Cardiovascular disease in women

Cardiovascular disease in women may be misdiagnosed or underdiagnosed in women for a number of reasons. CVD, especially heart attacks, often presents symptoms in women differently than in men due to anatomical and hormonal differences.[7] Research has shown that women may present with symptoms that are classically associated with heart attacks, such as chest pain and shortness of breath, but also with atypical symptoms such as neck, jaw, arm, or shoulder discomfort, nausea or vomiting, heartburn or indigestion, fatigue, headaches, and palpitations.[8] Some healthcare providers may misidentify the causes of these symptoms, attributing them to gastrointestinal or psychological causes instead.

Moreover, although certain factors traditionally associated with developing CVD include age, hypertension, smoking, diabetes mellitus, and dyslipidemia and are similarly influential on women as on men, recent research has found additional risks that should be added to this list as non-traditional or emerging factors. These include pregnancy-associated disorders such as preeclampsia and gestational diabetes, polycystic ovary syndrome, and even depression. This discrepancy is furthered by the under-enrollment of women in research studies establishing a CVD treatment baseline in women for healthcare practitioners.[9]

Furthermore, the anatomical features of the cardiovascular system have some differences in size between men and women. The size of the vessels in women is generally smaller in comparison to men. Thus, a smaller blockage can cause as much damage to women as a regular-sized blockage in men.[10] Women also have a smaller ventricle size than men. This lowers the volume pumped out of the ventricle to the rest of the body, thus requiring their heart to beat faster to ensure a similar amount of blood is pumped out as men.[10] These differences in addition to the cardiovascular functional differences, i.e. a slower fight or flight response, sympathetic activity, and a high rest and digest response, parasympathetic activity, may result in differing presentations of women's illnesses.[11]

According to a survey conducted by the AHA in 2000, women are now more aware of CVD as the leading cause of death in women than in 1997.[12] Close to 90% of women are now aware that women experience heart disease symptoms gradually in later years and that the initial hours of treatment are critical to reducing damage to the brain and heart. This is further supported by a study done in Italy in 2022 that found a vast majority of their participants were able to successfully identify CVD as a leading cause of death in women.[13]

However, many women are still unaware of the impact of CVD on women's health. This may be due to infrequent exposure to the concerns and a deficit of personalization in education to these groups, and little involvement of women in CVD research until 1986.[14] Numerous studies have noted that many women were unable to identify common risk factors or acknowledge whether they were at possible risk of developing CVD, with quite a few even believing that CVD was a male-exclusive condition.[13]

This lack of awareness seems to also be prominent in the age groups of 25 to 34 years. Nearly 72% of women in this age group consider cancer to be the leading cause of death; however, as age increases, the understanding of heart diseases has also been shown to increase. A national survey conducted by AHA in 2012, suggested increased rates of awareness and consciousness. According to the fifteen-year trend report, some of the significant changes are as follows:[15]

• In 2012 the level of awareness increased in women from different ethnicities with percentages rising up to 65% white, 36% black, and 34% Hispanic.
• In terms of knowledge of the symptoms of heart attack, 18% of women responded with nausea, while 56% responded with chest pain.
• In case of experiencing a heart attack, 10% of Hispanic women were reported to initially take aspirin, compared to 22% black and 18% of white women.
• The top 3 health management issues were reported to be exercise (by 49% of women), weight (by 47%), and cholesterol (by 45%).
• Analysis of data suggests further improvement in the educational efforts and awareness among women, especially of racial and ethnic minorities, as they face higher mortality rates.

As a follow up, a recent 2019 AHA survey of the awareness of CVD being the leading cause of death in women has been on the decline in the last decade.[16] The greatest differences were seen among Hispanic women, non-Hispanic Black women and the age group of 25 to 34 year old.[16] These trends are similar to those ones found in the 2012 survey done by the American Heart Association. This shift in knowledge demonstrates a great need for cardiovascular health programs targeted to women, to ensure that they are able to successfully access the needed resources to ensure successful CVD treatment and prevention.

