Cardiac Disease as the Leading Cause of Mortality in Women

Podcast Transcript

Announcer:

Welcome to Cleveland Clinic Cardiac Consult, brought to you by the Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute at Cleveland Clinic.

Vikas Sunder, MD:

Good morning, everyone. My name's Vik Sunder, a cardiologist who practices at the Cleveland Clinic in the section of Preventive Cardiology. This morning we'll be talking about cardiac disease as the leading cause of mortality in women and what are we doing to address this.

So we know that cardiovascular disease is the leading cause of mortality for women globally. One in three women die from cardiovascular disease. There are sex-specific differences that exist in the relative risk conferred by traditional risk factors as well as unique sex-specific risk factors for cardiovascular disease.

In the United States, there's been a 7% increase in cardiovascular disease rates in middle-aged women from the years of 2013 to 2017. In the patient population with atrial fibrillation, even when we adjust for differences in stroke risk factors, women have 20 to 30% higher risk of stroke.

What this table shows is, as you can see, the Y-axis is 50%. We think about women as being a unique patient population, but really this is the majority of our population in the United States. So we really have to be cognizant about risk assessment in this population. How can we identify women at an elevated cardiovascular risk?

Women with diabetes, smoking, hypertension, and obesity have a greater relative cardiovascular disease risk as compared to men with those exact same risk factors. This is interesting. Female smokers have a 25% greater risk of cardiovascular disease than men who smoke. Also, oral contraceptive use in women increases risk of cardiovascular disease, specifically in women who smoke.

What we know is early menarche, so under the years of 12 years of age or even occurring prior to 10 years of age, increases cardiovascular disease risk, and it has been linked with obesity and metabolic syndrome. Interestingly, late menarche, above the age of 17 years, also increases risk of cardiovascular disease and has been associated with PCOS and decreased lifetime estrogen exposure.

Our latest cardiology prevention guidelines include premature menopause occurring before 40 years of age as a risk enhancer for atherosclerotic cardiovascular disease, and this occurs in about 1% of women. However, early menopause, occurring before 45 years, has also been associated with cardiovascular disease, and this occurs in 10% of women. This is really related to deficiency in protective estrogens and an increase in endogenous androgens. When you look at data models, there's a lower risk for cardiovascular disease in women where menopause occurs at a later age and in which the reproductive lifespan is longer.

So that's the difference between menarche and menopause. This really has to do with the role of estrogen and vascular health. That's what the theory and the science tells us is that estrogen is very protective in that it reduces accumulation and oxidation of LDL, reduces production of inflammatory cytokines like TNF alpha and interleukins and NF kappa beta, and estrogen also promotes vasodilation as well.

Our traditional risk calculators with Framingham took into account age, hypertension, smoking, hyperlipidemia, and determinants for coronary artery disease. However, for women, up to 20% of coronary events occur in the absence of these risk factors. We know now that atherothrombosis is a complex process. It's not just about lipid deposition. We have to take into account inflammation, endothelial dysfunction, hemostasis, as well as plaque stability.

A number of years ago, there was a risk score proposed, the Reynolds Risk Score, for estimating 10-year cardiovascular risk in women over the age of 45. This does take into account biomarkers like high-sensitivity CRP, which can indicate subclinical inflammation. I think this is a very interesting model that has been proposed and I want to highlight the authors for contributing to this in terms of this layered risk assessment strategy for our female patients.

Taking into account that there is a disparity in traditional risk factors like diabetes, hypertension, obesity, and smoking, but then understanding that there are certain conditions that increase cardiovascular risk that are predominant in the female population. Those are migraine headaches, rheumatoid arthritis, lupus, and depression.

Moving further out in this model, we see that there are sex-specific risk factors: adverse pregnancy outcomes, infertility and the use of assisted reproductive technology, PCOS, early menopause, as we discussed earlier, and early and late menarche, as well as parity. This is an illustration from our Preventive Cardiology Guidelines in Women, which Dr. Cho, our section head, was the lead author on.

It also includes some additional risk factors such as cardiotoxic chemotherapy, chest wall radiation, and this model actually incorporates social determinants of health, so race and ethnicity, education, income and zip code, and taking into account those factors for cardiovascular risk assessment for women.

We know we have to be aggressive about screening for traditional risk factors such as hypertension management in female patients. The prevalence increases after menopause, so we really have to be focused on maintaining normal BMI, moderating salt intake, in women, limiting alcohol intake to no more than one drink per day, encouraging physical activity, and trying to achieve that target of less than 130 over 80 millimeters of mercury.

Interestingly, a condition called fibromuscular dysplasia affects about 3.3% of the general population, but women account for more than 90% of the cases of FMD or fibromuscular dysplasia. That is a condition we want to keep an eye out for.

