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. Author manuscript; available in PMC: 2025 Mar 1.
Published in final edited form as: J Card Fail. 2023 Nov 17;30(3):513–515. doi: 10.1016/j.cardfail.2023.10.482

Infertility and Subclinical Antecedents of Heart Failure with Preserved Ejection Fraction in the Framingham Heart Study

Joyce C Zhou a,b, Yunong Zhao b,c, Natalie Bello d, Emelia J Benjamin e,f, Vasan S Ramachandran f,g,h, Daniel Levy g,h,i, Susan Cheng d, Joanne M Murabito g,h,j, Jennifer E Ho k, Emily S Lau b,l
PMCID: PMC10947933  NIHMSID: NIHMS1945931  PMID: 37979670

Abstract

Background:

Infertility has been shown to be associated with a greater risk of incident heart failure with preserved ejection fraction (HFpEF). We studied the association of infertility with subclinical markers of HFpEF, including echocardiographic signs of cardiac remodeling and cardiac biomarkers.

Methods and Results:

History of infertility was ascertained in 2002 women enrolled in the Framingham Heart Study. We examined the association of infertility with echocardiographic measures and cardiac biomarkers with multivariable-adjusted linear regression models. Among 2002 women (mean age 40.84 ± 9.71 years), 285 (14%) reported a history of infertility. Infertility was associated with a greater E/e’ ratio (β=0.120, SE 0.057, p=0.04) even after adjustment for common confounders. Infertility was not associated with other echocardiographic measures or cardiac biomarkers.

Conclusions:

Infertility was associated with a greater E/e’ ratio, a marker of diastolic dysfunction which may signal earlier subclinical cardiac remodeling in women with infertility.

Keywords: infertility, heart failure, echocardiography, biomarkers

Lay Summary

  1. Infertility is a common reproductive condition impacting 15% of women in the United States. Infertility has been shown to be associated with the development of future heart failure.

  2. Compared with women without a history of infertility, women with infertility had a greater E/e’ ratio, a marker of cardiac dysfunction on echocardiographic imaging that is associated with heart failure with preserved ejection fraction (HFpEF).

  3. An infertility assessment should be considered in comprehensive preventative health screening for cardiovascular disease.

Introduction

Heart failure with preserved ejection fraction (HFpEF) is a growing public health challenge, yet underlying mechanisms remain poorly understood. One consistent epidemiologic observation is that the prevalence of HFpEF is markedly higher in women than men. Recent evidence suggests that reproductive factors such as early age of menopause and nulliparity may contribute to the female susceptibility to HFpEF.1 Infertility, a common reproductive factor that affects over 15% of reproductive-aged women in the United States, is consistently underrecognized with respect to cardiovascular risk.2,3 We previously demonstrated that infertility was associated with greater risk of incident HFpEF in 38,528 postmenopausal women enrolled in the Women’s Health Initiative.4 To further elucidate this relationship, we sought to examine the association of infertility with subclinical markers of HFpEF, including echocardiographic signs of cardiac remodeling and cardiac biomarkers.

Methods

The Framingham Heart Study (FHS) is a community-based, longitudinal cohort study. We included all female FHS participants in the Generation 3, Omni 2, and New Offspring 2 cohorts who attended examinations 1 and 2. We excluded individuals with missing fertility status (n=4), prevalent myocardial infarction and heart failure (n=4), and missing covariates (n=11). For echocardiography analyses, we excluded individuals with missing echocardiographic measures (n=207) or cardiac strain measures (n=89), yielding final samples of n=1541 for echocardiographic and n=1460 for strain analyses. For cardiac biomarker analyses, we excluded individuals with missing N-terminal pro-B-type natriuretic peptide (NT-pro BNP) (n=6) or high-sensitivity cardiac troponin I (hs-cTnI) (n=55), yielding final samples of n=1784 for NT-pro BNP and n=1911 for hs-cTnI analyses. The study was approved by the Boston University Institutional Review Board.

The exposure of interest was infertility, defined as the self-reported inability to conceive after ≥1 year of trying to become pregnant. The dependent measures of interest included six pre-defined echocardiographic measures—left ventricular (LV) ejection fraction (LVEF), LV mass, early diastolic mitral annular velocity (e’), ratio between peak early mitral inflow velocity and mitral annular early diastolic velocity (E/e’ ratio), left atrial (LA) dimension, and global longitudinal strain (GLS)—and two cardiac biomarkers, NT-pro BNP and hs-cTnI. Dependent measures were selected among variables included in clinical HFpEF risk algorithms (e.g. H2PEF and HFA-PEFF scores) that were available in FHS.5,6 We conducted multivariable linear regression analyses adjusted for age, race and ethnicity, body mass index (BMI), systolic blood pressure, use of hypertension medications, diabetes, hyperlipidemia, and current smoking status. All tests were two-sided; a p-value of <0.05 was considered significant. Statistical analyses were conducted using R version 4.2.2.

