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Cardiovascular Anatomy and Physiology in the Female
0899-5885/97 $0.00 + .20 Cardiovascular Disease in Women
Cardiovascular Anatomy and Physiology in the Female Sue Wingate RN, DNSc, CS
In recent years, health professionals have been sensitized to the clinical differences that exist between men and women in the area of cardiovascular disease. Increased attention has been focused on the female manifestations of cardiovascular illness in an attempt to understand underlying gender differences. Most important, however, in gaining a better understanding of the gender differences in cardiovascular illness, is recognizing and undep;tanding the basic anatomic and physiologic differences between the sexes. Men and women have very important differences in their cardiovascular anatomy and physiology. When one comprehends these basic differences, the clinical manifestations are easier to understand. The purpose of this article is to review selected anatomic and physiologic differences in the cardiovascular system between men and women. The following areas are reviewed: anatomy, resting physiology, exercise physiology, electrocardiogram, lipids, hemostasis, and effects of estrogen.
From the Critical and Acute Care Patient Services, Warren Grant Magnuson Clinical Center, The National Institutes of Health, Bethesda, Maryland
Anatomy Women have smaller and lighter hearts than men.11 • 16 Body mass index is also lower in women, and body mass index is a strong predictor of left ventricular (LV) mass in normotensive men and women. 17 Although LV mass increases with age for both sexes, this increase is greater in women. In fact, between the ages of 70 and 79 years, women's LV mass increases by approximately 15%, while men's decreases slightly by about 6%.21 Studies using animal models have elucidated potential reasons as to why men have higher LV mass than women and why women's LV mass increases more with age. Estrogen and androgen receptors have been found in the blood vessels and cardiac tissue of animals. 21 It has been postulated that decreased levels of estrogen in postmenopausal women may influence the increase in LV mass that occurs as women age. As with overall heart size, LV dimensions are significantly related to body surface area;12 thus, most women have smaller LV dimensions than men. In terms of the coronary arteries, the cross-sectional area of the coronary arteries is smaller in women, 32 but this difference owes solely to differences in the weight of the heart between the sexes.11 A female
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heart weighs approximately 375 grams, while a male heart weighs approximately 500 grams.32 In addition, the right coronary artery has been reported to be more dominant in women. 19
Resting Physiology There are differences in heart volume between the sexes, but one-fourth to one-third of this variance is likely owing to body weight and thoracic diameter rather than to gender itself.30 Thus, women have lower LV enddiastolic pressures and volumes than men; however, women have both a higher ejection fraction and a higher rate of ejection than men.2 Buonanno et al2 summarized these findings by noting that women have a smaller left ventricle, with diastolic filling occurring at a lower pressure owing to greater ventricular distensibility. Women's hearts contract more in systole and at a higher velocity, which suggests that women are in a constant hyperdynamic state.2 Animal studies have indicated that stroke work is higher in men, which may indicate that there are fundamental differences in cardiac contractility between the sexes.21Further, there are gender differences in oxygen transportation and delivery owing to women's lower V0 2max, lower hemoglobin levels, and smaller blood volume.21 Women also have a higher age-adjusted rate of LV hypertrophy at all blood pressure levels 26 and have a more exaggerated LV hypertrophy response to a chronic pressure load. 21' 37 Animal studies have also indicated that sex hormones influence the deposition of fibrous proteins such as collagen and elastin in the heart; specifically, testosterone increases this deposition and estrogen decreases this deposition.13 This may be a factor in women's higher incidence of LY rupture postmyocardial infarction.
Exercise Physiology Women, have approximately a 15% lower oxygen consumption than men; 12however, oxygen consumption and aerobic capacity are similar when oxygen consumption is indexed to body weight. 18 Before puberty, there is no difference in V0 2 max between the sexes.
