HEART DISEASE IS DIFFERENT IN WOMEN

The medical community is becoming more aware of its discrepancies in caring for women with heart disease. Women with early onset of heart disease—before age 55—are less likely than men to receive therapy with statins or antiplatelet drugs. Even when treated, women experience a higher risk of problems such as statin intolerance. If a woman has a heart attack, she is twice as likely to die from that heart attack.

Why is heart disease more dangerous and under-treated in women? Part of the inequities in care have been a lack of awareness of heart disease by care providers and women themselves.

There is a myth that heart disease is man’s disease. It would be great for women if it were so. Unfortunately, lower heart disease incidence in younger women disappears after menopause. Just as in men, heart disease is the leading cause of death in women. While 1 in 39 women may die of breast cancer, 1 in 3 will die of heart disease. According to the Women’s Heart Alliance survey published in 2017, only 56% of women are aware of this risk. Were you?

Perceived “atypical” symptoms in women also cause delays and differences in the treatment of heart disease. Men have defined the “norm” for heart attack symptoms because they account for 2 to 3 times the number of heart attack cases. Symptoms of heart disease in women are different because the actual processes in the heart that break down are often different in men and women.

How is heart disease different in women?

1. Women have differences in metabolic health relative to men that change pre- and postmenopausal.
2. Women have unique risks of cardiac complications related to pregnancy, oral contraceptives, and hormone replacement therapy.
3. There are 3 different kinds of heart attacks; women are more prone to 2 of them.
4. Women can have symptoms related to problems in the small arteries of the heart that go undetected.
5. Blood pressure affects men and women differently.
6. Blood lipid levels have different meanings in men and women.
7. Medications like statins and PCSK9 inhibitors have different effects in women.
8. There is much less research on heart disease in women.

Estrogen and metabolic health

Estrogen is the magic hormone that protects women from developing heart disease the way men do. Men have some estrogen, of course, just as women have some testosterone (and we share many other hormones). Estrogen has a powerful influence on how fat is stored and used in women’s bodies—which has a protective effect on your heart.

Heart disease is tied very closely to metabolic syndrome, which causes elevated insulin after a meal and even full-blown diabetes. It’s defined by a high waist circumference (indicating visceral fat inside the abdomen), high blood pressure, elevated triglyceride, low HDL cholesterol, and high blood glucose. Estrogen delays the occurrence of metabolic syndrome in women.

In men, energy is stored to be easily accessible for physical exertion. Men accumulate subcutaneous fat in the upper body and around our organs, called visceral fat. Under the influence of estrogen, women accumulate subcutaneous fat in the lower body and less in the upper body and viscera. Women lose visceral fat more readily and hold on to lower body subcutaneous fat more strongly. This pattern assures adequate energy storage for pregnancy and lactation. It also provides relative protection from the excess accumulation of visceral fat that begets inflammation, metabolic syndrome, and heart disease.

Pregnancy

Many women develop high blood pressure or elevated blood sugar during pregnancy. We now know these conditions are associated with a greater likelihood of developing high blood pressure, diabetes, and heart disease later in life.

Heart disease can first show itself in pregnancy. Cardiovascular disease (the umbrella term for conditions including heart disease and atherosclerosis, or plaque in the arteries) is the most common cause of maternal death (28.5%). Women with complications during pregnancy, such as preeclampsia, gestational diabetes, and preterm labor, appear to be more affected by chronic inflammatory conditions.

• Women who develop hypertension during pregnancy have a 67% greater risk for developing CVD later in life, while preeclampsia during pregnancy is associated with a 75% greater risk for death from CVD.
• Gestational diabetes increases the risk of developing future cardiovascular disease by 56%.
• Blood pressure-related complications occur in 1-5% of pregnancies. This rate doubled between 1993 and 2014. Hypertension during pregnancy is not only dangerous for mother and child, but it also predicts future cardiovascular events.
• The risk of spontaneous coronary artery dissection (SCAD) also increases in the peripartum period.
• Peripartum cardiomyopathy is a weakening of the heart muscle that occurs in about 1 in 1,000 to 4,000 pregnancies. Proposed causes include autoimmunity, genetics, nutritional deficiencies, and vascular dysfunction. Advanced maternal age, preeclampsia, gestational hypertension, multiparity (twins), or being a person of color increase the risk.

