February 2019 Issue

Sex, Gender, & CVD
By Karen Collins, MS, RDN, CDN, FAND
Today's Dietitian
Vol. 21, No. 2, P. 18

Learn about the differences in the pathophysiology, etiology, and presentation of CVD in men and women.

For many years, diagnosis and treatment of CVD in men and women was based on research conducted mostly in men. However, work in the last two decades has led to recognition of differences between the sexes in pathophysiology, symptoms, efficacy of diagnostic tests and medications, and health-related behavior patterns. All these may contribute to differences in clinical outcomes.

This article reviews the current understanding of differences in how CVD develops and presents in men and women and considers the implications for dietitians' messages about its prevention and treatment.

Sex and Gender
People may use the terms "sex" and "gender" interchangeably, but in medical discussions on CVD, they refer to different aspects of variations between men and women.

• Sex refers to biological differences, including differences in gene expression from sex chromosomes, hormones, and sex organs, which often are reproducible in animal models. Sex differences lead to differences in the structure and function of the cardiovascular systems of men and women. The result is differences in autonomic regulation, hypertension, diabetes, and vascular and cardiac remodeling.1

• Gender differences are unique to humans and develop from cultural norms, influenced by factors such as ethnicity and socioeconomic environment. Gender is expressed through values, perceptions, and behaviors.2 It's been suggested that since about 80% of heart disease may be preventable through lifestyle choices and risk factor management,3 gender differences in risk factor–related behaviors may play a greater role in outcomes among women with heart disease than do biological sex differences.1,2

CVD Trends
After decades of annual reductions in age-adjusted CVD mortality, rates in recent years have plateaued and even increased modestly.3 Alarmingly, this increase principally has occurred among a group traditionally considered low-risk: women aged 35 to 54.3,4 This increase has been attributed to a rising prevalence of risk factors among these women, especially hypertension and diabetes.4

Comparing men with women, absolute number of annual CVD deaths has been higher in women since 1984, but the latest national data show deaths in men now is slightly higher.3 Age-standardized CVD mortality rate is higher in men, and the prevalence of CVD among men exceeds that of women until age 80.3,5 CVD tends to occur at a later age in women, when they may be more frail and have more complications from comorbidities. Within five years after a heart attack, women are more likely than men to develop heart failure or die.6

CVD in Men and Women
The largest contributor to CVD and CVD mortality for both men and women is ischemic heart disease (IHD),3,7 which can refer to ischemia originating in the coronary arteries, in the microcirculation, or due to an imbalance in myocardial oxygen supply and demand.

In men, cardiac ischemia primarily involves anatomically obstructive coronary artery disease (CAD).7 This is the description of heart disease with which most people are familiar: Plaque builds up and narrows coronary arteries, reducing blood flow and thus reducing oxygen to the heart muscle. Heart attack can be due to this blockage or to a thrombus produced when the plaque ruptures. This obstructive disease of the coronary arteries can be successfully diagnosed with angiography.

In women, CAD is also common but less prevalent than in men. Nearly 60% of women with ischemic symptoms reportedly have no flow-limiting stenosis,7 and, among people with stable IHD, women are five times more likely to be diagnosed with normal coronary arteries than men.2 IHD in women often can be attributed to abnormal coronary reactivity, microvascular dysfunction, endothelial dysfunction, vasomotor abnormalities, spontaneous coronary artery dissection (SCAD), and stress-induced cardiomyopathy.1,2,7

This has been problematic for diagnosing heart disease in women and communicating about this diagnosis. Without obstructive CAD that can be identified by angiogram, it wasn't unusual, particularly in years past, for women presenting with angina-type symptoms to be told that their blood vessels were "clean." This could result in symptoms then attributed to psychological issues rather than pathophysiological problems that could be treated.1 A nonobstructive pattern of IHD has been identified, consisting of a triad of chest pain, an abnormal stress test consistent with ischemia, and the absence of significant obstructive IHD on angiography. Women account for about 70% of its prevalence.2

In women, heart attack due to plaque erosion with subsequent thrombus formation is more common than in men.1,2,7 Myocardial infarction with nonobstructive coronary arteries, which has been identified as representing about 6% of all myocardial infarctions, is more frequent in women.1 SCAD, which isn't associated with atherosclerosis, occurs overwhelmingly in women. Although relatively rare overall, it may be the cause of acute coronary syndrome in up to 35% of women aged 50 and younger and is the most common cause of myocardial infarction in pregnancy.8

The leading cause of long-term adult disability and the fifth-leading cause of death in the United States is stroke.9 About 87% of strokes are ischemic, commonly linked to atherosclerosis.9,10 Hemorrhagic strokes typically are associated with chronic, uncontrolled hypertension and/or vascular malformations.