However, after puberty, women do not attain as high a V0 2max as men because (1) women have a higher percent body fat; (2) women have a lower oxygen-carrying capacity (owing to a lower hemoglobin level, a smaller heart and a smaller blood volume); and (3) ;omen have a smaller muscle fiber area (85% of mean fiber area of men). 29 Women and men demonstrate the same level of exercise effort18· 29 although there are some significant differences in the cardiac response to exercise between the sexes. Women have a proportionately higher cardiac output during exercise, likely owing to a lower oxygen-carrying capacity and a lower peripheral oxygen extraction. 29 Women also have a slightly higher heart rate response to exercise at submaximal exercise, whereas heart rate is age-dependent at maximal exercise.29 While both men and women increase the stroke volume during exercise, they do so by different mechanisms. Men increase the stroke volume by increases in ejection fraction, with no major increases in end-diastolic volume. Women, however, do not demonstrate large increases in ejection fraction with exercise; rather, they increase the enddiastolic volume as a means of increasing stroke volume. 18 These ejection fraction changes have been found to occur independently of physical fitness levels. 18 The ECG response to exercise testing has long been seen as being quite different in women and women have shown abnormal respon;es to exercise tests despite having normal coronary arteries. Cumming et al 8 studied normal women aged 20 to 83 years and found that 25% of women 20 to 39 years, 50% of women 40 to 59 years, and 66% of women over 60 years had ECG changes consistent with ischemia. The major reason for this high rate of false-positive exercise tests in women is the lower prevalence of coronary heart disease in women. Other factors that may be operative include women's lower hematocrit level women's higher systemic and pulmo, . M d nary pressure response to exercise, an 1 women's higher level of circulating estrogen 6 (estrogen has a similar chemical structure to digitalis and may cause a digitalis-like effect on the ECG). The article by Laurienzo in this issue provides more detail on the issue of exercise testing in women.
CARDIOVASCULAR ANATOMY AND PHYSIOLOGY IN THE FEMALE
The phase of the menstrual cycle may be important in determining the vascular volume dynamics during exercise, although these changes may be more pronounced in inactive, rather than trained, women. 29 A study by Clark et al5 showed that there was a greater probability for an abnormal exercise test during the menstrual and pre-ovulatory phases of the cycle, likely owing to the progesterone flux during these times. They found no relationship between the estrogen phase of the cycle and abnormal exercise test results.
Electrocardiogram The ECG does not, in itself, represent anatomic or physiologic differences between the sexes. However, underlying anatomic and physiologic differences are what cause the ECG to portray different configurations between the sexes. Women have a higher resting heart rate than men owing to a higher parasympathetic tone in men, 31 and a physiologic sympathetic hyperactivity in women.2In terms of heart rate variability, women have a higher frequency of heart rate fluctuation and an overall higher complexity of their heart rate dynamics. 34 Women also have a longer sinus cycle length, perhaps owing to differences in exercise capacity, and this cycle length varies throughout the menstrual cycle.3 Although there are minor differences between the sexes in the amplitudes of the R, S, and T waves on the limb leads of the ECG, women have smaller R, S, and T amplitudes on the precordial leads of the ECG. 36 The QRS and PR intervals are shorter in women in the limb leads,31, 36 and the QRS interval is also shorter in women on the signal-averaged ECG. 28 The QRS interval is longer in men by approximately 8 milliseconds (ms) and is due to men's larger heart size.31 The rate-corrected QT interval is longer in women during their reproductive years and this is owing to a highly significant shortening of this interval in men after puberty rather than a prolongation of this interval in women after menarche. 31 This may be owing to the sex differences in serum calcium in young adults (increased serum calcium in boys and a decreased serum calcium in girls after menarche). 31
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Lipids That lipoprotein levels are different in men and women of the same age largely is owing to endogenous, gonadal hormones. Estrogen increases the levels of HDL and triglycerides and lowers the level of LDL, while testosterone decreases the levels ofHDL and triglycerides and increases the level ofLDL. In general, LDL levels are lower in women until the age of 55 years, when female levels then become higher than male levels. At a given level, LDL may be less atherogenic in women because estrogen may protect the arterial wall against LDL deposition. However, as women age, the percentage of smaller, dense LDL increases and these smaller, dense LDL particles are more susceptible to oxidation. 