Erin Michos: Cardiovascular Disease in Women: Prevention, Risk Factors, Lipids, and more

Cardiovascular Disease in Women

• Cardiovascular disease (CVD) is the leading cause of death in women 
  • More women die from CVD than cancer
  • However, women often fear breast cancer more than CVD
• In younger individuals (<65), cancer is the leading cause of death in women 
  • But heart disease mortality is rising in younger women
  • If trends continue, heart disease may overtake cancer as the leading cause of death in younger women
• Lack of awareness about CVD in women is worrisome 
  • In 2009, 65% of women knew that heart disease was the leading cause of death
  • In 2019, only 44% of women knew that heart disease was the leading cause of death
  • Awareness is particularly low among non-​​Hispanic black women, Hispanic women, and younger women

Factors Contributing to Fear of Breast Cancer Over CVD

• Lingering notion that heart disease is a man’s disease
• Breast cancer has more visible campaigns and awareness efforts
• Women may feel more in control of breast cancer risk factors (e.g., mammograms) than CVD risk factors
• CVD symptoms may be less recognizable or dramatic than cancer symptoms

Importance of Primordial Prevention

• Starting preventive efforts early in life can have significant long-​​term benefits
• Addressing modifiable risk factors can greatly reduce the risk of CVD 
  • Smoking cessation, blood pressure treatment, and controlling apolipoprotein B (apoB) levels are key factors
• Reversing current trends in CVD mortality is crucial for improving overall health and longevity
  Women in Clinical Trials and Cardiovascular Disease 
• Historically, women have been under-​​enrolled in randomized clinical trials 
  • Limited data on efficacy and safety of therapies in women
  • Clinicians more likely to perceive women as being at lower risk, leading to under-treatment
• Women with familial hypercholesterolemia (FH) are under-treated 
  • FH affects 1 in 250 individuals, equally affects men and women
  • Associated with a 20-​​fold increased risk of cardiovascular disease (CVD)
  • Women with FH have an earlier onset of atherosclerotic cardiovascular disease (ASCVD) than women without FH

Cardiovascular Disease in Young Adults

• Cardiovascular disease is not just an old person’s disease 
  • Half of men who experience a major adverse cardiac event in their life will do so before the age of 65
  • One-​​third of women who experience a major adverse cardiac event in their life will do so before the age of 65
• Young adults with high blood pressure or high cholesterol should be treated early 
  • Prevention is better implemented when started earlier

Importance of Lifestyle Changes

• Healthy lifestyle should begin in utero
• Cardiometabolic health needs improvement in young adults and women of reproductive age 
  • Poor cardiometabolic health increases the risk of adverse pregnancy outcomes like preeclampsia and gestational diabetes
  • These outcomes impact the risk of complications even decades after pregnancy

Double Standard in Treating Causal Agents

• Smoking and blood pressure are treated as causal agents for cardiovascular disease 
  • Physicians recommend smoking cessation and treat hypertension in young adults
• Apolipoprotein B (APO B) is a causal agent for cardiovascular disease, but not treated the same way 
  • Frustration with the double standard in treating APO B compared to smoking and blood pressure
    Causal Factors in Atherosclerosis
• Overwhelming evidence that LVL is a causal factor in atherosclerosis 
  • Data from observational studies, genetic studies, and interventional trials
• Speculation on why there hasn’t been a greater uptick in treating younger ages 
  • Focus on ten-​​year risk score
  • Randomized clinical trials not based on ten-​​year risk scores, but on other factors
  • Overreliance on ten-​​year risk scores

2019 Accha Primary Prevention Guidelines

• Acknowledge limitations of ten-​​year risk scores 
  • Can overestimate risk in older adults and those with higher socioeconomic status
  • Can underestimate risk in those with social deprivation and unique risk factors
• Risk assessment as a starting point 
  • Very low risk individuals: lifestyle changes may be enough
  • High risk individuals: use high-​​intensity statin to lower LDL by 50% or more
  • Borderline/​​intermediate risk: consider risk-​​enhancing factors (e.g., APO B, Lipoprotein A, early menopause, adverse pregnancy outcomes)
  • Use coronary artery calcium score to refine risk and guide shared decision-making

