Mass General Study Details How Premature Menopause Impacts Heart Health

Pradeep Natarajan, MD, MMSc

New research from a team at Massachusetts General Hospital is shedding new light on how premature menopause can influence risk of cardiovascular disease.

Results of the study, which included whole-genome sequencing of nearly 20k women in the US and UK, details the mechanism behind premature menopause and its link to increased risk of cardiovascular disease while also uncovering a potential biomarker for identifying women at greater risk.

"We recently found that the presence of chronological-age-associated mutations in blood cells—called clonal hematopoiesis—without overt cancer is a new risk factor for coronary artery disease," said lead investigator Pradeep Natarajan, MD, director of Preventive Cardiology at MGH and an assistant professor of Medicine at Harvard Medical School, in a statement. "We wondered whether earlier age at menopause independently was associated with clonal hematopoiesis."

Investigators designed date current study in an effort to determine whether clonal hematopoiesis of indeterminate potential (CHIP), was associated with premature menopause. With this in mind, Natarajan and a team of colleagues sought to assess this association using blood sample data from the UK Biobank and the Women’s Health Initiative.

From the UK Biobank and Women’s Health Initiative, investigators identified cohorts of 11,495 postmenopausal women 40-70 years of age and 8111 postmenopausal women 50-79 years of age, respectively, for inclusion in their analysis. Of note, patients from the UK Biobank had a median follow-up of 10.0 years and those from the Women’s Health Initiative had a median follow-up of 13.1 years. For the purpose of analysis, investigators defined premature menopause as natural or surgical menopause occurring before 40 years of age.

The primary outcomes of the analysis were the presence of any CHIP and CHIP with variant allele frequency greater than 0.1. Investigators used logistic regression to test the association of premature menopause with CHIP and adjusted for age, race, the first 10 principal components of ancestry, smoking, diabetes mellitus, and hormone therapy use. Investigators pointed secondary analysis assessed natural versus surgical premature menopause and gene-specific CHIP subtypes and multivariable-adjusted Cox models were used to test associations between CHIP and incident coronary artery disease.

Of the 19,606 women included in the study, 418 (2.1%) met the investigators' definition for natural premature menopause and 887 (4.5) met the definition for surgical premature menopause. Among the study population, CHIP prevalence was greater among postmenopausal women with a history of premature menopause compared to those with (8.8% vs 5.5%; P <.001).

In adjusted models, results suggested premature menopause was independently associated with CHIP (all CHIP: OR, 1.36; 95% CI, 1.10-1.68, P=.004; CHIP with VAF >.1: OR 1.40; 95% CI 1.10-1.79, P=.007). Investigators noted these associations were larger among those with natural premature menopause (all CHIP: OR, 1.73; 95% CI, 1.23-2.44, P=.001; CHIP with VAF >.1: OR, 1.91; 95% CI, 1.30-2.80, P <.001) and were smaller and non-significant among those with surgical premature menopause.

In gene-specific analyses, results suggested only DNMT3A CHIP was significantly associated with premature menopause. Additional analysis by investigators indicated CHIP was independently associated with indecent coronary artery disease (all CHIP: HR, 1.36; 95% CI, 1.07-1.73, P=.012; CHIP with VAF >.1: HR, 1.48; 95% CI, 1.13-1.94, P=.005).

"Our work suggests that women with premature menopause are enriched for clonal hematopoiesis, and screening may facilitate novel precision medicine strategies for coronary artery disease in affected women," Natarajan added.

This study, “Premature Menopause, Clonal Hematopoiesis, and Coronary Artery Disease in Postmenopausal Women,” was published in Circulation.