Clinical research has revealed men and women often have different presentations for cardiovascular disease (CVD). This includes sex differences in terms of symptom presentation, diagnostic imaging and lab values. This may result in poor outcomes for women, whose symptoms do not match the classic presentations in males suffering from coronary ischemia. This can lead to female cardiac issues going undiagosed or misdiagnosed, accentuating a need for new approaches in diagnosing and treating women. At the same time, these discoveries have underscored a public health concern for women with CVD. While heart disease is the No. 1 killer of women in the U.S. according to the American Heart Association (AHA) — responsible for 1 in 3 deaths annually — a 2017 study found that 45 percent of women were unaware of this fact.1
Symptomatic Cardiac Differences Based on Gender
As with any disease state, different approaches are taken for diagnosing and treating symptomatic versus asymptomatic patients, and cardiovascular disease is no different. In the context of heart disease, however, women can be a challenge because they often do not present the same classic symptoms as men. “Women tend to come in for advice because of symptoms,” said Louise Thomson, MBChB, FRACP, program director of the cardiovascular imaging fellowship and co-director of nuclear medicine at the S. Mark Taper Foundation Imaging Center at Cedars-Sinai Hospital.
For men, severe chest pain is one of the most common and recognized symptoms of a heart attack. The same is true for women, according to the Mayo Clinic, but the pain is often less severe for women and sometimes does not present at all. A 2010 AHA survey found that only 53 percent of women would call 911 immediately if they thought they were having a heart attack.
For this reason, other symptoms that should be assessed when diagnosing women with heart disease include:
• Neck, jaw, shoulder, upper back or abdominal discomfort;
• Shortness of breath;
• Pain in one or both arms;
• Nausea or vomiting;
• Lightheadedness or dizziness; and
• Unusual fatigue
The difference is that women present with different types of ischemic heart disease, tending toward non-obstructive coronary artery disease (CAD), particularly in the small vessels. This produces different symptoms than might typically be seen with obstructive CAD.
To Screen or Not to Screen?
Assessment of CVD risk takes different forms depending on whether the patient is symptomatic or asymptomatic.
Asymptomatic patients. Asymptomatic women, like any other asymptomatic patient, male or female, were traditionally assessed with established global risk scores like the Framingham, used to assess the 10-year CVD risk for an individual. Originally designed to measure risk of coronary heart disease, the model was updated in 2008 to assess 10-year risk of broader CVD, cerebrovascular events, peripheral artery disease (PAD) and heart failure. Even with these broader considerations, it was determined that the Framingham risk score “really low-balled risk in women,” according to Sharon Mulvagh, M.D., FRCPC, FACC, FASE, FAHA, professor, Department of Medicine, Division of Cardiology, Dalhousie University, Nova Scotia Health Authority, Halifax, Canada, and emeritus professor at Mayo Clinic.
The 2011 update to the AHA’s “Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease in Women” adds that the focus for women should be on long-term risk for cardiovascular disease, rather than solely on the 10-year risk for coronary heart disease assessed by the Framingham score. Furthermore, the 2011 guidelines suggest that few women under age 75 will qualify for aggressive CVD prevention when 10-year risk is the determinant of need.2
Subsequent risk models have worked to improve on the Framingham risk score, and today the most widely used model is the American College of Cardiology (ACC)/AHA Atherosclerotic Cardiovascular Disease (ASCVD) Risk Calculator. The ACC/AHA ASCVD Risk Calculator, also known as the Pooled Cohort Score, does take gender (as well as race) into account.
Mulvagh explained that current guidelines recommend immediate initiation of statin therapy for patients, male or female, with a 10-year risk score of 7.5 percent or greater. The path forward is less clear for patients (particularly women) at intermediate risk of 5 to 7.5 percent.
Cardiovascular mortality trends of the last several decades suggest that age is definitely still a factor for intervention. Overall CV mortality for women has decreased since 1979, with middle-aged women 50 to 55 seeing their mortality risk flatten or slightly increase as a group. On the other hand, mortality risk has not decreased as greatly in recent years for women 55 and under.3
“If they’re low-risk [less than 20 percent chance of developing CVD over the next decade], testing is more dangerous and the risks outweigh the benefits,” said Mulvagh.