25 The occurrence of small, dense LDL particles have been associated with hypertriglyceridemia. In men and younger women, triglyceride levels are not independent predictors of coronary risk when HDL and LDL levels are considered in the risk analysis. However, in older postmenopausal women, triglyceride levels are an independent risk for coronary disease .1· 4 HDL levels decrease in men after puberty, owing to androgens, but HDL levels do not decrease in women; in fact, HDL levels continue to be higher in women even after menopause.25 HDL is a more potent predictor of cardiovascular risk in women than in men, suggesting that HDL may function differently in women than it does in men. 25 Lipoprotein A, also known as Lp(a), is a molecule with both lipoprotein and clotting potential that has been shown to be a risk factor for cardiovascular disease in both men and women.9• 35 Some studies have indicated that there are gender differences in the level of this molecule,35 whereas others have noted no differences.38 Estrogen is a dominant influence on lipoprotein levels during the menstrual cycle as seen by LDL levels decreasing early and staying low even in the second half of the cycle. 25 During pregnancy, HDL and LDL levels increase owing to the increase in endogenous estrogen and progesterone. LDL levels stay elevated until several weeks after delivery, but HDL levels decrease at the 24th week of pregnancy and are only slightly higher than nonpregnant levels at the time of delivery. Triglyceride levels increase during pregnancy
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but fall more rapidly after delivery than do LDL levels.25
premenopausal women have a more efficient metabolism of homocysteine derivatives, which protects them against accumulations of these byproducts. 38
Hemostasis Presented here is a very general summary of differences in hemostasis between men and women. Refer to the article by Mayo in this issue for more detailed information on hemostasis and thrombosis in women. There are no gender differences in plasma viscosity; however, whole blood viscosity is higher in men than women. Io, 11 Whole blood volume is also higher in men because of their higher hematocrit levels.Io Platelet counts are similar between genders, although the platelet count does vary for women throughout their menstrual cycle. 38 Platelet function, however, does not change during the menstrual cycle nor during pregnancy. Bleeding time and coagulation factors are similar between men and women, although fibrinogen and factor VII levels are slightly but not significantly higher in women. 38 Levels of protease inhibitors that serve as regulators of activated coagulation do not differ between the sexes but may be affected by sex hormones.38 In general, men have lower tissue plasminogen activator (tPA) levels and higher plasminogen activator inhibitor-one (PAI-1) levels than women. 22 PAI-1 is a glycoprotein that binds to endothelium-derived plasminogen activator, thus inactivating the main vascular mechanism for inhibiting thrombus formation and propagation. 20 • 33 Elevated PAI-1 levels have been associated with an increased risk of myocardial infarction. With age, however, tPA and PAI-1 levels increase in women so that by the age of 60 years, women have higher PAI-1 levels than men. An elevation of plasma homocysteine levels has been found to alter vascular function and has been recognized as a risk factor for occlusive vascular disease. Homocysteine affects endothelial function by enhancing the binding of Lp(a) to vascular cells and by decreasing thrombin inactivation and fibrinolysis at the endothelial surface. Healthy young women have lower homocysteine levels than do healthy men, with the difference diminishing with aging. It has been suggested that
Effects of Estrogen The difference in sex hormones between the sexes likely accounts for many of the physiologic differences between men and women. Research in this area is promising and becoming quite extensive; however, only a summary of this information is presented here as a more detailed review is beyond the scope of this article. Estrogen effects are multifactorial, and new insights are steadily being gleaned from ongoing research. Estrogen has both acute and chronic effects that are important in cardiovascular physiology and the manifestation of cardiovascular illness. Acutely, estrogen has important effects on the vascular system and the response of the arterial wall to physiologic and biochemical stimuli. One of the important effects of estrogen is related to its interaction with nitric oxide. Nitric oxide is produced continuously within endothelial cells of blood vessels, and it appears to regulate vascular homeostasis by affecting vascular tone, controlling the cellular composition of the vessel wall, and inhibiting platelet and inflammatory cell attachment to the endothelium.7 There are estrogen-induced decreases in circulating LDL that may decrease the tissue concentration of oxidized LDL and therefore facilitate nitric oxide synthesis and release. Further, estrogen-induced decreases in Lp(a) could enhance nitrous oxide bioactivity if concentrations of oxidized Lp(a), which inhibit nitric oxide bioactivity,15 were decreased within the vessel wall. Estrogen also increases the local production of prostacycline, which leads to vasodilation and the prevention of platelet aggregation.27 In addition, postmenopausal estrogen treatment has been found to decrease PAI-1 levels by approximately 50%, presumably a favorable effect on thrombogenic potential. 23 All of these effects indicate that estrogen has powerful, beneficial effects on the arterial wall, vasodilation, platelet aggregation, and thrombogenesis.