Results

Among 2002 women, 285 women (14%) reported a history of infertility. Women with and without a reported history of infertility were similar in age at the time of assessment (42 vs. 41 years), BMI (26.7 vs. 25.8 kg/m2), and physical activity (3.4 vs. 3.4 hours/week of moderate activity). Comorbidity profiles were similar between women with and without infertility (hypertension: 8.8% vs. 8.5%, diabetes: 5.6% vs. 5.2%, hyperlipidemia: 6.3% vs. 4.9%). In multivariable analyses, a history of infertility was significantly associated with greater E/e’ ratio. Specifically, women with a history of infertility had a 0.12-standard deviation higher E/e’ ratio compared with women without infertility (β=0.120, SE 0.057, p=0.04, Figure). There were no significant differences in other echocardiographic measures or cardiac biomarkers (p≥0.05 for all).

Figure:

Figure:

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Infertility is associated with greater subclinical cardiac remodeling ascertained by E/e’ ratio

Discussion

In a community-based sample of healthy women, we observed that a history of infertility was significantly associated with a greater E/e’ ratio, an estimation of LV filling pressure, subclinical marker of diastolic dysfunction, and component of the current HFpEF diagnostic criteria.5,6 A greater E/e’ ratio among women with history of infertility may signal earlier cardiac remodeling in women with infertility, posing a higher risk for future HFpEF.7 We did not observe differences in other echocardiographic measures or cardiac biomarkers between women with and without infertility. This is potentially owing to the relatively young age of the study participants: as clinical HFpEF does not often manifest until the sixth or seventh decade of life, even subclinical markers may not yet have been evident.

To our knowledge, this is the first study to systematically evaluate the association of infertility with subclinical markers of HFpEF, adding to the nascent body of literature examining female-specific contributors to HFpEF. The mechanisms underlying this relationship is still unclear. Sex hormones have previously been linked to adverse LV remodeling and heart failure risk and may explain the association between infertility and subclinical cardiac remodeling.8 This association may also be in part explained by shared risk factors including diabetes, hypertension, or obesity, or mediated by biological processes associated with infertility and implicated in HFpEF pathogenesis including activation of systemic inflammation and vascular dysfunction. Further investigation to better understand the mechanistic underpinnings of the link between infertility and HFpEF is warranted.

Strengths of this study included our large sample of women across several FHS generations, with robust ascertainment of infertility and extensive phenotypic data including clinical assessments, echocardiography, and cardiac biomarkers. There are several limitations worth noting. First, infertility was self-reported, though self-report is a well-validated method for ascertainment of infertility status. Second, the relative youth of our sample may have limited our ability to fully capture the longitudinal impact of infertility on the development of subclinical HFpEF. Third, the absolute difference in E/e’ ratio between women with and without infertility was relatively modest; the clinical implication of this difference is uncertain. Fourth, E/e’ ratio is an estimation of LV filling pressure and only one measure used in the ascertainment of diastolic dysfunction. More comprehensive assessment of diastolic dysfunction was not feasible due to availability of echocardiographic measures. Fifth, as this was an exploratory analysis, we did not adjust for multiple hypothesis testing and results should be interpreted as hypothesis-generating.

Conclusions

Infertility was associated with a greater E/e’ ratio, a marker of diastolic dysfunction and a component of the current HFpEF diagnostic criteria. Our finding signals that subclinical cardiac remodeling may occur earlier in women with history of infertility which may contribute to the association between infertility with incident HFpEF. Future research is needed to further elucidate the mechanisms underlying the association of infertility with HFpEF and to better understand the impact of infertility on long-term cardiovascular health. Our study underscores the potential benefit of assessing for infertility as part of preventative cardiovascular health screening.

Tweet: New research report out in @JCardFail shows that history of infertility is associated with greater E/e’ ratio, a subclinical marker of diastolic dysfunction. @joycezhou27 @emilyswlau

Highlights.

  • Infertility was associated with greater E/e’, a marker of diastolic dysfunction.

  • Women with infertility may experience earlier subclinical cardiac remodeling.

Biography

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Footnotes

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