Moreover, trends have also demonstrated a difference in CVD risk and treatment amongst women from different ethnicities. In the 1980s, African American women had double the mortality rates compared to other women between the ages 30 to 39.[14] Although this number has improved, in comparison to white women, the disparity still persists.[17] A 2007 study that black and Hispanic women were nearly half as aware (31% and 29% respectively) than their white counterparts (68%).[17] This is alarming as minority groups have been shown to be at an increased risk of higher cholesterol levels and many other risk factors that cause CVD.[18][19] Studies have found this may be due to lack of educational intervention being targeted to these groups to ensure equity access to health resources.[20]

Future research is working to establish gender-specific guidelines and ensure that treatments, diagnoses, and overall practices are adjusted to encompass the differences of women with CVD into clinical application.

CVD is the leading cause of death in women worldwide.[4] Studies have shown a recent successful decline in CVD mortality overall. However, there is a strong indication for male-specific reductions being implemented in practice, thus female mortality still remains high, despite the incidence of CVD being lower.[21][22] The number of women surviving and dying from CVD far outweighs the number of men in comparison.[23]

Due to anatomical and biological differences, women with CVD have been shown to present with the expected symptoms, as well as unusual and not expected symptoms of CVD in comparison to men. The traditional, or common, symptoms seen in both men and women include:

1. Chest pain or feeling of crushing pain in the chest
2. Radiating pain in the arms or shoulder
3. Heartburn

However, some studies have shown that chest pain is not as common a symptom in women.[24] Thus, its absence cannot rule out the likeliness of CVD.

For the atypical symptoms, there are numerous that are commonly vague and seem to be unattached to specific diagnoses. Women generally develop angina and are less likely to present with myocardial infarction at the onset of cardiovascular diseases. The other symptoms to account for include:

1. Pain or discomfort in neck, jaw, upper back, or abdomen
2. Shortness of breath
3. Nausea/vomiting
4. Sudden and random sweating
5. Fatigue
6. Lightheadedness or dizziness[25]

Overall, these symptoms seem to be more present at rest than any other time of day for women, and at times of emotional distress. Women also tend to report milder symptoms, while also experiencing a combination of more symptoms than men.[26][25]

To ensure that practitioners are able to catch all cases and forms presented to them, it is crucial to ensure that women's diagnostic tests are adjusted to include all of these symptoms appropriately.

As there are a variety of CVDs and causes for CVD, there is no one specific mechanism that can cause CVD. However, there are general components shown to promote CVD development which can be found in a few pathways.

Reactive Oxygen Species (ROS): ROS are produced through numerous processes in our cells, including the induction of oxidative enzymes. The notable species involved in human cells include superoxide anion (O₂⁻), hydroxyl radicals (OH), and hydrogen peroxide (H₂O₂).[27] Not only does ROS physiologically have a role in controlling the vasculature through tone and endothelial and cardiac function, but it also is a vital player in inflammation, promoting apoptosis, angiogenesis and much more.[28] Additionally, ROS causes oxidative stress within the body which, although may not be the sole proprietor, exacerbates the various factors that contribute to developing CVD, especially hypertension.[29] Finally, ROS also act as signaling molecules to induce the body's inflammatory response to prevent any further damage from happening, which can lead to cell and tissue damage of the vasculature if not moderated appropriately.[30]

Induction of oxidative enzymes: Cytosolic oxidases are another critical component in ROS production. These enzymes transfer electrons to create radicals or superoxide, and increase oxidative stress.[31] These enzymes have also shown to be present in various physiological stressful situations, which is associated with hypertension and other traditional risk factors negatively impacting CVD.[27]

• Xanthine oxidase (XO): XO, under normal circumstances, is an important enzyme in producing uric acid, released from the kidneys.[32] These are typically located in the liver, however under times of stress from ROS, can increase its activity.[32] This elevates vascular tone and even ROS production in the form of superoxide, thus contributing to higher oxidative stress.[32]
• Nitric oxide synthase: Nitric oxide synthases are known for producing nitric oxide, which has numerous functions in the body including vasodilation – i.e. widening of the vessels.[27] Nitric oxide reacts with other forms of ROS to create potent oxidants, consequently causing other pathologic conditions, including heart failure and myocardial infarction.[27] Moreover, this family of enzymes are crucial signaling molecules in regulating vascular tone and multiple other functions.[33] Thus, any disruption in regular functioning impacts the vascular tone regulation.
• NADH/NADPH oxidase: These enzymes contribute significantly to the amount of ROS present in the body.[34] If in cardiac distress, an individual may induce excessive production, which may in turn lead to the pathogenesis of varying forms of tissue damage and cellular dysfunction in cardiac muscles.[27]