CARDIOVASCULAR ANATOMY AND PHYSIOLOGY IN THE FEMALE
On a more chronic basis, estrogen has effects on the lipid profile that help to retard atherosclerosis. As previously noted, estrogen decreases levels of total cholesterol, LDL, and Lp(a) and increases levels of HDL and triglycerides. It is important to note that there are several estrogen preparations available and that these
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preparations may cause different effects. For example, synthetic estrogens may overstimulate the hepatic production of proteins (such as renin and angiotensinogen), which may lead to hypertension, vasoconstriction, and platelet aggregation, whereas natural estrogens do not stimulate the hepatic production of proteins.27
SUMMARY Important differences in male and female cardiovascular anatomy and physiology may account for many of the gender differences seen in various cardiac disease states. Predominant influences on female disease manifestations include (1) women's smaller body size, hence smaller hearts and smaller coronary vessels and (2) women's fluctuating levels of estrogen throughout their lifespan. Understanding these critical anatomic and physiologic differences allows the clinician to better predict and plan care for women. For example, knowing that women generally have a smaller body surface area than men allows one to better understand why men have higher creatine kinase (CK) values than do women6· 39-an important distinction when interpreting these values in the acute care setting. The fact that women's hearts and coronary vessels are generally smaller than men's also helps one understand why women have a higher inhospital mortality than men post-coronary artery bypass graft surgery14 (see article by Allen in this issue for more detailed information on revascularization). These are only a few examples of the many opportunities that acute care nurses have to integrate their knowledge of anatomy and physiology into proactive planning for their female cardiac patients.
REFERENCES 1. Austin MA: Epidemiologic associations between hypertriglyceridemia and coronary heart disease. Semin Thromb Hemost 14:137, 1988 2. Buonanno C, Arbustini E, Rossi L, et al: Left ventricular function in men and women: Another difference between the sexes. European Heart J 3:525, 1982 3. Burke JH, Goldberger]], Ehlert FA, et al: Gender differences in heart rate before and after autonomic blockade: Evidence against an intrinsic gender effect. Am J Med 100:537, 1996 4. Castelli WP: The triglyceride issue: A view from Framingham. Am Heart J 112:432, 1986 5. Clark P, Glasser S, Lyman G, et al: Relation of results of exercise stress tests in young women to phases of the menstrual cycle. Am J Cardiol 61:197, 1988 6. Cook JC, Wong E, Haywood LJ: Creatine kinase: Race-gender differences in patients hospitalized for suspected myocardial infarction. J Nat Med Assoc 82:249, 1990 7. Cooke JP, Tsao PS: Cytoprotective effects of nitric oxide. Circulation 88:2451, 1993 8. Cumming GR, Dufresne C, Kich L, et al: Exercise electrocardiogram patterns in normal women. Br Heart J 35:1055, 1973
9. Dahlen GH: Incidence of Lp(a) lipoprotein among populations. In Scanu AM (ed): Lipoprotein (a). New York, Academic Press, 1990, p 151 10. deSimone G, Devereux RB, Chien S, et al: Relacion of blood viscosity to demographic and physiologic variables and to cardiovascular risk factors in apparently normal adults. Circulation 81 :107, 1990 11. deSimone G, Devereux RB, Roman MJ, et al: Gender differences in left ventricular anatomy, blood viscosity and volume regulatory hormones in no rmal adults. Am J Cardiol 68:1704, 1991 12. Devereux RB, Lutas EM, Casale PN, et al: Standardization of m-mode echocardiographic left ventricular anatomic measurements. J Am Coll Cardiol 4:122, 1984 13. Fischer GM, Swain ML: Effects of sex hormones on blood pressure and vascular connective tissue in castrated and noncastrated male rats. Am J Physiol 232:H617, 1977 14. Fisher LD, Kennedy ]W, Davis KB, et al: Association of sex, physical size, and operative mortality after coronary artery bypass in the Coronary Artery Surgery Study (CASS). J Thorac Cardiovasc Surg 84: 334, 1982 15. Galle J, Bengen J, Schollmeyer P, et al: Impairment of endothelium-dependent dilation in rabbit renal
