Takeshita A. Coronary microvascular spasm causes myocardial ischemia in patients with vasospastic angina J Am Coll Cardiol 2002;39:847-851.[Abstract/Free Full Text]
  56. Mohri M, Shimokawa H, Hirakawa Y, Masumoto A, Takeshita A. Rho-kinase inhibition with intracoronary Fasudil prevents myocardial ischemia in patients with coronary microvascular spasm J Am Coll Cardiol 2003;41:15-19.[Abstract/Free Full Text]
  57. Murakami T, Ohsato K. Prognostic impacts of practical assessment for microvascular coronary vasomotor dysfunction J Am Coll Cardiol 2002;39:231A(abstr).
  58. Sambuceti G, L’Abbate A, Marzilli M. Why should we study the coronary microcirculation? Am J Physiol Heart Circ Physiol 2000;279:H2581-H2584.[Free Full Text]
  59. Uren NG, Melin JA, De Bruyne B, Wijns W, Baudhuin T, Camici PG. Relation between myocardial blood flow and the severity of coronary-artery stenosis N Engl J Med 1994;330:1782-1788.[Abstract/Free Full Text]
  60. Uren NG, Marraccini P, Gistri R, de Silva R, Camici PG. Altered coronary vasodilator reserve and metabolism in myocardium subtended by normal arteries in patients with coronary artery disease elsewhere J Am Coll Cardiol 1993;22:650-653.[Abstract]
  61. Bolognese L, Carrabba N, Parodi G, et al. Impact of microvascular dysfunction on left ventricular remodeling and long-term clinical outcome after primary coronary angioplasty for acute myocardial infarction Circulation 2004;109:1121-1126.[CrossRef][ISI][Medline]
  62. Lagerqvist B, Säfström K, Stahle E, Wallentin L, Swahn E, FRISC II Study Group Investigators Is early invasive treatment of unstable coronary artery disease equally effective for both women and men? J Am Coll Cardiol 2001;38:41-48.[Abstract/Free Full Text]
  63. Wiviott SD, Cannon CP, Morrow DA, et al. Differential expression of cardiac biomarkers by gender in patients with unstable angina/non–ST-elevation myocardial infarctiona TACTICS-TIMI 18 (Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction 18) substudy. Circulation 2004;109:580-586.[CrossRef][ISI][Medline]
  64. Farb A, Burke AP, Tang AL, et al. Coronary plaque erosion without rupture into a lipid corea frequent cause of coronary thrombosis in sudden coronary death. Circulation 1996;93:1354-1363.[ISI][Medline]



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