#230 ‒ Cardiovascular disease in women: prevention, risk factors, lipids, and more | Erin Michos, M.D.
Dr. Erin Michos, a preventive cardiologist at Johns Hopkins, discusses the rising trends in cardiovascular disease (CVD) in women, emphasizing female-specific risk factors like PCOS, pregnancy, and menopause. She highlights the critical need for early prevention and aggressive lipid management.
Deep Dive Analysis
16 Topic Outline
Erin Michos's Background and Preventive Cardiology Focus
Rising Cardiovascular Disease Mortality Trends in Women
Importance of Early Prevention and Lifetime Risk Assessment
Metabolic Syndrome Epidemic and GLP-1 Agonists
Female-Specific Cardiovascular Risk Factors: An Overview
Polycystic Ovary Syndrome (PCOS) and Cardiometabolic Impact
Impact of Grand Multiparity and Oral Contraceptives on CVD Risk
Physiological Lipid Changes During Pregnancy
Familial Hypercholesterolemia (FH) in Women and Undertreatment
Statins: Efficacy in Women and Addressing Misconceptions
New Lipid-Lowering Therapies: PCSK9 Inhibitors, Inclisiran, Bempedoic Acid
Impact of Lifestyle Factors: Diet, Exercise, and Stress
Lipoprotein(a) as a Risk Enhancer and Emerging Therapies
Menopause, Hormonal Changes, and Accelerated CVD Risk
Approach to Hormone Replacement Therapy (HRT) in Menopause
Underrepresentation of Women in Clinical Trials and Future Needs
6 Key Concepts
Familial Hypercholesterolemia (FH)
FH is an autosomal dominant genetic disorder affecting about 1 in 250 individuals, characterized by very high LDL cholesterol levels (typically above 190 mg/dL). It leads to a significantly increased lifetime risk of cardiovascular disease, with an earlier onset of ASCVD by 20-30 years, and women with FH do not experience the typical premenopausal protection seen in the general population.
Polycystic Ovary Syndrome (PCOS)
PCOS is the most common endocrine abnormality in women of reproductive age, affecting 5-13% of the population. It's characterized by hyperandrogenism, irregular menses, and polycystic ovary morphology, with insulin resistance being a hallmark of its pathogenesis, driving cardiometabolic complications like dyslipidemia and hypertension.
Nocebo Effect (Statin-Associated Muscle Symptoms)
The nocebo effect refers to the phenomenon where patients experience adverse symptoms (like muscle pain) from a treatment due to negative expectations or beliefs, even if the treatment itself is not causing the symptoms. In statin trials, up to 90% of reported statin-associated muscle symptoms were also elicited by placebo, highlighting the psychological component.
PCSK9 Inhibitors
These are a class of drugs, including monoclonal antibodies (evolocumab, alirocumab) and small interfering RNA (inclisiran), that inhibit the PCSK9 protein. By preventing PCSK9 from degrading LDL receptors on liver cells, they lead to an upregulation of these receptors, resulting in greater clearance of LDL cholesterol from circulation and significant reductions in LDL and Lp(a).
Bempedoic Acid
Bempedoic acid is an oral drug that blocks ATP citrate lyase, an enzyme in the cholesterol synthesis pathway upstream of where statins act. It works by blocking cholesterol synthesis, which upregulates LDL receptors on the liver and increases LDL clearance. Notably, its activation enzyme is only in the liver, not muscle, potentially reducing statin-associated muscle symptoms.
Lipoprotein(a) (Lp(a))
Lp(a) is an LDL-like particle composed of ApoB and a unique Apo(a) moiety, which has pro-atherogenic, pro-inflammatory, and pro-thrombotic properties. It is largely genetically determined, 5-10% higher in women than men, and increases after menopause, serving as an independent risk enhancer for ASCVD and calcific aortic stenosis, even with low LDL levels.
8 Questions Answered
Cardiovascular disease mortality is rising in younger women (age 45-64) at 0.5% per year, narrowing the gap with cancer deaths, primarily due to epidemics of obesity, diabetes, and other cardiometabolic diseases, coupled with a concerning lack of awareness among women that heart disease is their leading cause of death.
Both early menarche (before age 11) and late menarche (after age 17) are associated with an increased risk of cardiovascular disease later in life, likely due to hormonal, adipokine, and cardiometabolic imprinting, with elevated BMI being a risk factor for early onset menarche.
PCOS is strongly linked to cardiovascular risk, primarily driven by insulin resistance, leading to dyslipidemia (elevated LDL, triglycerides, low HDL), hypertension, and increased subclinical atherosclerosis (e.g., coronary calcium). Women with PCOS also face higher risks of preeclampsia and gestational diabetes during pregnancy.