Cardiometabolic Health in the US

• Trends in obesity, insulin resistance, type 2 diabetes, NAFLD, NASH, and gestational diabetes 
  • All growing out of metabolic syndrome
  • Over 1 in 10 US adults have diabetes, many undiagnosed
  • Alarming trends, especially with available prevention therapies
  • Emphasizing healthy lifestyle from childhood is crucial

Causes of Obesity and Potential Solutions

• Societal and population problems contribute to obesity 
  • Easy access to poor quality, highly processed foods
  • Sedentary jobs and long commutes
  • Lack of access to safe places to exercise
  • Increased stress levels
  • Food deserts and food swamps
• Need for regulation and policy on a population level
• New pharmacological agents for weight loss without cardiovascular harm (e.g., GLP‑1 receptor agonists) 
  • Beneficial in reducing risk of major adverse cardiovascular events and stroke in patients with type 2 diabetes
  • Outcome trial ongoing for overweight and obese individuals without diabetes
• Focus on prevention of obesity in the first place is crucial
  Somaglitide and Traceptubide for Weight Management
• Somaglitide: FDA approved for type 2 diabetes and weight loss 
  • Approved for obese individuals (BMI > 30) or overweight (BMI > 27) with obesity-​​related cardiovascular risk factors
• Traceptubide: not yet FDA approved for weight management, but likely to be soon 
  • Approved for type 2 diabetes
• Mechanism for reducing cardiac events not fully understood 
  • Benefits independent of A1C lowering
  • May be related to favorable changes in blood pressure, weight loss, lipid panel improvements, anti-​​inflammatory effects, and antiascrotic effects
  • Reduction in albinuria observed

Physiology of Women and Lipids

• Women have unique risk factors for cardiovascular disease 
  • Early or late menarche, polycystic ovary syndrome, infertility, spontaneous pregnancy loss, preeclampsia, lack of breastfeeding, early menopause, and chronic inflammatory conditions
• Estrodiol (E2) is the predominant female sex hormone in women of reproductive age 
  • Has beneficial effects on lowering LDL and conferring cardiovascular protective properties
• Lipids change throughout the menstrual cycle 
  • Total cholesterol and LDL increase rapidly after menses, peak during follicular phase, and decline in luteal phase
  • HDL is highest around ovulation
  • Triglycerides do not have a consistent pattern during the menstrual cycle
• It is recommended to measure lipid panel during menses for consistency

Cardiovascular Risk in Women

• Women have a 10-​​year offset in developing ASCVD compared to men 
  • Possibly due to lower LDL levels during childbearing years and higher levels after menopause
  • However, women with familial hypercholesterolemia (FH) or diabetes do not have this advantage
• It is important to recognize that women are at lower risk, but not zero risk, for cardiovascular events during their reproductive years
  PCOS and Cardiovascular Health
• Polycystic ovary syndrome (PCOS) is the most common endocrine abnormality in women of reproductive age 
  • Affects 5–13% of women in the general population
  • Characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovary morphology
• Insulin resistance is a key factor in PCOS 
  • 95% of obese women and 75% of lean women with PCOS have insulin resistance
• PCOS is associated with increased cardiovascular risk 
  • Elevated LDL, elevated triglycerides, and low HDL
  • Hypertension and incident hypertension (independent of BMI)
  • Increased subclinical atherosclerosis and future cardiovascular disease risk

Oral Contraceptives and Cardiovascular Health

• Oral contraceptives can impact lipid levels, depending on the formulation 
  • Older formulations with higher estrogen doses can increase triglyceride levels and lower LDL
  • Newer, lower estrogen formulations have more modest effects on lipids
• Transdermal contraceptives (e.g., the patch) are less likely to cause significant elevations in triglycerides
• Progesterone-​​based contraceptives (e.g., IUDs) can marginally lower HDL, but usually revert to pre-​​insertion levels within a year 
  • Recommended for women with FH or established cardiovascular disease