Women have a higher lifetime stroke risk and have been found to have recurrent strokes more frequently than men, primarily because of their longer life span.9 Before age 75, a greater proportion of CVD events in men involves CAD, while a greater proportion in women involves stroke.6

Higher stroke risk among women at younger ages is thought to be linked to risks during and after pregnancy (ie, preeclampsia or eclampsia, and gestational diabetes) and to other hormonal factors, such as use of oral contraceptives.9 After stroke, women have higher mortality rates, are more likely to be institutionalized, and have worse quality of life compared with men.10,11

Presentation of CVD
In addition to the dissimilarities in pathophysiology and etiology, CVD often presents differently in men and women. The "classic" IHD symptom of chest pain occurs in 42% of men and 31% of women.7 Men commonly describe this pain as crushing; women more often use words such as pressure or tightening.2 Women are somewhat more likely to have shortness of breath, unusual fatigue (often for days or weeks in advance), nausea or loss of appetite, palpitations, lightheadedness, or pain in the back, shoulders, and jaw.2,4,7

Angina pain seems to occur more often with mental stress and at rest in women, whereas it's most associated with physical exertion in men. This difference may be linked to the distinctions in ischemia due to vasospastic or microvascular disease in women, rather than coronary artery obstruction in men.2

Classic symptoms of stroke shared by men and women usually (but not always) have sudden onset. The acronym FAST highlights common findings of facial drooping, arm numbness or weakness, and speech difficulty, indicating time to call 911. Other symptoms are common, however, such as severe headache with no known cause. Men primarily tend to exhibit the classic symptoms, sometimes with nystagmus; women may have more generalized symptoms, including mental status changes or weakness.10

Men and women differ not only in symptomatic presentation of CVD but also in their behavioral response. Following public education campaigns in recent years, this is beginning to change, but women are less likely to recognize symptoms they're experiencing as emergencies.

Delay in seeking treatment in response to symptoms is more common in women, particularly in younger women and women with economic, educational, social/cultural, and health care disparities.2,4,7 Studies suggest this can be due to women's lack of awareness of CVD risk, inaccurate symptom attribution, interpretation of symptoms as nonurgent and temporary, prioritizing role responsibilities over seeking health care, and barriers to accessing care.2 In the case of stroke, this may cause delay beyond the window for optimal treatment.

Risk Factors
Combining all major risk factors into prediction equations, an individual's estimated probability of developing CVD provides a basis for primary prevention strategies.12,13 Approximately 80% of IHD is reportedly preventable.2,3 Thus, risk factor modification, preferably beginning in early childhood, is essential for its prevention.

Traditional risk factors for CVD are similar in men and women: dyslipidemia, diabetes mellitus, hypertension, obesity, inactivity, smoking, family history, and older age. However, some risk factors have a stronger association with IHD or stroke in men and women. Diabetes and abdominal obesity have stronger association with IHD or stroke in women than in men; in younger adults, hypertension is more prevalent and increases risk of stroke more in men, whereas at older age, prevalence and association with CVD is greater in women.3,4,7,14 Although age is a significant risk factor in both sexes, women are typically 10 years older than men when heart disease is diagnosed.2

Risk factors often overlap. A major part of the association of age with IHD is the increased prevalence of risk factors, according to epidemiologic studies. For example, by midlife, more than 80% of women have at least one of the traditional cardiac risk factors.2 Obesity often is associated with type 2 diabetes or hypertension, yet it also is a risk factor on its own.3

Novel risk factors in women have been identified that may improve estimation of risk and diagnosis of IHD. Use of traditional risk factors alone tends to underestimate IHD risk in women, particularly among women with subclinical disease.2

