Trends in NHLBI-Funded Research on Sex Differences in Hypertension

The data related to NHLBI and NIH funding trends were obtained from the Research Portfolio Online Reporting Tool (RePORTER) (https://projectreporter.nih.gov/reporter.cfm) using the following combinations of search terms:

These searches were restricted to fiscal years (FYs) 1991 to 2014. The abstracts and specific aims of each award were then classified according to disease categories, type of research (basic versus clinical), or inclusion of sex (male versus female or both). Basic research was defined as studies aimed at understanding the mechanisms of blood pressure hypertension (whether in vitro, in animals, or in humans). Clinical research was defined as all applied research in humans, including clinical trials.

Global trends in FY2014 related to research on “sex differences in hypertension” (Online Figure IV) were obtained from Über Research, which is a global award database covering over 65 funders and over $700 billion in historical awards (http://www.uberresearch.com). The search term used was sex differences+hypertension.

To examine current and historic funding trends related to “sex differences,” the first challenge was to define the term “sex.” On the basis of the definition adopted by the Institute of Medicine, sex is “being male or female according to reproductive organs and the functions assigned by chromosomal complement (XX for female and XY for male).”⁷ Thus, for the purposes of our search and analyses, we used the terms y chromosome, x chromosome, and sex hormones to define biological differences between males and females, that is, “sex differences.” According to the Institute of Medicine “sex refers to social and cultural factors related to being a man or a woman in a particular historical and cultural context.” Because of the fact that the term “sex” is often being incorrectly used as a synonym for “sex” in the scientific literature, we also used the term “sex” in our search to ensure that all the relevant awards were included in the analyses.

The analysis of NHLBI-funded awards related to “sex differences” in general revealed that there was a progressive increase in both the number of awards and the overall dollar investment during FY1991 to FY2014. This trend was paralleled by a similar increase in the number of publications related to “sex differences” in biomedical research and research related to diseases relevant to the mission of NHLBI during the past decade (unpublished data obtained from PubMed search using terms: sex differences, heart, lung, and blood published in the past 10 years). Although the focus of our analyses was hypertension, the analysis of “sex differences” in general provided an interesting insight into other diseases related to the mission of NHLBI in which sex differences are being examined. In FY2014, hypertension only comprised ≈15% of the total number of awards in the field of “sex differences,” and this roughly parallels the percentage of NHLBI-funded awards related to hypertension in general.

As with “sex differences” in general, the field of “sex differences in hypertension” (including or excluding pregnancy) has developed during the past couple of decades, both in the field of basic and clinical research. The field has not only grown in the number of awards and the dollar amount per award, but most importantly in the number and diversity of research topics being covered by these awards. Several of these NHLBI-supported awards have led to seminal observations in the field. For instance, using the 4 core genotype mouse model in which gonadal sex is separated from the sex chromosome complement, a study has shown that, in a gonadectomized state, blood pressure levels are higher in XX mice compared with XY mice.⁸ These observations challenged the dogma that blood pressure levels are lower in females merely because of the presence of estrogens or higher in males because of the presence of androgens. Rather, the study brought to attention that in addition to sex hormones, X- or Y-linked genes, parental imprinting, or X mosaicism contributes to sex differences in hypertension. Unrelated to sex differences, in 2007, an NHLBI-supported study by Guzik et al⁹ identified the importance of T cells in the development of angiotensin II–induced hypertension. This ground breaking observation marked a new direction in the research on blood pressure regulation. However, this study only included males and did not question whether T cells play the same role in the development of hypertension in females. More recently, a couple of NHLBI-supported studies showed that there are significant sex differences in the contributions of T cells to the regulation of blood pressure. Although angiotensin II infusion increases blood pressure after adoptive transfer of male T cells into male Rag-1^−/− mice lacking T and B cells (as shown by Guzik et al⁹), female Rag-1^−/− mice are resistant to male T-cell–mediated increases in angiotensin II–induced hypertension.¹⁰ Furthermore, male Rag-1^−/− that received adoptive transfer of female T cells exhibited lower blood pressure levels after angiotensin II infusion compared with male Rag-1^−/− mice, which had male T cells adoptively transferred.¹¹ These studies indicated that both the sex of the host and the sex of the T cell are important factors in blood pressure regulation, and recently awarded grants from NHLBI are further investigating the mechanisms of sex differences in the immune modulation of hypertension. Other NHLBI-supported studies related to “sex differences in hypertension” include studies examining the role of the renin–angiotensin and endothelin systems in blood pressure regulation, the contribution of sex hormones to fetal programming of hypertension, sex differences in the central regulation of blood pressure, obesity–hypertension, and sex differences in hemodynamic factors in essential hypertension in humans. Although these are the areas that are currently being funded by NHLBI, there are several research gaps that have been identified by members of the NLHBI Working Group on Sex Differences Research in Cardiovascular Disease.¹²

In addition to the increase in the number of awards and research topics related to “sex differences in hypertension,” the geographic funding distribution has also broadened during the past couple of decades, further contributing to the increase in diversity of research in the field. Interestingly, although most of the research on “sex differences in hypertension” at the “top 10” funded institutions is being funded through the R01 mechanism, several of these institutions have active research programs or centers with a focus on sex differences or women’s health (eg, University of Mississippi Medical Center: Women’s Health Research Center). This observation suggests that a critical mass of researchers with a common interest in sex differences research is an important factor for developing a successful research program in this field.

Although the field of “sex differences in hypertension” seems to be growing by all indices considered in our analyses, there are several caveats to this conclusion. Although the overall investment into research in the field has increased over the years, the absolute number of awards and dollars invested are only a small fraction of NHLBI’s total investment into research in general and hypertension in particular. Having said this, although the overall budget for “sex differences in hypertension” increased 12.5-fold between FY1991 and FY2014, the total NHLBI budget increased only 2.7-hold for the same time period (https://officeofbudget.od.nih.gov/history.html), suggesting that this is an emerging field. Of course, it is difficult, if not impossible, to determine the adequate number of awards for any one research field. However, given that hypertension affects both women and men similarly, it is reasonable to suggest that additional research into “sex differences in hypertension” is warranted. Another caveat is the fact that only about half of the awards related to “sex differences in hypertension” truly focus on directly comparing males and females. Although there is certainly tremendous importance and relevance in examining the effects of gonadal hormones on blood pressure regulation in either sex, valuable knowledge on the underlying mechanisms of sex differences can be gained from direct comparisons of males and females. To encourage such studies, the NIH now mandates that sex as a biological variable be factored into the research design, analyses, and reporting in vertebrate animal and human studies (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-15–102.html).

Over the past decade, NHLBI has continuously supported and contributed to the evolution of the field of “sex differences in hypertension.” Looking into the future, the increased scientific interest coupled with the new NIH guidelines are poised to expand our understanding about the important effects of sex in many fundamental physiological and pathological processes across the board and to contribute to the development of personalized strategies needed to prevent and cure human disease, including hypertension, in both men and women.

We thank the members of the Vascular Biology and Hypertension branch (NHLBI) for their valuable input and critical review of the portfolio analysis data and Dr Denis Buxton (NHLBI) for feedback and review of the article.