Uncoupling of Mitochondrial electron transport chain: The mitochondria is a contributor to the levels of ROS we see within our body. Not only does it produce it, but is also vulnerable to the damage caused by ROS. It also is a key player of cell function in the cardiovascular system.[35] With this damage to the mitochondria, the cell's function may be altered as not enough energy is being produced as needed, thus hindering the cell's ability to function optimally.[30] These events create a disastrous feedback loop where further mitochondrial damage results in increased ROS production, which furthers the damage and contributes to the risk of developing CVD.[30]

Immune cell infiltration and cytokines: A large contributing risk factor to the development of CVD is the production of plaque, also known as atherogenesis or atherosclerosis. This condition is known to involve multiple inflammatory cascades from the immune system responding to varying pathogens.[36] Elevated inflammatory cytokines, including interleukin-6 and tumor necrosis factor-⍺, initiate a cascade conducive to plaque production.[37]

There are numerous risk factors that have been found to be associated with developing CVD. A number of them are considered traditional, as they are found in men and women with CVD at high rates. However, there are also unique risk factors found only in women that are commonly associated with this group developing CVD. The following list includes the predominant ones found in many cases of CVD in women.

CVD is an umbrella term to encompass numerous conditions of the cardiovascular system. These can be chronic, i.e. ongoing issues, or acute, i.e. having a sudden onset. There are several different types of CVD, of which the most prevalent are:

Depending on the risks associated based on age, type of disease, prognosis, pregnancy or menopausal stages, the following primary preventions can be prescribed to women under the guidance and proper consultation with their healthcare provider.[39][41]

Nutrition and exercise: Adjusting an individual's lifestyle through their diet choices and increased physical activity has shown to reduce the long-term negatives associated with most risk factors, including plaque buildup and weakening of the heart muscle. Exercise has been shown to strengthen the heart muscle, allowing it to pump greater blood volume at a regular pace, thus preventing overexertion and tissue damage.[82] Additionally, a diet with low trans fat, saturated fat, refined carbohydrates, and sugar-sweetened beverages, and enriched with fruits, vegetables, whole grains, and unsaturated fats have reflected a significant reduction in the risk of developing.[83]

Smoking cessation: The adverse effects associated with smoking have overwhelmingly shown it to contribute to numerous risk factors that cause CVDs. These include contributing to atherosclerosis and contributing to blood clot formation.[84] For patients that have a history of smoking, it is important to focus on quitting smoking to prevent additional damage and allow healing to begin.

As CVD is the primary result of long-term damage to the cardiovascular system, research has been unable to develop a way to cure it permanently. However, through the available therapies and prevention strategies, there are methods of bettering its effects and making it so the individual's quality of life remains. This can help manage and reduce further risk of developing life-threatening CVDs. The strategies that have been established in routine care include pharmacological therapies, lifestyle changes (including nutrition and exercise), surgery, and smoking cessation.

Pharmacological therapy: Various medications have shown to mediate the negative symptoms of CVD. These typically work to lower the individual's blood pressure or widen their