Symptomatic patients. For women presenting with symptoms of cardiovascular disease, the most pertinent question is whether they require subsequent testing in the cath lab or the radiology department. According to Mulvagh, additional testing may not be worth it, or even dangerous, for women at low risk (less than 20 percent chance of developing CVD over the next decade), as the risks likely outweigh the benefits. On the other end of the spectrum, high-risk patients (80 percent or greater 10-year risk) are automatically sent for further testing. As with asymptomatic patients, Mulvagh said the intermediate-risk group between those two extremes are often the best candidates for further assessment via diagnostic imaging.
Cardiac Imaging for Women
Several recent studies have assessed the efficacy of various cardiac imaging modalities between the sexes, highlighting differences that clinicians must take into account.
CCTA. The PROMISE study results were presented at the 2016 American College of Cardiology (ACC) annual meeting, comparing the predictive capabilities of coronary computed tomography angiography (CCTA) and a functional stress test in both sexes.4 The study found that cardiovascular events occurred at the same rate in both sexes. More women had a positive stress test than with CCTA; however, the event rate meant a smaller proportion who had a positive stress test went on to have a CV event.
Coronary Artery Calcium Scoring. Recent evidence suggests coronary artery calcium (CAC) scoring via CT is a beneficial screening tool for female patients, particularly those at intermediate CVD risk. A 2016 study published in Circulation: Cardiovascular Imaging looked at 2,363 asymptomatic women and men at low-intermediate Framingham risk to determine long-term prognosis with CAC scoring.
The study found that 18.8 percent of older women had a CAC score greater than or equal to 100, compared to 15.1 percent of older men. Most significantly, the female group had a nearly 1.5 times higher 15-year adjusted mortality hazard, ranging from 5 percent (CAC score 0) to 23.5 percent (CAC score ≥ 400). Women with CAC scores greater than 10 had a higher mortality risk compared with men.5 Mulvagh stated that among female intermediate-risk patients, CAC scoring has been shown to be most beneficial for those in AHA Class 2B.
Nuclear Imaging. Nuclear imaging has traditionally been a key element of cardiovascular risk assessment via nuclear stress testing, also known as myocardial perfusion imaging (MPI), where the patient’s blood flow is examined at rest and while performing metabolic tests such as walking on a treadmill or climbing stairs. Single-photon emission computed tomography (SPECT) has long been the gold standard for MPI due to its high sensitivity and specificity.
Not all patients, however, are able or suited to undergo stress testing. If an intermediate-risk patient has a normal electrocardiogram (ECG) reading and they can exercise on a treadmill, current indications are for treadmill-only testing with no imaging, according to Mulvagh. Patients are prescribed pharmacologic stress testing if they have an abnormal ECG reading and/or if they are unable to perform metabolic tests.
Positron emission tomography (PET) is also sometimes used for MPI. The Evaluation of Integrated Cardiac Imaging in Ischemic Heart Disease (EVINCI) Trial, completed in 2012, found that PET actually had a higher diagnostic accuracy (sensitivity and specificity) than SPECT for functional cardiac imaging.6 Recent research has also explored another potential use for the modality — assessment of coronary flow reserve (CFR). A 2014 study published in Circulation employed PET imaging to quantify CFR, with CFR values below 2 used to define the presence of coronary microvasculature disease, which was then tied to major adverse cardiovascular events (MACE). End results showed greater risk of MACE was associated with CFR measures below the CMD threshold.7
While CT and nuclear imaging are critical tools in the diagnostician’s armamentarium, they must keep in mind that women have a higher sensitivity to radiation than men. The 2014 AHA consensus statement on the role of noninvasive testing in the clinical evaluation of women with suspected ischemic heart disease notes that clinicians should carefully weigh the risks and the benefits of radiation-based imaging modalities. According to the statement, average annual background radiation exposure in the U.S. is approximately 3.1 mSv. Comparatively, average dose for common diagnostic imaging procedures including invasive coronary angiography, rest-stress MPI SPECT and CCTA is between 7-11 mSv.8
The statement adds that for low-risk premenopausal women, alternative tests without radiation exposure or a no-testing strategy should be strongly considered.8 Pharmacological stress echocardiography is recommended for this particular patient group for identification of obstructive CAD and estimation of prognosis.
Much research is also being conducted on the role of magnetic resonance imaging (MRI) in cardiac diagnosis. A recent study out of Cedars Sinai Medical Center used cardiac MRI to assess patterns of scarring in 369 women age 25-75 with symptoms from the larger WISE-CVD study.9 Follow-up at one year found that the number of women with scarring increased, according to Louise Thomson at Cedars Sinai.