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arteries by oxidized lipoprotein (a): Role of oxygenderived radicals. Circulation 92:1582, 1995 Glazer MD, Hurst]W: Coronary atherosclerotic heart disease: Some important differences in men and women. Am J Noninvas Cardiol 1:61, 1987 Hammond IW, Devereux RB, Alderman MH, et al: Relation of blood pressure and body build to left ventricular mass in normotensive and hypertensive employed adults. J Am Coll Cardiol 12:996, 1988 Higginbotham MB, Morris KG , Coleman RE, et al: Sex-related differences in the normal cardiac response to upright exercise. Circulation 70:357, 1984 Holm K, Penckoffer S, Keresztes P, et al: Coronary artery disease in women: Assessment, diagnosis, intervention, and strategies for lifestyle change. AWHONN's Clinical Issues in Perinatal and Women's Health Nursing 4:272, 1993 Joannides R, Haefeli WE, Lindner L, et al: Nitric oxide is responsible for flow-mediated dilation of human peripheral conduit arteries in vivo. Circulation 92:1314, 1995 Klapholz M, Buttrick P: Myocardial function and cardiomyopathy. In Douglas PS (ed): Cardiovascular Health and Disease in Women. Philadelphia, WB Saunders, 1993, p 105 Koh SC, Yuen R, Viegas OA, et al: Plasminogen activators t-PA, u-PA and its inhibitor (PAl) in normal males and females. Thromb Haemostas 66:581, 1991 Kroon U-B, Silfverstolpe G, Tengborn L: The effects of transdermal estradiol and oral conjugated estrogens on hemostasis variables. Thromb Haemostas 71:420, 1994 Kusmi F, Bruce RA, Ross MA, et al: Elevated arterial pressure and post-exertional ST segment depression in middle-aged women. Am Heart J 92:576, 1976 LaRosaJC: Lipoproteins and lipid disorders. In Douglas PS (ed): Cardiovascular Health and Disease in Women. Philadelphia, WB Saunders, 1993, p 175 Lauer MS, Anderson KM , Levy D: Influences of contemporary versus 30-year blood pressure levels on left ventricular mass and geometry: The Framingham Heart Study.] Am Coll Cardiol 18:1287, 1991
27. L'Hermite ML: Risks of estrogens and progestogens. Maturitas 12:215, 1990 28. Macfarlane PW, McLaughlin SC, Devine B, et al: Effects of age, sex, and race on ECG interval measurements. J Electrocardiol 27 Suppl:l4, 1994 29. O'Toole ML: Exercise and physical activity. In Douglas PS (eel): Cardiovascular Health and Disease in Women. Philadelphia, WB Saunders, 1993, p 253 30. Rautaharju PM, Lacroix AZ, Savage DD, et al: Heart size estimates indexed optimally to body and chest size. Am J Noninvas Cardiol 4:104, 1990 31. Rautaharju PM, Zhou SH, Wong S, et al: Sex differences in the evolution of the electrocardiographic QT interval with age. Can J Cardiol 8:690, 1992 32. Roberts CS, Roberts WC: Cross-sectional area of the proximal portions of the three major epicardial coronary arteries in 98 necropsy patients with different coronary events. Circulation 62:953, 1980 33. Rosselli M, Imthurn B, Keller PJ, et al: Circulating nitric oxide (nitrite/nitrate) levels in postmenopausal women substituted with 17{3-estradiol and noresthisterone. Hypertension 25 (part 2):848, 1995 34. Ryan SM, Goldberger AL, Pincus SM, et al: Genderand age-related differences in heart rate dynamics: Are women more complex than men? J Am Coll Cardiol 24:1700, 1994 35. Sandkamp M, Assmann G: Lipoprotein (a) in PROCAM participants and young myocardial infarction survivors. In Scanu AM (ed): Lipoprotein (a). New York, Academic Press, 1990, p 205 36. Simonson E, Blackburn H, Puchner TC, et al: Sex differences in the electrocardiogram. Circulation 22:598, 1960 37. Topol EJ, Traill A, Fortuin NJ: Hypertensive hypertrophic cardiomyopathy of the elderly. N Engl J Med 312:277, 1985 38. Weksler BB: Hemostasis and thrombosis. In Douglas PS (ed): Cardiovascular Health and Disease in Women. Philadelphia, WB Saunders, 1993, p 231 39. Wong ET, Cobb C, Umehara MK, et al: Heterogeneity of serum creatine kinase activity among racial and gender groups of the population. Am] Clin Pathol 79:582, 1983 Address reprint requests to Sue Wingate, RN, DNSc, CS 12434 Galesville Drive Gaithersburg, MD 20878
Cardiovascular Anatomy and Physiology in the Female Sue Wingate RN, DNSc, CS
In recent years, health professionals have been sensitized to the clinical differences that exist between men and women in the area of cardiovascular disease. Increased attention has been focused on the female manifestations of cardiovascular illness in an attempt to understand underlying gender differences. Most important, however, in gaining a better understanding of the gender differences in cardiovascular illness, is recognizing and undep;tanding the basic anatomic and physiologic differences between the sexes. Men and women have very important differences in their cardiovascular anatomy and physiology. When one comprehends these basic differences, the clinical manifestations are easier to understand. The purpose of this article is to review selected anatomic and physiologic differences in the cardiovascular system between men and women. The following areas are reviewed: anatomy, resting physiology, exercise physiology, electrocardiogram, lipids, hemostasis, and effects of estrogen.