Menopause

The median age of natural menopause (going 12 months without a period) is 51 years, meaning that women may spend as much as 40% of their lives postmenopausal.

After menopause, lower levels of estrogen no longer protect against metabolic disease, and women’s propensity for atherosclerotic heart disease rapidly catches up to men. Reduced estrogen compounds the risk: increased appetite, increased upper body and visceral fat mass, lower muscle mass, and reduced physical activity are all risk factors for cardiovascular disease. A woman’s lipid (cholesterol) profile also becomes more atherogenic, with increasing LDLc and lower HDLc.

Randomized trials show that aggressive lifestyle intervention can help stave off these changes (but not menopause). While a low-fat, calorie-restricted diet has been the conventional recommendation, my experience as a functional cardiologist shows that the benefit of this approach is usually temporary. We recommend attention to body composition and metabolic health through a nutrient-dense diet, low carbohydrate/ketogenic diets, fasting, and strength training without conscious calorie restriction.

Hormone Replacement Therapy (HRT)

Can estrogen supplementation—known as hormone replacement therapy—also help prevent some of the postmenopausal health changes? It’s complicated, and so far, the research is incomplete.

In 2002, the Women’ Health Initiative (WHI) did a study to measure the risks of heart disease and cancer in women receiving HRT. Participants were given synthetic oral estrogen and progesterone. The study put the brakes on estrogen-progesterone therapy for prevention of heart disease. The risk of CVD events increased by the absolute level of 1 event per thousand over 6 years. Breast cancer risk increased by about the same amount. These results have since been challenged.

Later studies show different effects on heart disease depending on the type of estrogen used, dose given, the route of delivery, the duration of therapy, age of the patient, and time since menopause. For example, high doses of estrogen are found to increase CRP, a measure of inflammation, and superoxide, a marker of oxidative stress.

On the other hand, there is growing evidence that lower-dose transdermal estradiol—a form of bioidentical, not synthetic, estrogen—does not increase inflammation and may not carry the increased risk of CVD events.

Current societal guidelines do not recommend long-term estrogen therapy to reduce CVD risk. HRT is recommended only to reduce menopausal symptoms and can be considered safe for as long as 10 years post menopause, and up to age 65.

In the most recent Cochrane systematic review evaluating HRT for preventing cardiovascular disease in postmenopausal women, among women starting hormone therapy younger than age 60 and fewer than 10 years since menopause, risk was reduced by roughly half and all-cause mortality by 30%.

“The evidence supports cardiovascular benefit for MHT initiated early among women with premature or surgical menopause and within 10 years of menopause in women with natural menopause. The benefits of MHT (i.e., including lower rates of diabetes, reduced insulin resistance, and protection from bone loss) appear to outweigh risks for most early menopausal women. Perimenopausal women should be provided individualized guidance and options for treatment, particularly when vasomotor symptoms are present.”

If you’re postmenopausal, do the research on HRT, work closely with your doctor, and be sure to employ lifestyle changes to maintain or improve your body composition and metabolic health.

Microvascular disease

What if you have all the symptoms of a heart attack, but testing shows that you have no blockages in your artery? No plaque rupture, no plaque erosion, no coronary dissection. You may have something in common with 60% of women who have chest pain: microvascular dysfunction.

Coronary arteries that develop plaque are on average 2 to 3 mm in diameter. You can easily see them on angiograms and CT scans. Just like a river leading to an irrigation system, arteries branch multiple times into very small arteries that bring blood to every individual cell in your heart. When they become too small to be seen with naked eye, these arteries are called microvasculature. They’re 100 to 200 micrometers in diameter, about the size of a human hair. These microscopic vessels are in charge of blood flow to your heart muscle, so it’s very important that they’re functioning well.

Microvascular dysfunction is a symptom of endothelial dysfunction, the condition that sets the stage for plaque buildup in larger coronary arteries. Microvascular dysfunction can cause symptoms of chest discomfort or exercise intolerance that are frustrating because typical heart testing, geared toward identifying larger coronary blockages, doesn’t identify the problem.

