Heart disease remains the leading cause of death in women worldwide, but the way it develops is often misunderstood. Atherosclerotic cardiovascular disease (ASCVD) refers to a group of conditions caused by the gradual buildup of cholesterol-rich plaque inside the walls of arteries. Over time, this plaque narrows or blocks blood flow to vital organs such as the heart and brain, which can lead to chest pain (angina), heart attack, stroke, or other serious complications. This condition is often a silent disease, meaning it can begin early in life and progress for decades without noticeable symptoms. Many women first learn they have heart disease only after a major event such as a heart attack or stroke. In a prior blog, Dr. West reviewed how both standard cholesterol testing and advanced lipoprotein measurements help assess cardiovascular risk more accurately. In this article, we focus on a critical life stage for women—the menopause transition—when changes in hormones can accelerate the processes that contribute to plaque buildup and increase cardiovascular risk. Understanding why these changes occur and what can be done about them offers a powerful opportunity to prevent them and support lifelong heart health. Why Women’s Heart Disease Has Been Historically Underestimated Real progress in both understanding and treating women’s heart health began in the mid-1990s, as high-level scientific randomized clinical trial data for women finally started to emerge. Trials prior to this time evaluated mostly men. So many of our previous beliefs and paradigms which were based on men’s data or observational (nonrandomized) trials of women have had to undergo radical rethinking.
Cholesterol 101: Why Particle Number Matters When we talk about cholesterol, we’re really talking about how fat and cholesterol travel through your bloodstream. Because oil and water don’t mix, your body packages cholesterol and triglycerides (another type of blood fat) into tiny “transport ships” called lipoprotein particles. Low-Density Lipoproteins (LDLs, or “bad cholesterol”) and Very-Low Density aLipoproteins (VLDLs) are the two major players in plaque development and inflammation. These particles consist of a core of lipids (triglycerides and cholesterol) surrounded by a single structural protein, called apolipoprotein B (apoB). The number of LDL particles or “ships” (LDL-P) are the major culprits in initiating and worsening arterial plaque. Even if each particle carries only a little cholesterol, a high number of particles means more chances for particles to enter the artery wall, trigger inflammation, and contribute to plaque buildup over time. In other words, more particles = more opportunities for trouble, even if the cholesterol number looks “okay.” This risk is most accurately measured by the LDL-P test (which directly counts the number of LDL particles) or the apoB test (since there is typically one apoB per particle, an apoB blood test is essentially another way to count particles directly.) It can also be estimated by their cholesterol “cargo” – what the particle “ship” is carrying — with the LDL-C test (the cholesterol in LDL particles only) or non-HDL-C test (all the types of cholesterol that are in the particles that aren’t the “good cholesterol” HDL). We exclude the High-density lipoproteins (HDLs) because they are different – they have apolipoprotein A-I, not apoB as their covering protein and their crucial functions have no relationship to their particle number (HDL-P) or cholesterol cargo (HDL-C). Unlike what has previously been taught, although low HDL-C is usually a risk factor, increased HDL-C is not necessarily beneficial.
Atherosclerosis: How Heart Attacks and Strokes Occur It is now recognized that atherosclerosis (ASCVD) is a chronic inflammatory disease of the arteries that begins very early in life, with the slow development of cholesterolcontaining, inflammation-producing plaques. Plaque buildup eventually leads to arterial narrowing which causes clinical events in adulthood including chest pain with exertion, stents, and ultimately heart attacks or strokes. It is the rupture of small, non-obstructing plaques which generates blood clots (thrombi) and further narrows or occludes (blocks) arteries reducing or stopping blood flow. These heart or stroke attacks (called infarctions) cause most of the morbidity and mortality of cardiovascular disease. Sadly, in too many individuals, the first symptom is sudden death.
What Happens to Cholesterol During the Menopause Transition Menopause isn’t just a change in periods—it’s also a shift in hormones that can change how your body processes fats (lipids) and blood sugar. With respect to the menopausal transition, in the first two years after the final menstrual period the following lipid changes are typical: Total cholesterol (TC) increases by 10-15% LDL-C (“bad cholesterol”) similarly increases by 10-15% or 10-20 mg/dL Triglycerides (TG) increase by 10-20% HDL-C (“good cholesterol”) drops due to a reduction in larger, cholesterol-rich HDLs HDL functionality declines ApoB and LDL-P increase 8-12% with a shift to smaller LDL particles The big picture is this: during menopause, the bloodstream often ends up with more of the particles that can enter artery walls and contribute to plaque. Even if someone has had “good cholesterol numbers” most of their life, this midlife shift can quietly change the risk trajectory. Here’s why: •
Hormone changes can increase insulin resistance
Many of these changes are related to the loss of both estrogen and testosterone. One of estrogen’s beneficial properties is to act as an insulin sensitizer which helps control both glucose and lipoproteins (lipids). During menopause when estrogen and testosterone concentrations decline, there is a decrease in insulin sensitivity and an increase in insulin resistance, often associated with increased adiposity (weight gain).
This is part of the explanation for the increasing triglycerides and apoB, and decreasing HDL-P and HDL-C concentrations. •
Menopause can reduce your body’s ability to clear LDL (“bad cholesterol”) from the blood
The loss of estrogen also affects a protein called PCSK9 that modulates the LDLreceptors (LDLR). With decreased estrogen there is increased PCSK9 activity which reduces LDLRs also resulting in increased LDL-P, apoB and LDL-C concentrations. All of these changes, unless modified with lifestyle and medications if needed, can slowly but surely increase a woman’s ASCVD risk. Prevention, Timing, and Personalized Treatment We now better understand that lifestyle and pharmacological therapies can prevent the development of plaques or stabilize those which may already exist. Doing so has been successful in improving cardiovascular outcomes. Decreasing potentially atherogenic (atherosclerosis-causing) lipoproteins levels or modifying them into less-atherogenic particles is emerging as a very effective strategy. Estrogen itself is not approved to treat existing heart disease but the FDA has recently changed recommendations noting that when instituted during the menopause transition or in the early years of menopause it can help promote arterial health. Thus, the timing of estrogen therapy earlier versus later in menopause is emerging as critical to vascular response. The Bottom Line: Earlier Awareness Leads to Better Outcomes If we are to begin to make real progress in the battle against cardiovascular disease in women, we must identify risk much earlier in life using our new diagnostic tools and must become more aggressive in our therapies, including lifestyle and pharmacologic strategies. We also need to fine tune who will or will not benefit from estrogen.[EW3.1] Thomas Dayspring, MD, FACP, FNLA is a board-certified internist and clinical lipidologist with more than four decades of experience in cardiovascular prevention and women’s heart health. A nationally recognized educator and former Associate Editor of the Journal of Clinical Lipidology, he was the first physician in the United States to be certified as both a Menopause Practitioner by The Menopause Society and in Lipidology by the American Board of Clinical Lipidology. He has received multiple national awards for his contributions to cardiovascular medicine and lipid education.