From the Critical and Acute Care Patient Services, Warren Grant Magnuson Clinical Center, The National Institutes of Health, Bethesda, Maryland
Anatomy Women have smaller and lighter hearts than men.11 • 16 Body mass index is also lower in women, and body mass index is a strong predictor of left ventricular (LV) mass in normotensive men and women. 17 Although LV mass increases with age for both sexes, this increase is greater in women. In fact, between the ages of 70 and 79 years, women's LV mass increases by approximately 15%, while men's decreases slightly by about 6%.21 Studies using animal models have elucidated potential reasons as to why men have higher LV mass than women and why women's LV mass increases more with age. Estrogen and androgen receptors have been found in the blood vessels and cardiac tissue of animals. 21 It has been postulated that decreased levels of estrogen in postmenopausal women may influence the increase in LV mass that occurs as women age. As with overall heart size, LV dimensions are significantly related to body surface area;12 thus, most women have smaller LV dimensions than men. In terms of the coronary arteries, the cross-sectional area of the coronary arteries is smaller in women, 32 but this difference owes solely to differences in the weight of the heart between the sexes.11 A female
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heart weighs approximately 375 grams, while a male heart weighs approximately 500 grams.32 In addition, the right coronary artery has been reported to be more dominant in women. 19
Resting Physiology There are differences in heart volume between the sexes, but one-fourth to one-third of this variance is likely owing to body weight and thoracic diameter rather than to gender itself.30 Thus, women have lower LV enddiastolic pressures and volumes than men; however, women have both a higher ejection fraction and a higher rate of ejection than men.2 Buonanno et al2 summarized these findings by noting that women have a smaller left ventricle, with diastolic filling occurring at a lower pressure owing to greater ventricular distensibility. Women's hearts contract more in systole and at a higher velocity, which suggests that women are in a constant hyperdynamic state.2 Animal studies have indicated that stroke work is higher in men, which may indicate that there are fundamental differences in cardiac contractility between the sexes.21Further, there are gender differences in oxygen transportation and delivery owing to women's lower V0 2max, lower hemoglobin levels, and smaller blood volume.21 Women also have a higher age-adjusted rate of LV hypertrophy at all blood pressure levels 26 and have a more exaggerated LV hypertrophy response to a chronic pressure load. 21' 37 Animal studies have also indicated that sex hormones influence the deposition of fibrous proteins such as collagen and elastin in the heart; specifically, testosterone increases this deposition and estrogen decreases this deposition.13 This may be a factor in women's higher incidence of LY rupture postmyocardial infarction.
Exercise Physiology Women, have approximately a 15% lower oxygen consumption than men; 12however, oxygen consumption and aerobic capacity are similar when oxygen consumption is indexed to body weight. 18 Before puberty, there is no difference in V0 2 max between the sexes.
However, after puberty, women do not attain as high a V0 2max as men because (1) women have a higher percent body fat; (2) women have a lower oxygen-carrying capacity (owing to a lower hemoglobin level, a smaller heart and a smaller blood volume); and (3) ;omen have a smaller muscle fiber area (85% of mean fiber area of men). 29 Women and men demonstrate the same level of exercise effort18· 29 although there are some significant differences in the cardiac response to exercise between the sexes. Women have a proportionately higher cardiac output during exercise, likely owing to a lower oxygen-carrying capacity and a lower peripheral oxygen extraction. 29 Women also have a slightly higher heart rate response to exercise at submaximal exercise, whereas heart rate is age-dependent at maximal exercise.29 While both men and women increase the stroke volume during exercise, they do so by different mechanisms. Men increase the stroke volume by increases in ejection fraction, with no major increases in end-diastolic volume. Women, however, do not demonstrate large increases in ejection fraction with exercise; rather, they increase the enddiastolic volume as a means of increasing stroke volume. 18 These ejection fraction changes have been found to occur independently of physical fitness levels. 18 The ECG response to exercise testing has long been seen as being quite different in women and women have shown abnormal respon;es to exercise tests despite having normal coronary arteries. Cumming et al 8 studied normal women aged 20 to 83 years and found that 25% of women 20 to 39 years, 50% of women 40 to 59 years, and 66% of women over 60 years had ECG changes consistent with ischemia. The major reason for this high rate of false-positive exercise tests in women is the lower prevalence of coronary heart disease in women. Other factors that may be operative include women's lower hematocrit level women's higher systemic and pulmo, . M d nary pressure response to exercise, an 1 women's higher level of circulating estrogen 6 (estrogen has a similar chemical structure to digitalis and may cause a digitalis-like effect on the ECG). The article by Laurienzo in this issue provides more detail on the issue of exercise testing in women.
