Erin Michos: Cardiovascular Disease in Women: Prevention, Risk Factors, Lipids, and more
Attia presents Erin Michos, an expert in preventive cardiology and women’s cardiovascular health. Erin discusses rising major adverse cardiac events, risk factors, interventions, and female-specific contributors to cardiovascular disease (CVD). She explores LDL-cholesterol, apoB, Lp(a), statins, GLP‑1 agonists, and PCSK9-inhibitors. Erin covers pregnancy, oral contraceptives, menopause, and PCOS as CVD risk factors. She shares her approach to hormone replacement therapy and offers advice on lifestyle changes and medications for risk reduction.
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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
- Frustration with the double standard in treating APO B compared to smoking and blood pressure
- 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
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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
- Don’t exclude women of childbearing age if they have a plan for preventing pregnancy and adequate contraception
- 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
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