Pregnancy and Cardiovascular Health

• Lipid levels can rise significantly during pregnancy 
  • Triglyceride levels can increase, potentially raising ApoB levels and increasing cardiovascular risk
• It is important to optimize women’s cardiometabolic health before and between pregnancies to prevent long-​​term complications
• Parity (number of live births) has a J‑shaped relationship with cardiovascular disease risk 
  • Higher parity (4–5+ live births) is associated with increased risk, potentially due to weight gain and dysregulation of adipokines during pregnancy
  • Risk is also present in men, suggesting potential confounding by socioeconomic and cultural factors
    Lipids and Lipoproteins During Pregnancy
• Lipid panel changes during pregnancy 
  • Total cholesterol, triglycerides, LDL cholesterol, lipoprotein, and HDL cholesterol levels increase
  • Peak during the third trimester
  • 25% to 50% increase in total cholesterol
  • 150% to 300% increase in triglycerides
  • 66% increase in LDL
• Physiological reasons for lipid changes during pregnancy 
  • Promote accumulation of maternal fat stores
  • Provide calories for mother and fetus during later stages of pregnancy
  • Cholesterol increase needed for utero placental vascularization, placental steroid synthesis, and placental transport function
• Pregnancy not a good time for baseline lipid panel

Familial Hypercholesterolemia (FH)

• Affects 1 in 250 people
• Autosomal dominant, affects women and men equally
• Phenotype: LDL above 190
• Genetic testing available
• Untreated FH: 30% of women have a myocardial infarction before age 60
• No increased risk of congenital malformations or preeclampsia
• Contraception recommendations: avoid high estrogen compounds, use low-​​dose estrogen oral contraceptives, IUDs, or barrier techniques

Statins and Pregnancy

• Statins not likely teratogenic, but still caution during pregnancy
• Most women stop statins during conception, pregnancy, and breastfeeding
• FDA removed strongest warning label, allowing more flexible options
• Statins being investigated for preeclampsia prevention 
  • Animal studies show decreased inflammation and oxidative stress
  • Ongoing randomized clinical trial with 1500 high-​​risk women

Statins and Women’s Health

• Misconception: statins don’t work in women for primary prevention
• Meta-​​analysis of 18 randomized clinical trials with over 40,000 women 
  • Statins benefit women in both primary and secondary prevention
  • No interaction by sex
  • Primary prevention: 15% reduction in major adverse cardiovascular events
  • Secondary prevention: 22% reduction
  • All-​​cause mortality lower in women with statins
• Number needed to treat (NNT) depends on primary vs. secondary prevention
  Statin Usage in Women
• Women less likely to be offered statins 
  • Palm registry shows this trend
  • Women more likely to decline or discontinue statins
• Women 30–50% more likely to report statin-​​associated muscle symptoms 
  • Leads to stopping statin usage
• Young women under 55 less likely to be on statins after myocardial infarction 
  • Despite being high-​​risk individuals
• Medical Expenditure Panel Survey 
  • Women 45% less likely to be treated with statins than men

Reasons for Lower Statin Usage in Women

• Combination of factors: 
  • Women may perceive themselves as lower risk
  • Women may be more fear-averse
  • Women more likely to report muscle symptoms
• Nocebo effect
  • Real-​​world practice shows up to 30% of statin-​​treated patients report muscle symptoms
  • Samsung trial: 90% of statin-​​associated symptoms also elicited by placebo

Statin Workflow and Options

• High-​​risk patients 
  • Start with high-​​intensity statin
  • Use combination therapy early
• Lower-​​risk primary prevention patients 
  • Start with moderate-​​intensity statin
• Options for patients with statin-​​associated muscle symptoms or statin intolerance 
  • Re-​​challenge with statins
  • Other options: zetamine, PCSK9 inhibitors, bempidoic acid