• Angiotensin II receptor blockers (ARB) & Angiotensin-converting enzyme inhibitors (ACEI): Both types of drugs work to limit the effects of angiotensin II, which raises blood pressure through a feedback loop in the kidneys.[85] They have shown to greatly reduce the mortality associated with CVDs, with ACEIs being more effective than ARBs.[86]
• Aspirin: Aspirin, or ASA, promotes platelet function inhibition which reduces the risk of plaque buildup in vessels.[87] This has been shown to alleviate the effects of vessel narrowing and blood flow impairment, and prevent numerous CVDs. The Women's Health Study in 2005 also found that Aspirin reduced the risk of developing stroke, as well as myocardial infarction in some age groups, in the long term.[88]
• Beta-blockers: Beta-blockers impede the effects of adrenaline, also known as epinephrine, and subsequently slow the heart rate.[89] This type of medication is generally prescribed for hypertension, a major risk factor for many CVDs. However, recent studies have shown that this medication may lead to a higher rate of heart failure than men, thus these medications should be taken with precaution.[90]
• Blood thinners: Blood thinners prevent clot formation, which contribute to vessel blockage, and is an effective method of anticoagulation that naturally plays an important role in cardiovascular system conditions.[91] Low dose blood thinners have shown to significantly reduce the risk of developing stroke, heart attacks and even the mortality associated with CVD.[92]
• Calcium channel blockers: Calcium channel blockers are vasodilators, i.e. widen our arteries by regulating the calcium entering the cells, which lowers blood pressure. This has shown to be effective across all patient groups regardless of age and severity.[93] This has been shown to be even more effective in combination with other therapies and must be used in moderation to prevent chronic cell damage.[94]
• Diuretics: Diuretics assist the kidneys in clearing extra fluid present in the body to help maintain a steady blood volume for the heart to pump around.[95] This helps bring blood pressure down, relieving pressure on the vessels and, consequently, the heart, thus making it a successful treatment for hypertension.[96]
• Hormone Replacement Therapy (HRT): HRT is taken by women to replace the declining estrogen levels during times of menopause.[97] This is to control the cardio-protection offered by estrogen as women hit menopause and their levels decline.[98] 
• Nitroglycerin and Other Nitrogen Oxides: Nitroglycerin and other nitrogen oxide use have been a strong influence on vasodilation, cell permeability, inflammation, and various other cardiovascular processes.[99]
• Statin therapy: This form of therapy aims to reduce levels of fat in the blood, specifically triglycerides and cholesterols.[100] The proposed mechanisms for them are that they stabilize the plaque and reduce blood clots, which prevents most CVDs from developing. As a primary prevention, they are significantly effective on patients at reducing the mortality and other life-threatening aspects of CVD.[101]

Surgery: In severe cases of CVD, various forms of surgeries offer a more permanent treatment to replace or remake the affected vasculature to prevent this from reoccurring.[102]

• Coronary angioplasty: the insertion of a thin tube with a balloon on the end into the clogged artery which becomes inflated to widen the channel for blood to pass through. In some cases, a stent is left behind to maintain the opening and prevent further relapse of the artery.[103]
• Coronary artery bypass graft: using another blood vessel to replace and divert blood around an occluded vessel to maintain regular blood flow of nutrients and oxygen, and prevent tissue death.[104]
• Heart transplant: the replacement of an individual's heart that is affected by disease with one of a healthy donor.[105]

CVD remains the most common cause of death for women, with approximately one-third of deaths worldwide attributed to CVD.[106] In 2015, approximately 8.5 million women died from the disease.[107]

In the United States, approximately 47.8 million women over the age of 20 were diagnosed with CVD between 2011 and 2014, and data from 2015 shows over 400,000 deaths due to CVD in women.[1] While overall deaths from CVD are falling, the decline is slower in women, particular black women.[108] The death rate for women with CVD surpasses that of men from CVD.[109] In Europe, over half of the deaths in women are attributed to CVD.[110] The death rate in some Eastern European countries is high, with over 500 deaths per 100,000 population attributed to CVD. Studies predict that in certain developing countries in Asia and Africa, women will account for a greater percentage of deaths related to CVD by 2040.[106]

Cardiovascular disease is more prevalent in older populations. On average, women develop CVD approximately 10 years after their male counterparts.[109] In the United States, approximately 6% of women over 20 have coronary heart disease.[111] The highest prevalence of CVD is present in adults over the age of 80, and women and men have similar rates of disease after the age of 60.[1]

In the last few decades, the greatest changes have been made to acknowledge and focus on sex as an influential factor, thus establishing a great need to incorporate women into research. The events of significance are as follows:

• In 1994, the United Nations stated that in order to establish a policy, there must be more sex-specific research done regarding treatment efficacy, thus encouraging researchers to pursue this line of inquiry.[112]
• The Food and Drug Administration (FDA) of the United States established their Office of Women's Health around this time, in 1991, concentrating on the underrepresentation of women in research, especially with CVD.[113]
• In 1993, the FDA created a guide for researchers to follow when including women in their studies, with an updated action plan for this published in 2014.[114][115] It is important to note that the 1993 policy effectively reversed one established in 1977 that called on fertile women to be excluded from clinical trials, which had furthered the lack of women present in research at the time.[116] This was done to address concerns of birth defects among infants and changes in estrogen and progesterone in postmenopausal women. Between 1988 and 1991, only 50% of the data analysis from trials that were not designed for women, accounted for the difference in gender. It was assumed that the drugs given to men would work if prescribed to women.[14]
• The Institute of Medicine, also from the United States, moved forward with other milestones by publishing papers in 2001 and 2010 that recognized sex and gender for the first time as variables crucial in women's health.[117]
• Also in 2010, the Canadian Institutes of Health Research and the Canadian Institute of Gender and Health produced a tool to make incorporating sex and gender as variables easier in research.[118]
• This was followed shortly by the World Health Organization, which in 2014, promoted more gender-specific approaches to data analysis and health-inequality monitoring to ensure that a more sustainable approach was taken to this research.[119]
• In 2015, the National Institutes of Health and the United Nations both endorsed the necessity for gender-specific reporting or providing a reason for why it was not included in studies to ensure that researchers are held accountable.[120][121] The United Nations specifically advocated for gender-sensitive strategies to be established by 2030.
• Following in North America's footsteps, the League of European Research Universities proposed a list of suggestions for how to undertake gender-specific research for universities, governments, and more.[122]
• In 2016, two vital reports from Oxford and the United Nations, "Women's health: a new global agenda" and "Global Strategy for Women's, Children's, and Adolescents' Health (2016–2030)", were published, bringing much-needed attention to this issue.[123][124]
• The European Commission in 2016 provided a published guide for Horizon 2020 to address participation gaps for women in research and strategies to approach this.[125]

These are not the only steps that have been taken to include women in the scientific community. There have been numerous policies and practices already established and continuing to be added to address the growing concern of CVD.

• The Centers for Disease Control and Prevention division of heart disease and stroke prevention initiated the Well-Integrated Screening and Evaluation for WOMen Across the Nation (WISEWOMAN) awareness campaign in 1993.[126] It was created to educate women on the risk factors associated with CVD and encourage healthier lifestyles to limit that risk.
• In 1999, the AHA created the Guide to preventive cardiology for women guideline to be used by the scientific community.[127] This was the first of its kind in advising CVD management in women.
• In 2004, the 1999 guideline was replaced by the Evidence-based guidelines for cardiovascular disease prevention in women by the American Heart Association.[128] These guidelines underlined the importance of including women in research and challenged the notion that men and women are the same for CVD pathogenesis and these differences should encourage research and treatment to be approached accordingly. There were additional updates to this in 2007 and 2011.
• The European Society of Cardiology and European Health Network in 2006 started the transnational project for the prevention and management of CVD, where its objective was to "Address the significant burden of CVD in Europe and to determine specific areas of intervention to contribute to preventing avoidable deaths and disability".[129]
• The Hellenic Cardiac Society, a European organization, followed this up with a national action plan for CVD projected for 2008 to 2012. Its aim, through the American Heart Association and many other guidelines, was to prevent CVD, primarily heart disease and stroke.[130]
• In 2011, the American House of Representatives put forward huge legislation called the "Heart Disease, Education, Analysis, Research, Treatment for Women Act or Heart for Women Act".[131] This is intended to provide healthcare professionals and others with gender-specific information for appropriate medical treatments.
• Also in 2011, the European Society of Cardiology released guidelines for the management of cardiovascular diseases during pregnancy: the Task Force on the Management of Cardiovascular Diseases During Pregnancy of the European Society of Cardiology.[132] As pregnancy is a crucial unique factor to consider in women, these guidelines encouraged the scientific community to be able to tailor treatment plans accordingly. There was one update to this made in 2018.
• The Journal of American College of Cardiology released a state-of-the-art review in 2017 called "Quality and equitable health care gaps for women: attributions to sex differences in cardiovascular medicine".[133] This discussed the quality and equity of health care received by women.
• In that same year, the released survey results that provided insight into the awareness within healthcare providers, and the gaps present in the research and clinical applications thus far.[134]

• Go Red for Women
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• Women & Cardiovascular Diseases