CARDIOVASCULAR ANATOMY AND PHYSIOLOGY IN THE FEMALE
The phase of the menstrual cycle may be important in determining the vascular volume dynamics during exercise, although these changes may be more pronounced in inactive, rather than trained, women. 29 A study by Clark et al5 showed that there was a greater probability for an abnormal exercise test during the menstrual and pre-ovulatory phases of the cycle, likely owing to the progesterone flux during these times. They found no relationship between the estrogen phase of the cycle and abnormal exercise test results.
Electrocardiogram The ECG does not, in itself, represent anatomic or physiologic differences between the sexes. However, underlying anatomic and physiologic differences are what cause the ECG to portray different configurations between the sexes. Women have a higher resting heart rate than men owing to a higher parasympathetic tone in men, 31 and a physiologic sympathetic hyperactivity in women.2In terms of heart rate variability, women have a higher frequency of heart rate fluctuation and an overall higher complexity of their heart rate dynamics. 34 Women also have a longer sinus cycle length, perhaps owing to differences in exercise capacity, and this cycle length varies throughout the menstrual cycle.3 Although there are minor differences between the sexes in the amplitudes of the R, S, and T waves on the limb leads of the ECG, women have smaller R, S, and T amplitudes on the precordial leads of the ECG. 36 The QRS and PR intervals are shorter in women in the limb leads,31, 36 and the QRS interval is also shorter in women on the signal-averaged ECG. 28 The QRS interval is longer in men by approximately 8 milliseconds (ms) and is due to men's larger heart size.31 The rate-corrected QT interval is longer in women during their reproductive years and this is owing to a highly significant shortening of this interval in men after puberty rather than a prolongation of this interval in women after menarche. 31 This may be owing to the sex differences in serum calcium in young adults (increased serum calcium in boys and a decreased serum calcium in girls after menarche). 31
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Lipids That lipoprotein levels are different in men and women of the same age largely is owing to endogenous, gonadal hormones. Estrogen increases the levels of HDL and triglycerides and lowers the level of LDL, while testosterone decreases the levels ofHDL and triglycerides and increases the level ofLDL. In general, LDL levels are lower in women until the age of 55 years, when female levels then become higher than male levels. At a given level, LDL may be less atherogenic in women because estrogen may protect the arterial wall against LDL deposition. However, as women age, the percentage of smaller, dense LDL increases and these smaller, dense LDL particles are more susceptible to oxidation. 25 The occurrence of small, dense LDL particles have been associated with hypertriglyceridemia. In men and younger women, triglyceride levels are not independent predictors of coronary risk when HDL and LDL levels are considered in the risk analysis. However, in older postmenopausal women, triglyceride levels are an independent risk for coronary disease .1· 4 HDL levels decrease in men after puberty, owing to androgens, but HDL levels do not decrease in women; in fact, HDL levels continue to be higher in women even after menopause.25 HDL is a more potent predictor of cardiovascular risk in women than in men, suggesting that HDL may function differently in women than it does in men. 25 Lipoprotein A, also known as Lp(a), is a molecule with both lipoprotein and clotting potential that has been shown to be a risk factor for cardiovascular disease in both men and women.9• 35 Some studies have indicated that there are gender differences in the level of this molecule,35 whereas others have noted no differences.38 Estrogen is a dominant influence on lipoprotein levels during the menstrual cycle as seen by LDL levels decreasing early and staying low even in the second half of the cycle. 25 During pregnancy, HDL and LDL levels increase owing to the increase in endogenous estrogen and progesterone. LDL levels stay elevated until several weeks after delivery, but HDL levels decrease at the 24th week of pregnancy and are only slightly higher than nonpregnant levels at the time of delivery. Triglyceride levels increase during pregnancy
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but fall more rapidly after delivery than do LDL levels.25
premenopausal women have a more efficient metabolism of homocysteine derivatives, which protects them against accumulations of these byproducts. 38