• Pregnancy-associated risks: Hypertension that develops during pregnancy, and especially preeclampsia or eclampsia, pose risk even after pregnancy. They double the risk of IHD, nearly double risk of stroke, and link to a three- or four-fold increase in risk of hypertension after pregnancy.1,12 Likewise, gestational diabetes (now defined as diabetes diagnosed after the first trimester of pregnancy) remains a lifelong risk factor for diabetes and increases risk of stroke and heart attack, possibly beyond the risk related to diabetes itself.1,7 Many of these pregnancy complications appear to reflect preexisting subclinical vascular and metabolic dysfunction that already were placing these women on a trajectory of increased cardiovascular risk.15

• Menopause: Reduced levels of estrogen seem to negatively affect arterial function, and levels of LDL and HDL cholesterol and triglycerides all tend to worsen.7 Prevalence of abdominal obesity and metabolic syndrome also tend to increase.6 Early menopause, whether natural or surgically induced, increases a woman's risk for IHD more than four-fold.7

• Hormone therapies: Oral contraceptives increase risk of ischemic stroke, possibly by promoting a hypercoagulable state.10 In young women, absolute risk remains low, but in women over 35 or who smoke or have other risk factors, the association is important. Estrogen may be cardioprotective early in adulthood, but after menopause it seems to increase atherosclerotic plaque instability. Thus, extended use of hormone replacement therapy seems to increase risk of IHD and stroke.11

• Breast cancer treatment: Several breast cancer therapies (such as anthracyclines, taxanes, endocrine therapies, HER-2 inhibitors, and radiation therapy) can lead to various forms of cardiac dysfunction and thrombosis.1,16 Risk of IHD begins a few years after treatment and can extend 20 years or more, with greatest risk for women who have preexisting risk factors.2 Radiation-related risk is directly proportional to radiation dose,2 and newer techniques limit dose and volume of heart exposure, hopefully with lower complication rates.16 Additional CVD risk can result from lifestyle changes that reduce cardiovascular reserve.2

• Psychosocial: Depression, a major risk factor for IHD, is twice as common in women as in men.2,4 It predicts both primary and recurrent IHD events. Loneliness, lack of social relationships, or stress in those relationships is particularly related to IHD risk in women. This is in contrast to conventional definitions of stress, based on more demands and less control, which is more important for IHD risk in men.2

Novel risk factors in men are fewer, at least based on current evidence.

• Erectile dysfunction (ED): In prospective cohort studies, ED significantly increases risk of CVD, CAD, stroke, and all-cause mortality. Although it commonly occurs in conjunction with conventional CVD risk factors, ED is considered to indicate risk independent of them.17 ED usually precedes CVD onset, and it may be an early marker of CVD, likely indicating reduced blood flow due to endothelial dysfunction and/or atherosclerosis.18

• Behavioral choices: On average, men are more likely to drink alcohol excessively and smoke.3,19 Some reports suggest that although lack of social connections have a stronger link to IHD risk in women, it's more common among men.

Nutrition Messages
Sex- and gender-based differences in CVD have important implications for recognition, diagnosis, and choice of medical treatments. However, evidence doesn't support different dietary approaches based on sex or gender alone, since differences in CVD pathology represent averages and aren't universal within a population group. Research continues to support prioritizing dietary choices on an individual basis depending on levels of risk factors and other personal variables that influence likelihood of long-term adherence.

Following are some important talking points to consider when speaking with clients and patients:

• To reduce risk of heart disease and stroke, focus on overall eating pattern, not a single nutrient. Replacing excess saturated fat with some combination of unsaturated fat and whole grains reduces LDL and non-HDL cholesterol, which decreases risk of CAD. This is a top priority in men and is of major importance in women, too. Mediterranean-style or DASH-style diets are associated with multiple aspects of cardiovascular health.20 Elements most associated with the Mediterranean diet's health benefits are vegetables, fruits, legumes, olive oil, nuts, and fish.20,21

• Reducing sodium intake by 1,000 mg/day reduces systolic blood pressure by about 5 to 6 mm Hg in people with hypertension and 2 to 3 mm Hg in normotensive individuals.22 A moderate decrease in sodium intake from reduced use of highly processed foods combined with increased consumption of fruits and vegetables may reduce blood pressure as effectively as a more drastic sodium cut within a less healthful eating pattern.23 A diet rich in whole plant foods increases potassium, which can counteract blood pressure elevation in response to dietary sodium.24,25 However, keep the focus on fruits and vegetables, since they also supply magnesium, polyphenols, and nitrates. Limited evidence shows potential for all of them to improve endothelial function, promote vasodilation, and reduce blood pressure.