PCSK9 Inhibitors

• Evolocumab and alirocumab 
  • Monoclonal antibodies that inhibit PCSK9 protein
  • Prevent LDL receptor degradation, leading to greater clearance of LDL from circulation
  • Lower LDL by 50–60%, modest lipoprotein(a) lowering around 25%
  • Reduce major adverse cardiovascular events
  • Preference between the two depends on patient’s insurance and approval
    New LDL Lowering Drugs
• Evalucomab:
  • Legacy effect with continued lower risk of events
  • Trials show women benefited similarly to men
  • No major adverse event difference between sexes
  • Used as an add-​​on to statins in high-​​risk patients
• Inclisiran:
  • Inhibits PCSK9 through a different mechanism
  • Subcutaneous injection given every six months
  • Designed for clinic setting
  • Approved for LDL lowering, but outcome data not yet available
• Bempidoic acid:
  • Oral drug that blocks ATP Citrase Lyase
  • Works in cholesterol synthesis pathway
  • Does not have the same muscle symptoms as statins
  • Does not increase glucose levels
  • Lowers LDL by about 18% alone, 21% in statin intolerant patients
  • Fixed dose combination with azetamide results in 36% reduction in LDL
  • May be a good choice for women who can’t tolerate statins

Statin Choice for Low to Moderate Risk Patients

• High-​​intensity statins like atorvastatin or rosuvastatin 
  • Start with a low dose to gain patient trust
  • Adjust dose based on progress and tolerance
• Emphasize the importance of diet and lifestyle changes

Dietary Impact on LDL

• About 80% of LDL is synthesized by the liver, with a strong genetic component
• 20% is influenced by diet 
  • Reduction in saturated fats
  • Focus on polyunsaturated and monounsaturated fats
  • Increase fiber, fruits, vegetables, and whole grains
  • Avoid processed foods and processed meats
• Combination of pharmacotherapy and lifestyle changes is important for patients with existing ASCVD
• For low-​​risk young adults, focus on healthy lifestyle changes to reduce the total burden of years with LDL elevation
  Lipoprotein(a) and Women’s Health
• Lipoprotein(a) or Lp(a) is an LDL-​​like particle 
• Comprised of ApoB (bad moieties) and Apo(a)
• Apo(a) has multiple isoforms, leading to heterogeneity in the population
• Higher Lp(a) levels seen in Black and South Asian individuals compared to White individuals
• Sex differences in Lp(a)
• Generally 5–10% higher in women than in men
• Relatively constant in men, but increases after menopause in women
• Increases during pregnancy (10–35 weeks), but falls back to pre-​​pregnancy baseline after delivery
• Lp(a) is pro-​​atherogenic, pro-​​inflammatory, and pro-thrombotic
• Associated with cardiovascular risk and likely causally related to ASCVD and calcific aortic stenosis
• Risk remains even when LDL is low (<70 mg/​​dL)
• Importance of measuring Lp(a)
• Can identify residual risk when LDL is low
• Helps determine if PCSK9 inhibitors are appropriate for patients with high Lp(a) and elevated LDL
• Potential therapies for lowering Lp(a)
• Apheresis for patients with very high Lp(a) and progressive cardiovascular disease
• Monoclonal antibodies (evolocumab and alirocumab) and inclisiran can lower Lp(a) by 20–25%
• New therapies being studied in trials

Menopause and Women’s Health

• Lp(a) tends to increase after menopause in women
• Further discussion needed on menopause, hormone replacement therapy (HRT), and their impacts on cardiovascular health
  Leprechaun A and Cardiovascular Risk
• Pellacarcin and Opacarin: new therapies targeting leprechaul A synthesis 
  • Horizon trial: ongoing cardiovascular outcome trial for Pellacarcin
• Lowering lipitol A and its relation to reduction in Mace (Major Adverse Cardiovascular Events) 
  • Modeling data suggests reducing lipidill A by 50–100 mg/​​dL for meaningful reduction in ASVD
  • Niacin and hormone replacement therapy lower lipo A but not recommended for sole purpose of lipidl A reduction
• Telocarcin and Opacyrin: reduce Lipidil A by 80–90%
  • Need outcome data to determine if lowering leprechaun A leads to significant reduction in Mace