Hemostasis Presented here is a very general summary of differences in hemostasis between men and women. Refer to the article by Mayo in this issue for more detailed information on hemostasis and thrombosis in women. There are no gender differences in plasma viscosity; however, whole blood viscosity is higher in men than women. Io, 11 Whole blood volume is also higher in men because of their higher hematocrit levels.Io Platelet counts are similar between genders, although the platelet count does vary for women throughout their menstrual cycle. 38 Platelet function, however, does not change during the menstrual cycle nor during pregnancy. Bleeding time and coagulation factors are similar between men and women, although fibrinogen and factor VII levels are slightly but not significantly higher in women. 38 Levels of protease inhibitors that serve as regulators of activated coagulation do not differ between the sexes but may be affected by sex hormones.38 In general, men have lower tissue plasminogen activator (tPA) levels and higher plasminogen activator inhibitor-one (PAI-1) levels than women. 22 PAI-1 is a glycoprotein that binds to endothelium-derived plasminogen activator, thus inactivating the main vascular mechanism for inhibiting thrombus formation and propagation. 20 • 33 Elevated PAI-1 levels have been associated with an increased risk of myocardial infarction. With age, however, tPA and PAI-1 levels increase in women so that by the age of 60 years, women have higher PAI-1 levels than men. An elevation of plasma homocysteine levels has been found to alter vascular function and has been recognized as a risk factor for occlusive vascular disease. Homocysteine affects endothelial function by enhancing the binding of Lp(a) to vascular cells and by decreasing thrombin inactivation and fibrinolysis at the endothelial surface. Healthy young women have lower homocysteine levels than do healthy men, with the difference diminishing with aging. It has been suggested that
Effects of Estrogen The difference in sex hormones between the sexes likely accounts for many of the physiologic differences between men and women. Research in this area is promising and becoming quite extensive; however, only a summary of this information is presented here as a more detailed review is beyond the scope of this article. Estrogen effects are multifactorial, and new insights are steadily being gleaned from ongoing research. Estrogen has both acute and chronic effects that are important in cardiovascular physiology and the manifestation of cardiovascular illness. Acutely, estrogen has important effects on the vascular system and the response of the arterial wall to physiologic and biochemical stimuli. One of the important effects of estrogen is related to its interaction with nitric oxide. Nitric oxide is produced continuously within endothelial cells of blood vessels, and it appears to regulate vascular homeostasis by affecting vascular tone, controlling the cellular composition of the vessel wall, and inhibiting platelet and inflammatory cell attachment to the endothelium.7 There are estrogen-induced decreases in circulating LDL that may decrease the tissue concentration of oxidized LDL and therefore facilitate nitric oxide synthesis and release. Further, estrogen-induced decreases in Lp(a) could enhance nitrous oxide bioactivity if concentrations of oxidized Lp(a), which inhibit nitric oxide bioactivity,15 were decreased within the vessel wall. Estrogen also increases the local production of prostacycline, which leads to vasodilation and the prevention of platelet aggregation.27 In addition, postmenopausal estrogen treatment has been found to decrease PAI-1 levels by approximately 50%, presumably a favorable effect on thrombogenic potential. 23 All of these effects indicate that estrogen has powerful, beneficial effects on the arterial wall, vasodilation, platelet aggregation, and thrombogenesis.
CARDIOVASCULAR ANATOMY AND PHYSIOLOGY IN THE FEMALE
On a more chronic basis, estrogen has effects on the lipid profile that help to retard atherosclerosis. As previously noted, estrogen decreases levels of total cholesterol, LDL, and Lp(a) and increases levels of HDL and triglycerides. It is important to note that there are several estrogen preparations available and that these
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preparations may cause different effects. For example, synthetic estrogens may overstimulate the hepatic production of proteins (such as renin and angiotensinogen), which may lead to hypertension, vasoconstriction, and platelet aggregation, whereas natural estrogens do not stimulate the hepatic production of proteins.27
SUMMARY Important differences in male and female cardiovascular anatomy and physiology may account for many of the gender differences seen in various cardiac disease states. Predominant influences on female disease manifestations include (1) women's smaller body size, hence smaller hearts and smaller coronary vessels and (2) women's fluctuating levels of estrogen throughout their lifespan. Understanding these critical anatomic and physiologic differences allows the clinician to better predict and plan care for women. For example, knowing that women generally have a smaller body surface area than men allows one to better understand why men have higher creatine kinase (CK) values than do women6· 39-an important distinction when interpreting these values in the acute care setting. The fact that women's hearts and coronary vessels are generally smaller than men's also helps one understand why women have a higher inhospital mortality than men post-coronary artery bypass graft surgery14 (see article by Allen in this issue for more detailed information on revascularization). These are only a few examples of the many opportunities that acute care nurses have to integrate their knowledge of anatomy and physiology into proactive planning for their female cardiac patients.
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