Studies Uncover Cardiovascular Disease Risk Factors in Women

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Heart disease is the leading cause of death for women in the United States, but women have been historically underrepresented in cardiovascular disease studies. Researchers at Massachusetts General Hospital looking to address this disparity found significant relationships between cardiovascular disease risk and hypertensive disorders of pregnancy and early menopause (before age 40). Their research was presented at the American Heart Association's Scientific Sessions 2019 in Philadelphia.

"There are a lot of gaps in our understanding of heart disease in women," says Mass General cardiology fellow and the studies' first author Michael Honigberg, MD, MPP. "The reality is that most cardiologists (and most other physicians) don't routinely ask women about pregnancy and menopause. Our findings show that if a woman has a history of either hypertension in pregnancy or premature menopause and hasn't yet developed hypertension, high cholesterol or diabetes, that's an opportunity for an aggressive lifestyle intervention or modification to reduce that woman's risk."

Historical Limitations

Evidence to clearly guide how clinicians should handle preventive cardiovascular medications, specifically statins, in women at intermediate risk for developing cardiovascular disease is modest. To address this knowledge gap, the American College of Cardiology and the American Heart Association updated their cholesterol management guidelines in 2018. The revised guidelines introduced two new cardiovascular disease risk-enhancing factors specific to women: hypertension in pregnancy and premature menopause.

"This change was celebrated by a lot of people who felt that women's cardiovascular health had historically been neglected," says Dr. Honigberg. "Women have been underrepresented in cardiovascular trials and studies, and even less than a generation ago cardiac disease was thought of as a 'man's disease.'"

Utilizing Big Data

To help close the gaps in understanding about women's cardiovascular disease risks, Dr. Honigberg and Pradeep Natarajan, MD, MMSc, director of the Cardiovascular Disease Prevention Center at Mass General, in partnership with the Broad Institute, utilized data from the UK Biobank, a data set of over a half-million adult residents of the United Kingdom recruited between 2006 and 2010. Subsets of participants underwent various imaging and noninvasive studies, answered extensive questionnaires and were followed on an ongoing basis through the National Health System.

"This prospective observational cohort study is a tremendous research tool and resource," says Dr. Honigberg. "The United Kingdom uses one health record, so it's fairly easy to capture everybody's health outcomes in a centralized system."

The Connection Between Hypertensive Disorders of Pregnancy and Cardiovascular Risk

In a study published in the Journal of the American College of Cardiology, Dr. Honigberg and Dr. Natarajan looked at a subset of 220,000 childbearing women included in the UK Biobank. Among them, 2,800 had a history of hypertension in pregnancy at least once. Researchers compared these women to those who did not develop hypertension in pregnancy. Investigators then followed both groups for an average of seven years to monitor cardiovascular disease development and arterial stiffness.

"Among those with measured arterial stiffness, women with a history of hypertension in pregnancy had stiffer arteries compared to women who didn't," says Dr. Honigberg. "This was measured decades after their childbearing years, suggesting a long-term effect."

Researchers validated a previous finding of a relationship between hypertension in pregnancy and coronary artery disease. They also found that these women were more likely to develop heart failure and two types of valvular heart disease: aortic stenosis and mitral regurgitation.

"The valve findings were surprising to us and have not previously been reported," says Dr. Honigberg. "When you put all of these things together, there's accelerated aging of both the vasculature and nonvascular cardiovascular structures, such as valves and heart muscle. This really suggests that hypertension in pregnancy is associated with a syndrome of accelerated cardiovascular aging that goes beyond just coronary artery disease."

Dr. Honigberg's team used causal mediation analysis to determine if their findings could be explained by the development of other conventional cardiovascular disease risk factors later in life. They found that chronic hypertension seemed to explain two-thirds of the link between hypertension in pregnancy and coronary disease and half of the relationship between hypertension in pregnancy and heart failure. But notably, it did not explain everything.

"It may be that we should be treating hypertension in this population differently, either with specific medications or more aggressively to lower blood pressure targets," says Dr. Honigberg. "Right now, women who experience gestational hypertension and go on to develop chronic hypertension are being treated the same as any woman who develops chronic hypertension. Yet, they're still developing cardiovascular disease at higher rates. That implies there is something different about blood pressure in this population. We need to figure out how to more effectively prevent and treat cardiovascular disease in this patient population."

Early Menopause Study Yields Significant Results

Dr. Honigberg and Dr. Natarajan's other study, published in the Journal of the American Medical Association, utilized the same cohort to look at 144,000 women who had completed menopause when they enrolled in the UK Biobank. Investigators compared women who had experienced menopause before age 40—both naturally and surgically due to bilateral oophorectomy—to women who didn't.

"Very few studies have compared these different types of menopause with each other, mostly because they've been too small," notes Dr. Honigberg. "It's much less common to have early menopause as the result of a surgical procedure. But because this cohort is so huge, we actually had the power and numbers to do that analysis."

The researchers followed the three groups of women—those who had natural early menopause, those who had surgical early menopause and those who did not undergo menopause before age 40—for an average of seven years, observing cardiovascular disease outcomes and risk factors, specifically hypertension, high cholesterol and type 2 diabetes.

They found that women who had experienced early menopause had a small but statistically significant increased risk for cardiovascular disease development. These findings validated previously reported associations with coronary artery disease. They also observed associations with heart failure, aortic stenosis, mitral regurgitation, atrial fibrillation, ischemic stroke, peripheral artery disease and venous thromboembolism.

Transforming Preventive Cardiovascular Care in Women

"We've described many new aspects of the 'whats.' Now we want to delve deeper into the 'whys' to inform potential new avenues for preventing and treating cardiovascular disease in these populations," says Dr. Honigberg.

Next steps involve genetic analysis to uncover the exact mechanisms of cardiovascular disease development in women with hypertension in pregnancy and premature menopause. Long-term follow-up studies could also provide a better understanding of these mechanisms and identify specific types of effective pharmacologic treatment.

Their findings also underscore the need for clinicians to ask female patients about pregnancy and menopause history, along with the importance of women sharing that information. Dr. Honigberg hypothesizes that this new standard would better inform how physicians handle primary cardiovascular prevention in women. He also notes that there is a need to include hypertension in pregnancy and premature menopause into cardiovascular risk assessments, bolstering recommendations from the current guidelines.

"We're still really scratching the surface of our understanding of risk factors that are unique to women," says Dr. Honigberg. "There's a lot of exciting science still to be done in this space, and we're just getting started."

Learn more about the Cardiovascular Disease Prevention Center

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