Combined oral hormonal contraceptives, especially older, higher-estrogen formulations, can increase triglyceride levels and lower LDL. While these changes are generally modest and the benefit of preventing unwanted pregnancy outweighs the risk for most women, they should be avoided in women with high baseline triglycerides or established cardiovascular disease.
During a normal pregnancy, serum total cholesterol, triglycerides, LDL, Lp(a), and HDL cholesterol all gradually increase, peaking in the third trimester. Triglycerides can increase by 150-300%, total cholesterol by 25-50%, and LDL by 66%, as part of normal physiological changes to support maternal fat stores and fetal development, typically returning to pre-pregnancy levels after delivery.
Yes, meta-analyses of over 18 randomized clinical trials show that statins benefit women in both primary and secondary prevention, with a 15% reduction in major adverse cardiovascular events in primary prevention and a 22% reduction in secondary prevention, without interaction by sex, meaning women benefit similarly to men at similar risk levels.
Negative psychological factors like stress, anxiety, and depression can indirectly harm cardiovascular health through poor coping habits (unhealthy diet, inactivity, smoking, alcohol) and directly by activating the sympathetic nervous system, increasing heart rate, blood pressure, cortisol release, insulin resistance, visceral fat deposition, and chronic inflammation.
Menopause, marked by a dramatic drop in estradiol, leads to relatively acute changes in the lipid panel, including increased total cholesterol, LDL, and triglycerides, and decreased HDL. This dyslipidemia, along with increased visceral fat, insulin resistance, and endothelial dysfunction, accelerates ASCVD risk, making it an important period for cardiovascular prevention.
47 Actionable Insights
1. Prioritize Preventable CVD
Focus on preventing cardiovascular disease by addressing modifiable risk factors, as over 90% of CVD is due to preventable causes. There is much that can be done for prevention.
2. Start ASCVD Prevention Early
Implement ASCVD prevention strategies, especially those targeting ApoB/LDL, as early as possible in life to minimize cumulative exposure. Prevention is better implemented when started earlier to prevent unchecked atherosclerosis propagation.
3. Minimize Lifetime ApoB Exposure
Actively work to minimize lifetime exposure to ApoB (and LDL cholesterol) by starting interventions earlier and aiming for lower concentrations. This strategy minimizes the ‘area under the curve’ of ApoB exposure, reducing long-term risk.
4. Treat Causal Agents Promptly
Treat causal agents of ASCVD, such as high blood pressure and elevated ApoB, early in life, even if short-term risk scores are low. Ignoring these high values does a disservice by allowing silent vascular damage to continue.
5. Adopt Lifetime Risk Perspective
Adopt a long-term perspective on health, focusing on preventing major adverse cardiac events over a lifetime (e.g., 40 years) rather than just short-term (e.g., 10-year) risk. This approach emphasizes comprehensive prevention for sustained health.
6. Emphasize Healthy Lifestyle from Childhood
Prioritize and emphasize healthy lifestyle practices, including diet and exercise, from childhood as a fundamental strategy for preventing obesity and cardiometabolic diseases. This is crucial for reversing alarming trends in cardiovascular disease mortality.
7. Prioritize Physical Activity
Engage in regular physical activity to improve overall cardiovascular risk, aid in weight maintenance, and increase fitness levels. Being more fit is one of the strongest favorable factors for lower cardiovascular risk.
8. Adopt Mediterranean Diet
Follow a Mediterranean-style dietary pattern, which is generally low in saturated fats, high in unsaturated fats, fruits, vegetables, and whole grains, for cardiovascular health. This diet is palatable and supported by observational and clinical trial data.
9. Address Mental Health for CVD
Actively address mental health, including managing stress, anxiety, and depression, as psychological factors directly and indirectly impact cardiovascular health. Stress can activate the sympathetic nervous system, increasing heart rate, blood pressure, and inflammation.
10. Combine Meds and Lifestyle
Recognize that managing cardiovascular risk effectively requires a combined approach of pharmacotherapy (if needed) and consistent healthy lifestyle changes, including diet and exercise. This comprehensive strategy is essential for optimal patient outcomes.
11. Live Healthy for Future Options
Prioritize healthy living in the first half of life to maximize options and minimize morbidity and mortality in the second half. This includes choices around menopause and cardiovascular health, giving you more flexibility later in life.
12. Screen for Familial Hypercholesterolemia
Be aware of Familial Hypercholesterolemia (FH) and advocate for screening, especially if LDL is above 190 mg/dL or there’s a family history of premature ASCVD. Early treatment is critical to prevent early onset myocardial infarction, which affects 30% of untreated women with FH before age 60.
