My doctor just put me on medicine for (AFib). Because I am 57 years old, we discussed whether menopause increases the risk of AFib since other cardiac risks seem to be more prevalent later in life. Wh

Your Menopause Question: My doctor just put me on medicine for (AFib). Because I am 57 years old, we discussed whether menopause increases the risk of AFib since other cardiac risks seem to be more prevalent later in life. What are your thoughts?

Our Response: AFib, short for atrial fibrillation, is a noteworthy cardiac condition and should not be ignored. It is the most common arrhythmia in the United States (U.S.), affecting over 3 million people (Lee, 2014). On electrocardiogram (ECG), the heart exhibits a supraventricular rhythm with uncoordinated atrial activity associated with an irregular, rapid ventricular response. While it is more common in men, women have more symptoms, poorer outcomes, and often receive less attention in healthcare facilities. Common symptoms are palpitations, fatigue, dyspnea, and dizziness, but the most serious outcomes involve atrial flutter, atrioventricular (AV) block, and stroke.

Because menopause is a strong marker of adverse cardiovascular risk, would not AFib fit that picture? Let us take a brief look at cardiac risk in menopause.
It is well known that heart disease in women differs from that in men (Murphy, 2014). For men, a heart attack is preceded by a series of biologic events in which oxidized cholesterol damages the endothelial cells that line the coronary arteries. Immune cells are drawn from the blood into these damaged coronary blood vessels, leading to the formation of plaques. When the plaques rupture, the released thrombus blocks the artery to produce cardiac damage.

For women, presumably due to their altered hormone profile, only tiny lipid plaques form that are distributed throughout the smaller blood vessels in the heart and, thus, produce more subtle cardiac symptoms.

But cardiac disease in menopause is more than simply changes in the heart. The intestine now is considered the second brain (Becker, 2020). During menopause, alterations in the intestinal bacteria and gut lining produce changes in how and what food products we absorb and signal to the brain to reduce energy expenditure by slowing the activity. The result is deposition of visceral fat around the mid-body. But visceral fat produces many of the inflammatory products that were kept suppressed when levels of estradiol, a powerful anti-inflammatory hormone, were high in the reproductive years. These inflammatory proteins now are fed directly into the liver and into the circulation. Moreover, visceral fat also lines many of the blood vessels, thus providing a second source of damage to the circulation (Rajsheker, 2009). The fatty depositions lead to a fat-laden liver, altered carbohydrate metabolism, insulin resistance, and the risk of metabolic syndrome.

With that as a background, does menopause increase the risk of AFib? Surprisingly, the answer in one study appears to be no. In what is the largest study of patients drawn from the Women’s Health Initiative (WHI), over 30,000 women were followed for 20.5 years. AFib was self-reported and confirmed by care providers (Wong, 2017). Of the 1,350 confirmed cases, after subdividing them into <45 years, 45-49, 50-54, and >54 years, no clear relationship of onset of menopause to cardiovascular events was found. However, a small increase in risk (1.2 risk factor) was noted if those with a prior hysterectomy were taking oral conjugated equine estradiol (PREMARIN®) alone while those on PREMPRO® (PREMARIN® plus medroxyprogesterone) showed no increased risk. These results raise questions as to whether AFib is different from other conditions in women’s cardiovascular risk, and whether the effect of oral PREMARIN® differs from the combination in PREMPRO®. Estrogen has been shown to alter the QT interval of the cardiac cycle and to influence cardiac ion channel dynamics (Sedlak, 2012, and Guhl, 2017). Estrogen regulation and protein expression in the female heart also differ from that of men (Murphy, 2014).

The conclusions of this study, while valuable based on its size, generate questions as well as provide answers. The Wong study avoided collecting data on other menopause symptoms with cardiac consequences. For example, no data was collected for vasomotor symptoms (hot flashes) that now are recognized to carry long-term cardiac risks in older, untreated women (Szmuilowicz, 2011).

But there is more to the story. It is no surprise that the science of the body is never simple. Many who read studies of “hormone replacement” in menopause may see the term “estrogen” without realizing the complicated nature of this hormone. “Estrogen” may refer to estradiol, the naturally produced estrogen from the ovaries.

On the other hand, conjugated equine estrogen (CEE, trade name PREMARIN®) in the WHI is a mixture of estrone sulfate (50% to 60%) and equilin sulfate (22% to 32%) with less than 5% being estradiol (Holder, 2010).

Moreover, timing of estrogen exposure is important. The WHI recruited women with an average age of 64 years for the study (Rossouw, 2013). This is 13 years later than most women in the U.S. enter menopause. In contrast, in some studies, early-onset menopause has been linked to stroke, heart failure, and heart attacks (Bernhardt, 2019). However, patients on hormone replacement who are less than six years into menopause exhibit an improved lipid profile (and reduced risk of cardiovascular events) when compared with those who are more than ten years into menopause, a time when estrogen appears to offer little protection (Hodis, 2015).

The delivery system of estrogen also is important (Custham, 2010). In the WHI, oral PREMARIN® alone or PREMPRO® was given. Oral estrogen requires a first pass through the liver after being ingested, which can lead to alterations in coagulation factors and a risk of vascular blood clotting. Transdermal estrogen, more widely used in hormone management during menopause today, does not seem to have that same adverse effect.

Many important questions remain for emerging and future cardiac scientists. With women dying of cardiac disease eight times more often than they die from breast cancer, it is important to understand the unique characteristics of women’s heart disease. As such, more complete analyses of AFib and its relationship to menopause are encouraged.

James Woods | 9/30/2021

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