Menopause and ASCVD (Atherosclerotic Cardiovascular Disease)

• Menopause: loss of estradiol leading to increase in LDL
• Hormonal changes during menopause 
  • Estrogen levels drop during perimenopause
  • Ovaries continue to produce androstenedione and testosterone after menopause 
    • Converted in fat and muscle tissue into estrone
• Postmenopausal women with higher androgen levels have greater risk of developing ASVD and heart failure 
  • Higher androgens also linked to coronary artery calcium progression, worse endothelial reactivity, and increased concentric remodeling
• Menopause-​​related changes 
  • More visceral fat deposition, insulin resistance, and Dyslipidemia
  • Increased triglycerides, LDL, and decreased HDL
  • More endothelial dysfunction, increased blood pressure, and increased sympathetic tone

Hormone Therapy in Menopause

• Favorable changes with hormone therapy 
  • Lower LDL and increase HDL
  • Dilate blood vessels through nitric oxide effect
• Unfavorable changes with hormone therapy 
  • Increase CRP (C‑reactive protein)
  • Pro-​​thrombotic effects (increase prothrombin, decrease antithrombin III)
  • Increase triglycerides
• Hormone therapy may not be beneficial for high-​​risk women or those farther from menopause transition
  Women’s Health Initiative and Hormone Therapy

• Women’s Health Initiative studied hormone therapy in women with a mean age of 63

  • Found increased risk of venous thromboembolism with oral conjugated equine estrogen and progestin
• Hormone therapy not recommended for cardiovascular disease prevention 
  • Other options like statins available
• Hormone therapy may be considered for symptomatic women under 60 or within ten years of menopause 
  • Helps with hot flashes, night sweats, and other menopausal symptoms
  • Not recommended for women over 65 or more than ten years out from menopause

Progesterone and Lipids

• Progesterone needed for women with intact uterus 
  • May influence the benefits of estrogen therapy
  • Not used for cardiovascular benefit

Underrepresentation of Women in Clinical Trials

• Historically, women under-​​enrolled in cardiovascular clinical trials (only 25–30%)
  • Analysis of lipid-​​lowering trials from 1992–2018 showed only 29% representation of women
• Some improvement in recent trials, but still underrepresented 
  • Clear Outcomes trial had nearly 50% women participants
  • Rewind trial (Dulaglutide) had 46% women participants

Increasing Women’s Participation in Clinical Trials

• Increase representation of women in trial leadership and steering committees 
  • More likely to report sex and gender-​​specific analysis
  • More women authors correlated with higher enrollment of women participants
• Include more patients and women in trial designs 
  • Patient-​​centered designs
  • Address barriers like hidden costs, transportation, time off work, and childcare
• Make study designs more inclusive and less restrictive 
  • Don’t exclude women of childbearing age if they have a plan for preventing pregnancy and adequate contraception
    Trials in Pregnant Women and Cardiovascular Disease
• Need more trials in pregnant women to understand what works and what’s safe 
• Barriers to overcome with trial teams, trial designs, funding agencies, institutions, and journals
• Randomized clinical trials are the largest evidence base
• Aim to ensure that treatments are efficacious and safe for women, and that they benefit similarly to men

Karen’s Marathon Experience

• Completed 38 marathons, aiming to do one in every state
• Completed marathons in 36 states, some states repeated
• Marathons canceled during COVID-​​19, affecting training and progress
• Registered for a marathon in New Jersey in October
• Emphasizes that one doesn’t have to be good at a hobby to enjoy it