There are pregnancy-associated conditions that increase risk of cardiovascular disease and they more than double the risk. That is preeclampsia, more than doubles the risk of ischemic heart disease, gestational hypertension more than doubles the risk, preterm birth, pregnancy loss, as well as intrauterine growth restriction.

We know that assisted reproductive technology, by an unclear mechanism, ovarian stimulation, fresh embryo transfer, frozen embryo transfer, increases cardiovascular risk. This may be related to that patient population and a higher prevalence of established cardiovascular risk factors such as advanced age, hypertension, diabetes, obesity. But we know there is a connection between assisted reproductive technology and cardiovascular disease risk.

Then shifting to our female predominant conditions: autoimmune disease; systemic inflammation predisposes to premature atherosclerosis; migraine headaches specifically, but migraine with visual aura [is associated] with an increased risk of stroke; and depression and anxiety. So we have to screen for these conditions and take them into account when creating our risk profile for our patients.

PCOS has a prevalence between five and 13% and is characterized by ovulatory dysfunction, hyperandrogenism, and we know confers an increased risk of ischemic heart disease. Interestingly, hyperandrogenism has been shown to lead to a higher progression of coronary artery calcium, actually. In this patient population, they're four times more likely, patients with PCOS, to develop type 2 diabetes. This really has to do with, starting at the level of the hypothalamus, with abnormal GNRH pulsation leading to an increase in the LH to FSH ratio, ultimately leading to increased thecal cell activity and hyperandrogenemia, which leads to insulin resistance, adipocyte dysfunction related to central obesity, again leading to insulin resistance, leading to type 2 diabetes, and increased risk of cardiovascular disease.

So the question is, is it the PCOS itself or is it associated cardiometabolic features that confer an increased cardiovascular disease risk? Nonetheless, all women with PCOS should be screened for cardiovascular disease risk. We should take action for aggressive cardiometabolic risk factor treatment in these patients, specifically with screening for diabetes, tracking weight, lipid profile, blood pressure checks, and considering medical therapy like metformin and possibly GLP-1 agonists.

So what can we do now? The Mediterranean diet. Recently in 2023, there was a meta-analysis that found 24% lower risk of cardiovascular disease in women who adhere to this Mediterranean pattern diet. That is something we want to spend some time discussing with our patients about what that dietary pattern entails and provide resources as we can, as we do in our clinic.

We have to be aggressive in our screening. Could there be a role for breast arterial calcifications as well as biomarkers in female patients such as high-sensitivity CRP? We know that there's really no role for hormone replacement therapy for prevention. Look at hormone replacement therapy in postmenopausal women, no cardiovascular prevention benefits and potential harm, potentially increased risk of venous thromboembolism. So, statins should be used for primary prevention.

Women are definitely at a higher ASCVD risk, greater than 20%, maybe for those with borderline or intermediate risk depending on the presence of some of these risk enhancers we discussed, or if the patient has type 2 diabetes. But we have to be careful with medication in pregnancy. Even in those female patients who are trying to conceive, we should not be using these medications. There's some limited safety data related to pravastatin.

Aspirin, we should be using for secondary prevention, of course, in female patients with coronary artery disease or prior history of stroke. For primary prevention, we're still looking for additional data on this, but should be considered in patients who smoke, have an elevated coronary artery calcium score, a strong family history of premature ASCVD, maybe even elevated lipoprotein(a) levels.

Our imaging has really advanced, our nuclear imaging technology, that we now can correct for breast attenuation artifacts with use of certain cameras that integrate CTs for attenuation correction. And we have cardiac PET now used for our nuclear imaging, which also helps provide us a higher spatial resolution. We should consider some of our other imaging techniques like CMR, cardiac MRI which omits the use of radiation, echocardiography, which is ultrasound technology, and cardiac CT can be useful in female patients as well, especially for describing plaque composition and characteristics.

But what else can we do? Interestingly, this was a study that came out earlier in 2024 that looked at sex differences in physical activity-associated mortality risk reduction. We always in our cardiology practices like to talk about 150 minutes of moderate intensity aerobic exercise. But what this study showed was that there was some additional benefits to be gained in terms of risk reduction in cardiovascular and all-cause mortality, and specifically in female patients when this activity was about 300 minutes per week. So, more is better than 150 minutes, and that's what this study at least showed. Female patients tended to drive a greater benefit from increasing their physical activity minutes per week. A combination of aerobic activity and muscle strengthening activity is what we recommend in our practice.

We need to assess women for traditional cardiovascular risk factors, sex-specific risk factors, and then conditions that have a higher prevalence in women and utilize both our pharmacologic, our medical therapy, as well as nonmedical therapy treatments. Cardiovascular disease remains the leading cause of mortality in women, and it's primary care providers and cardiologists who are really on the front lines and have to do better. Thank you all for your attention.

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