Cardiopulmonary Exercise Testing (CPET) is a test we perform at CFC that identifies microvascular dysfunction. If you are a woman with chest discomfort or shortness of breath, have trouble exercising, or you are just interested in heart health, CPET is the test you should have.

Blood pressure

High blood pressure is another potent cause of heart disease. It is more common in men younger than 65-years-old but is more common in women older than 65. By this age, 66% of women have hypertension. Estrogen protects against blood pressure elevation by decreasing angiotensin; so postmenopausal women see a rise in blood pressure.

Even mild blood pressure elevation has different implications in women. Stage 1 hypertension, a systolic blood pressure above 130, doubles the risk of cardiovascular disease in women. Stage 2 hypertension, systolic blood pressure above 140, triples the risk.

Women are more prone to low blood pressure episodes on treatment, although we don’t yet know if women have different behavior in blood pressure during the day, like white coat hypertension, masked hypertension, or failure of blood pressure to fall at night.

Oral contraceptive medications increase blood pressure and risk of clotting, but only with estrogen doses over 50ug. Modern low-dose oral contraceptives are not so much of a problem.

The three different kinds of heart attack

Women’s arteries become blocked in different ways than men’s, resulting in different heart attack symptoms and requiring different heart attack treatments. There are 3 different kinds of heart attacks, and women are more prone to 2 of them.

A heart attack, or acute myocardial infarction, occurs when blood flow in one of the heart arteries is suddenly cut off. The heart muscle downstream is deprived of oxygen and dies over several hours. A severe heart attack can kill.

There are three ways that the blood flow can be cut off in the coronary artery. The first and most common, especially in men, is a plaque rupture. This is akin to a volcanic eruption. Plaque, containing inflammatory cells, muscle cells, and often liquified cholesterol pools and separates from blood flow in the artery by a fibrous capsule. If the capsule bursts open, the liquified core of the plaque can cause the blood to clot and often completely block blood flow in the artery. This blockage can be opened with insertion of a coronary stent.

Another type of heart attack related to underlying plaque is plaque erosion. This is more akin to a skin scrape. The surface of the plaque is disturbed and a clot forms that partially or totally blocks the artery. When erosion causes a heart attack, symptoms may be more subtle and less typical than with a “usual” heart attack and may be missed (or brushed off) by a doctor. As a result, treatment may be delayed, and outcomes may be substantially worse.

We recognize plaque erosion more readily today. It occurs more often in younger people and women and may be better treated with blood thinners than with stents.

A third type of abrupt artery blockage is caused by dissection or tear of the artery, called spontaneous coronary artery dissection or SCAD. When a tear occurs in a coronary artery, blood flow is blocked, but not because of plaque in the artery. It is more common in women, especially right after giving birth. A condition called fibromuscular dysplasia (FMD) may underlie SCAD. FMD causes narrowing in other arteries in the neck or kidney as well. Inflammation in the arteries, e.g., from lupus or inherited conditions that cause weakness in the wall of the arteries like Ehrler’s-Danlos syndrome and Marfan’s syndrome, can lead to SCAD. A dissected coronary artery must be treated with great care. Placing a stent in a torn artery may be necessary but can also make the problem worse.

Because plaque erosion and SCAD occur less commonly than plaque rupture, and because they occur more often in women and younger patients, doctors often do not expect their occurrence and consider the symptoms to be atypical of heart attack.

What we don’t know about heart disease in women

Not surprisingly, most of the research on heart disease has been done on men. This leaves a great deal of uncertainty on how to apply the information to women’s hearts.

There is research that calls into question many of the assumptions we have about heart disease in women and how to treat it. Statin therapy may have different efficacy rates and side effects for women. High LDL cholesterol may be less important in women, while low HDL cholesterol may be a more important risk factor. One cholesterol trial on a majority of women, the MEGA trial, failed to show a statistically significant benefit of pravastatin.

Children are not just small adults, and women are not simply smarter men. There is renewed interest and excitement among cardiologists motivating us to learn more about the subtle and not so subtle differences in heart disease between men and women. Stay tuned to this space for updates as we learn more from research and from working with our patients at CFC.

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