Hypertension in Women
Last November, the ACC and AHA jointly released the first updated blood pressure management guidelines in more than a decade, with an increased focus on gender differences missing from previous guidelines. The guideline authors acknowledge that randomized clinical trials have not traditionally been sufficiently powered to determine the value of systolic blood pressure reduction in subgroups, including women.10 The new guidelines were largely based on the results of SPRINT (Systolic Blood Pressure Intervention Trial).11
Most importantly, the guidelines update the clinical classification of hypertension for all patients. Patients with systolic pressure of 130-139 are now categorized with “elevated” blood pressure and intervention is recommended — through lifestyle changes or, for some patients, medication. The ACC stated the new classification will result in nearly half of the U.S. adult population (46 percent) having high blood pressure, and will double the population of women under 45 with high blood pressure.
For women, the guidelines note the prevalence of hypertension is lower in women than men under age 50, but increases later in life.
The guidelines also address use of antihypertensive drugs in pregnant women, as well as women already diagnosed with hypertension who plan to become pregnant. Women in the second category should be transitioned to methyldopa, nifedipine, and/or labetalol during pregnancy. The guidelines also note that women with hypertension who become pregnant should not be treated with ACE inhibitors, ARBs or direct renin inhibitors.10
1. Bairey Merz, C.N., Andersen, H., Sprague, E., Burns, A., et al. Knowledge, Attitudes, and Beliefs Regarding Cardiovascular Disease in Women. Journal of the American College of Cardiology. 2017;70(2):123-132.
2. Lori Mosca, Emelia Benjamin, Kathy Berra, et al. Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease in Women. Circulation. 2011;123:1243-1262. https://doi.org/10.1161/CIR.0b013e31820faaf8
3. Wilmot, K.A., O’Flaherty, M., Capewell, S., Ford, E.S., Vaccarino, V. Coronary Heart Disease Mortality Declines in the United States From 1979 Through 2011: Evidence for Stagnation in Young Adults, Especially Women. Circulation. 2015; 132:997-1002.
4. Pagidipati NJ, Hemal K, Coles A, et al. Sex Differences in Functional Stress Test Versus CT Angiography in Symptomatic Patients With Suspected CAD: Insights From PROMISE. J Am Coll Cardiol 2016; Apr 4:[Epub ahead of print]. Volume 67, Issue 22, June 2016. DOI:10.1016/j.jacc.2016.03.523.
5. Kelkar, A.A., Schultz, W.M., Khosa, F., Schulman-Marcus, J., et al. Long-Term Prognosis After Coronary Artery Calcium Scoring Among Low-Intermediate Risk Women and Men. Circulation Cardiovascular Imaging. 2016 Apr;9(4):e003742.
6. Neglia D, Rovai D, Caselli C, et al. EVINCI Study Investigators. Detection of significant coronary artery disease by noninvasive anatomical and functional imaging. Circ Cardiovasc Imaging. 2015 Mar;8(3). pii: e002179. doi: 10.1161/CIRCIMAGING.114.002179.
7. Murthy, V.L., Naya, M., Taquet,i V.R., Foster, C.R., et al. “Effects of sex on coronary microvascular dysfunction and cardiac outcomes.” Circulation. 2014 Jun 17;129(24):2518-27.
8. Mieres, J.H., Gulati, M., Bairey Merz, N., Berman, D.S., et al. Role of Noninvasive Testing in the Clinical Evaluation of Women With Suspected Ischemic Heart Disease.”Circulation. 2014 Jul 22;130(4):e86.
9. Mekonnen G., Hayek SS., Mehta PK, et al. Circulating progenitor cells and coronary microvascular dysfunction: Results from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation - Coronary Vascular Dysfunction Study (WISE-CVD). Atherosclerosis. 2016 Oct;253:111-117. doi: 10.1016/
j.atherosclerosis.2016.08.026. Epub 2016 Aug 26.
10. Whelton, P.K., Carey, R.M., Aronow, W.S., Casey, D.E., 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.” Hypertension. 2017;HYP.0000000000000065.
11. Systolic Blood Pressure Intervention Trial (SPRINT) OVERVIEW. National Heart Lung and Blood Institute (NHLBI) website. November 14, 2017. Accessed Feb. 8, 2018. https://www.nhlbi.nih.gov/news/systolic-blood-pressure-intervention-trial-sprint-overview