13. Intensify Lipid Lowering Therapy
For high-risk individuals, especially those with established ASCVD, ensure lipid-lowering therapy is intensified to reach LDL goals, utilizing combination therapy including PCSK9 inhibitors if necessary. Many patients are undertreated and not at goal, leading to continued risk.
14. Recognize Statin Benefits for Women
Understand that statins are effective for women in both primary and secondary prevention of ASCVD, providing similar benefits to men without interaction by sex. Misconceptions that statins don’t work in women are false, as meta-analyses confirm their efficacy.
15. Start High-Intensity Statins Early
For very high-risk patients (e.g., recent coronary syndrome), initiate high-intensity statin therapy upfront and consider early combination therapy to achieve aggressive LDL lowering. This approach aims for optimal LDL reduction as quickly as possible.
16. Explore Alternative Lipid Agents
If statins are not tolerated or insufficient, explore alternative lipid-lowering agents like ezetimibe, PCSK9 inhibitors, or bempedoic acid with your doctor to reach LDL goals. These options provide additional pathways to manage high cholesterol effectively.
17. Re-Challenge Statin Symptoms
If experiencing statin-associated muscle symptoms, discuss a re-challenge with your doctor, as many reported symptoms may be due to the nocebo effect rather than the medication itself. Up to 90% of reported symptoms in some trials were elicited by placebo.
18. Start Low-Dose Statins
If statin-reluctant or intolerant, discuss starting with a very low dose (e.g., Rosuvastatin 5mg) to build trust and demonstrate tolerance. This can be a strategy to gradually increase or combine therapies later once the patient is comfortable.
19. Understand CoQ10/Vit D Limits
Understand that there is no strong data supporting the effectiveness of CoQ10 or Vitamin D supplements in preventing statin-associated muscle symptoms, though they may be taken for comfort. Physicians do not actively prescribe them for this purpose due to lack of evidence.
20. Measure Lipoprotein(a) for Risk
Consider measuring Lipoprotein(a) (Lp(a)) to assess residual cardiovascular risk, especially if LDL is low, as elevated Lp(a) can still contribute significantly to ASCVD risk. It is causally related to ASCVD and calcific aortic stenosis.
21. PCSK9 for Elevated Lp(a)
If you have elevated Lp(a) and another indication for intensive lipid lowering (e.g., elevated LDL, ASCVD), discuss PCSK9 inhibitors with your doctor, as they can modestly lower Lp(a) by 20-25%. Individuals with higher Lp(a) levels have shown greater benefit from these therapies.
22. Optimize Pre-Pregnancy Health
Improve cardiometabolic health in young adults and women of reproductive age, ideally before pregnancy, to prevent adverse pregnancy outcomes and long-term cardiovascular complications. Poor cardiometabolic health before pregnancy increases risks like preeclampsia and gestational diabetes.
23. Optimize Inter-Pregnancy Health
Actively work to optimize cardiometabolic health not only before pregnancy but also in the inter-pregnancy period to prevent long-term cardiovascular complications. Women tend to gain weight with each pregnancy, and dysregulation of adipokines may occur.
24. Manage FH During Pregnancy
For women with FH planning pregnancy, discuss with a lipid specialist about short-term interruptions of statin therapy during conception, pregnancy, and breastfeeding, rather than prolonged non-treatment. Short interruptions are better than decades of untreated high LDL.
25. Choose Safe Contraception (FH/CVD)
Women with FH or established cardiovascular disease should consider long-acting reversible contraception like IUDs or barrier methods, and avoid higher-estrogen oral contraceptives, especially if over 35. This is due to increased risk for atherosclerosis and prothrombotic effects of estrogen.
26. Optimize PCOS Cardiometabolic Health
If you have PCOS, prioritize optimizing a healthy lifestyle and weight management to mitigate associated cardiometabolic risks like hypertension and dyslipidemia. Insulin resistance is a hallmark of PCOS, driving many of these complications.
27. PCOS: Consider GLP-1 Agonists
For women with PCOS who are not trying to become pregnant, discuss GLP-1 receptor agonists with your doctor as a potential option for weight management and improving insulin resistance. These agents may be promising for managing the cardiometabolic phenotype of PCOS.
28. Consider GLP-1 for Weight
If struggling with obesity or overweight with risk factors, discuss GLP-1 receptor agonists with your doctor as a potential pharmacological aid for weight loss and improved cardiovascular health, in conjunction with diet and lifestyle. These agents have shown significant weight loss and may be cardiovascularly beneficial.
29. HRT Not for CVD Prevention
Do not use hormone replacement therapy (HRT) solely for cardiovascular disease prevention, as more effective and safer alternatives like statins are available. Guidelines do not recommend HRT for this purpose due to mixed outcomes in trials, especially in older women.