• Avoiding weight gain and achieving and maintaining modest weight loss, if ready to do so, are important elements of healthful eating pattern goals, too. Virtually all CVD risk factors are affected by excess body fat, especially abdominal fat. Weight loss of at least 5% of total body weight can bring meaningful reductions in blood pressure, LDL, triglycerides, and inflammation.26

• People at risk of heart disease or stroke include many people who don't consider themselves at risk. Fortunately, CVD is highly preventable, and people can make a difference without needing extreme dietary changes.27

— Karen Collins, MS, RDN, CDN, FAND, is a nutrition consultant specializing in cancer prevention and cardiometabolic health and nutrition advisor to the American Institute for Cancer Research.

References
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2. McSweeney JC, Rosenfeld AG, Abel WM, et al. Preventing and experiencing ischemic heart disease as a woman: state of the science: a scientific statement from the American Heart Association. Circulation. 2016;133(13):1302-1331.

3. Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease and stroke statistics — 2018 update: a report from the American Heart Association. Circulation. 2018;137(12):e67-e492.

4. Mehta LS, Beckie TM, DeVon HA, et al. Acute myocardial infarction in women: a scientific statement from the American Heart Association. Circulation. 2016;133(9):916-947.

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12. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines [published online November 8, 2018]. J Am Coll Cardiol. doi: 10.1016/j.jacc.2018.11.003.

13. Lloyd-Jones DM, Braun LT, Ndumele CE, et al. Use of risk assessment tools to guide decision-making in the primary prevention of atherosclerotic cardiovascular disease: a special report from the American Heart Association and American College of Cardiology [published online November 3, 2018]. J Am Coll Cardiol. doi: 10.1016/j.jacc.2018.11.005.

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17. Dong JY, Zhang YH, Qin LQ. Erectile dysfunction and risk of cardiovascular disease: meta-analysis of prospective cohort studies. J Am Coll Cardiol. 2011;58(13):1378-1385.

18. Gandaglia G, Briganti A, Jackson G, et al. A systematic review of the association between erectile dysfunction and cardiovascular disease. Eur Urol. 2014;65(5):968-978.

19. Chronic disease indicators. Centers for Disease Control and Prevention website. https://nccd.cdc.gov/cdi. Updated January 15, 2015. Accessed December 6, 2018.

20. Grosso G, Marventano S, Yang J, et al. A comprehensive meta-analysis on evidence of Mediterranean diet and cardiovascular disease: are individual components equal? Crit Rev Food Sci Nutr. 2017;57(15):3218-3232.

21. Estruch R, Ros E, Salas-Salvadó J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts. N Engl J Med. 2018;378(25):e34.

22. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71(6):1269-1324.

23. Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. N Engl J Med. 2001;344(1):3-10.

24. Institute of Medicine. Dietary Reference Intakes for water, potassium, sodium, chloride, and sulfate. https://www.nap.edu/read/10925/chapter/1. Published 2005.

25. US Department of Agriculture; US Department of Health and Human Services. Scientific report of the 2015 Dietary Guidelines Advisory Committee: advisory report to the Secretary of Health and Human Services and the Secretary of Agriculture. https://health.gov/dietaryguidelines/2015-scientific-report/PDFs/Scientific-Report-of-the-2015-Dietary-Guidelines-Advisory-Committee.pdf. Published February 2015.

26. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2014;129(25 Suppl 2):S102-S138.

27. Sotos-Prieto M, Bhupathiraju SN, Mattei J, et al. Changes in diet quality scores and risk of cardiovascular disease among US men and women. Circulation. 2015;132(23):2212-2219.