30. Consider HRT for Symptoms
If experiencing symptomatic menopause (hot flashes, night sweats) and are under 60 or within 10 years of menopause, discuss hormone therapy with your doctor, provided there are no contraindications. Vasomotor symptoms can be very disabling and are associated with cardiovascular risk.
31. HRT for Early Menopause
If experiencing early menopause (before age 45 or 40), consider menopausal hormone therapy until at least the natural age of menopause (around 51), provided there are no contraindications. Early menopause is associated with increased cardiovascular risk.
32. Assess CAC Before HRT
If considering HRT and cardiovascular risk is uncertain, discuss getting a coronary artery calcium (CAC) score. A zero score may provide reassurance for initiating HRT for vasomotor symptoms, but significant atherosclerotic disease would lead to not recommending it.
33. Avoid Oral Estrogens (CVD Risk)
Avoid oral estrogens for hormone therapy if you have a history of cardiovascular disease, blood clots, high triglycerides, gallbladder disease, or prior breast and endometrial cancer. These conditions are contraindications due to increased risks of adverse events.
34. Use Vaginal Estrogens Safely
If experiencing only genitourinary symptoms of menopause, vaginal estrogens can be used safely, even if you have cardiovascular disease or a history of stroke. They have minimal systemic absorption, making them a good option for high-risk women.
35. Standardize Lipid Panel Timing
For women, if serial lipid panels are being monitored, aim to measure them around the same time in the menstrual cycle, ideally during menses (e.g., day 5), for consistent and comparable results. This accounts for natural fluctuations in lipid levels throughout the cycle.
36. Avoid Pregnancy Lipid Baselines
Do not use lipid panels taken during pregnancy as a baseline, as physiological changes cause significant, temporary increases in cholesterol and triglycerides. Obtain a baseline before pregnancy if concerns exist, as levels return to pre-pregnancy levels after delivery.
37. PCSK9 for High CAC Scores
In high-risk primary prevention patients with very high coronary artery calcium scores (e.g., above 300), consider PCSK9 inhibitors in addition to high-intensity statins to achieve aggressive LDL lowering. A high CAC score indicates significant plaque burden, warranting intensive treatment.
38. Pursue FH Genetic Testing
If diagnosed with FH, consider genetic testing to identify specific mutations, which can inform cascade screening for family members and provide a more precise risk assessment. This helps in identifying monogenic FH versus polygenic risk.
39. Start Healthy Lifestyle Early
Promote healthy lifestyles and dietary changes starting even before birth (in utero) for optimal long-term health. This foundational approach can significantly impact an individual’s health trajectory.
40. Gain Bench Lab Experience
For those entering science and medicine, gain bench lab work experience. This provides a good foundation and understanding of scientific processes.
41. Enjoy Hobbies, Set Goals
Engage in hobbies for personal enjoyment and goal-setting, rather than striving for perfection or external validation. The act of doing something and setting goals for yourself can be fun and rewarding, regardless of skill level.
42. Advocate for Health Policies
Advocate for and support population-level interventions and policy changes that address social determinants of health. This includes improving access to quality food, safe exercise spaces, and reducing sedentary lifestyles to combat widespread health problems.
43. Diversify Trial Leadership
Advocate for and support increased representation of women in clinical trial leadership and steering committees. Greater female representation correlates with better enrollment of women participants and more sex-specific analyses in studies.
44. Include Patients in Trial Design
Advocate for patient-centered clinical trial designs that actively involve patients, especially women, to address practical barriers to participation. This includes considering factors like transportation, childcare, and flexible follow-up options.
45. Understand Trial Benefits
If considering clinical trial participation, seek education to dispel misconceptions and understand the benefits. Participants often gain access to gold-standard care and study investigators, even if the drug’s efficacy is unknown.
46. Reduce Trial Exclusion Criteria
Advocate for less restrictive inclusion/exclusion criteria in clinical trials, particularly for women of childbearing age. Women should be eligible if they have a plan for preventing pregnancy and adequate contraception.
47. Support Pregnant Women Research
Support and advocate for more clinical trials specifically involving pregnant women to better understand the efficacy and safety of interventions during pregnancy. This is crucial for improving maternal and fetal health outcomes.
6 Key Quotes
90% of myocardial infarction risk was due to preventable risk factors.
Erin Michos
If these trends are not overturned, heart disease is set to overtake cancer as the leading cause of death in younger women as well.
Erin Michos
It's not only really the magnitude of LDL elevation, but it's the duration of exposure.
Erin Michos
Women are not smaller men or have unique risk factors.
Erin Michos
Prevention is better implemented when started earlier.
Erin Michos
You don't have to be good at a hobby to enjoy it.
Erin Michos