REVIEW published: 05 January 2021 doi: 10.3389/fcvm.2020.617705 Gender-Related Differences in Heart Failure Biomarkers Germán Cediel 1,2 , Pau Codina 1,2 , Giosafat Spitaleri 1,2 , Mar Domingo 1,2 , Evelyn Santiago-Vacas 1,2 , Josep Lupón 1,2 and Antoni Bayes-Genis 1,2* 1 Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain, 2 Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain Important differences in comorbidities and clinical characteristics exist between women and men with heart failure (HF). In particular, differences in the kinetics of biological circulating biomarkers—a critical component of cardiovascular care—are highly relevant. Most circulating HF biomarkers are assessed daily by clinicians without taking sex into account, despite the multiple gender-related differences observed in plasma concentrations. Even in health, compared to men, women tend to exhibit higher levels of natriuretic peptides and galectin-3 and lower levels of cardiac troponins and the cardiac stress marker, soluble ST2. Many biological factors can provide a reliable explanation for these differences, like body composition, fat distribution, or Edited by: menopausal status. Notwithstanding, these sex-specific differences in biomarker levels Chris J. Pemberton, University of Otago, New Zealand do not reflect different pathobiological mechanisms in HF between women and men, Reviewed by: and they do not necessarily imply a need to use different diagnostic cut-off levels in Giuseppe Vergaro, clinical practice. To date, the sex-specific prognostic value of HF biomarkers for risk Gabriele Monasterio Tuscany Foundation (CNR), Italy stratification is an unresolved issue that future research must elucidate. This review Alexander E. Berezin, outlines current evidence regarding gender-related differences in circulating biomarkers Zaporizhia State Medical widely used in HF, the pathophysiological mechanisms underlying these differences, and University, Ukraine their clinical relevance. *Correspondence: Antoni Bayes-Genis Keywords: biomarker, heart failure, gender, troponin, natriuretic peptide, ST2, Galectine-3 abayesgenis@gmail.com Specialty section: INTRODUCTION This article was submitted to Heart Failure and Transplantation, Heart failure (HF) is a major health care issue in both sexes; it is associated with significant a section of the journal morbidity, mortality, and health care costs (1). Several differences between women and men Frontiers in Cardiovascular Medicine have been observed in HF, including the epidemiology, etiology, pathogenesis, risk factors, and Received: 15 October 2020 prognosis (2). The incidence of HF also differs between men and women, depending on the Accepted: 09 December 2020 study population analyzed (3, 4). For example, women had a lower risk of incident HF than Published: 05 January 2021 men, in middle-aged to older individuals, but women had a higher HF risk than men in the Citation: oldest age groups (5). Men tended to be at higher risk of developing HF with reduced ejection Cediel G, Codina P, Spitaleri G, fraction (HFrEF), and conversely, women were more likely to develop HF with preserved ejection Domingo M, Santiago-Vacas E, fraction (HFpEF) (6). This distinction might be attributable to the predisposition of women Lupón J and Bayes-Genis A (2021) Gender-Related Differences in Heart to develop coronary microvascular dysfunction/endothelial inflammation and the predisposition Failure Biomarkers. in men to develop macrovascular coronary artery disease and myocardial infarction (7). These Front. Cardiovasc. Med. 7:617705. sex-related differences in HF phenotypes and underlying pathophysiology are also reflected in HF doi: 10.3389/fcvm.2020.617705 biomarker dissimilarities. Frontiers in Cardiovascular Medicine | www.frontiersin.org 1 January 2021 | Volume 7 | Article 617705 Cediel et al. Heart Failure Biomarkers and Sex In 2007, the National Academy of Clinical Chemistry and effects of estrogens, which suppress cardiomyocyte apoptosis, the International Federation of Clinical Chemistry recommended and the potentially harmful effects of testosterone, which the development of sex-specific reference ranges for cardiac induces hypertrophy and apoptosis in cardiomyocytes (21–23). biomarkers used routinely in clinical practice (8). Consequently, Obesity was also independently associated with a positive, linear over the years, sex-driven differences in both reference and increase in the likelihood of high hs-cTn levels, as shown in a cut-off values have been described for several biomarkers in recent population-based study of subjects without cardiovascular cardiovascular disease (9). However, most of these cardiovascular disease at baseline. In that study, individuals with severe obesity biomarkers are used day-to-day by clinicians without taking and high hs-cTn levels had a >9-fold higher risk of incident HF sex into account. It is hypothesized that the lack of sex-specific compared to individuals with normal weight and undetectable thresholds for cardiac biomarkers might contribute to under- hs-cTn levels (24). All these variations could contribute to sex- diagnosing HF in women, which could potentially result in worse related differences in serum cTn concentrations and had allowed outcomes (10). the thoroughly study of sex-tailored cut-off values of hs-cTn Improving HF care requires consideration of all gender- in the setting fundamentally of ACS, where sex-specific cut-off related differences. Moreover, improving our understanding points might improve sensitivity for diagnosis of myocardial of gender-specific differences in HF biomarkers might enrich infarction in women (25). Diagnostic performance of hs-cTn our understanding of physiological differences between men for HF is however limited. In the general population, the and women with HF. Taking these points into consideration, application of dichotomous cut-off values of hs-cTn, lower in this review covers the four most important and frequent HF women than men: 4.7 vs. 7.0 pg/ml, respectively, for hs-cTnI biomarkers available in daily clinical practice, with a focus on as studied by Zeller et al., allowed substantial reclassification differences between women and men (Figure 1). information for prediction of cardiovascular disease, including HF, being considered an independent predictor of cardiovascular events (26). CARDIAC TROPONIN Prognostic Utility of cTn in HF Currently, assays are available for detecting cardiac troponin In the HF spectrum, the diagnostic utility of cTn is limited; (cTn) with high clinical sensitivity and high specificity for however, its prognostic value is highly relevant. Studies by Parikh myocardial tissue. Moreover, many assays are capable of early et al. (27) and by de Boer et al. (28) demonstrated that cTn levels cTn detection, when necrosis is minimal or even in the absence could predict incident HF in different community-based cohorts. of cell necrosis by different mechanisms (increased myocyte Recently, a meta-analysis that pooled data from 16 prospective turnover or increased cell wall permeability among others). Due studies and included nearly 67,000 subjects demonstrated a to these features, cTn has become the standard biomarker for strong association between cTn and the development of incident myocardial damage and the preferred biomarker for diagnosing HF, and this association was found in both men and women (29). acute myocardial infarction. In addition, individuals in the HF Robust evidence from a meta-analysis based on individual patient population frequently have increased concentrations of high- data from 10 studies and 11 cohorts (30) also suggested that cTn sensitivity cTn (hs-cTn). In up to 93% of patients with acute could become an affordable biomarker for risk stratification in HF and up to 74% of patients with stable chronic HF, hs-cTn patients with HF, due to the similarity of its prognostic value concentrations are above the 99th percentile of the reference between men and women. However, data are inconsistent as to value (11). However, several studies and critical reviews have whether the prognostic value of cTn differs with sex. Current examined sex-related differences in cTn levels that might affect evidence has indicated that the 99th percentile cutoff values were diagnostic and prognostic performance. higher in males than in females (26, 31). However, despite the widespread use of cTn in clinical practice, all available assays lack Variations in cTn Concentrations sex-specific reference values. According to Gender Marked variations in cTn concentrations have been detected NATRIURETIC PEPTIDES between women and men, with higher values commonly found in men (12, 13). This difference has also been evident in patients Natriuretic peptides are a group of neurohormones that play with HF (14, 15). Consequently, when interpreting cTn results, a central role in the regulation of electrolytes and water sex-related peculiarities in the pathobiology of cardiac disease balance through their diuretic and natriuretic effects (32). In must be considered. Men tend to have a greater cardiac mass humans, mainly three forms of natriuretic peptides are found: and a higher incidence of subclinical coronary artery disease A-type natriuretic peptide (ANP), B-type type natriuretic peptide than women (16, 17). Women tend to show less severity in (BNP), and C-type natriuretic peptide (CNP). CNP is primarily atherosclerosis, left ventricular hypertrophy, and cardiomyocyte produced in vascular endothelial cells; ANP and BNP are mostly apoptosis than men (18, 19). In addition, HFrEF (from ischemic found in the myocardium. Natriuretic peptides are released by and non-ischemic etiologies) occurs more frequently in men than the myocardium in response to stretch and hypoxic stimuli (33). in women, and HFpEF is more prevalent among women than The majority of clinical evidence on natriuretic peptides in the among men (6, 20). The possibility of an indirect hormonal setting of HF is related to BNP and the amino terminal of the influence should also be considered, in light of cardioprotective proBNP molecule (NT-proBNP). Therefore, this review focuses Frontiers in Cardiovascular Medicine | www.frontiersin.org 2 January 2021 | Volume 7 | Article 617705 Cediel et al. Heart Failure Biomarkers and Sex FIGURE 1 | Schematic of factors contributing to sex-related differences in HF biomarkers. HF, heart failure; Gal-3, Galectine 3; NT-proBNP, N-terminal pro-B-type natriuretic peptide; cTn, cardiac troponin; sST2, soluble interleukin-like receptor-like-1. on NT-proBNP, because it is the best choice for a diagnostic and natriuretic peptides. Most studies found that at baseline NT- prognostic biomarker in HF, according to the 2016 European proBNP levels were lower in males than in females (Figure 2) Society of Cardiology HF clinical guidelines (34). and, in both genders, increases were correlated with age (44). The most extensive evidence on the value of BNP-related in vitro diagnostic tests was published in the early 2000s. Sex Differences in NT-proBNP Levels Comparative studies that measured concentrations of the Although sex-specific differences in NT-proBNP levels have active BNP hormone vs. NT-proBNP generally demonstrated been documented, the precise mechanism that gives rise to diagnostic equivalency for differentiating HF from other causes higher NT-proBNP levels in women than in men is not well- of shortness of breath. The proBNP molecule contains 108 amino established in healthy subjects. Several possible explanations acids. The first 76 amino acids are biologically inactive, and have been explored. One reasonable pathobiological explanation amino acids 77–108 constitute the biologically active component involves the effects of sex hormones. Strong clinical evidence has of the molecule, BNP. shown that testosterone could lower cardiac natriuretic peptide Currently, NT-proBNP is a well-established, powerful levels, probably by upregulating neprilysin activity; this effect biomarker for the diagnosis and prognosis of HF (35–37). It is might explain why NT-proBNP levels are lower in men than in also a useful biomarker for risk stratification in other several women (45, 46). Other studies showed that estrogen increased cardiovascular disorders (38, 39). Strong clinical evidence cardiac natriuretic peptide gene expression and its release, has revealed that several factors influence NT-proBNP levels. which might explain the elevated cardiac natriuretic peptides Elevated concentrations were observed in patients with various levels in women compared to men. However, other reports cardiovascular disorders and in patients with renal dysfunction suggested that estrogen also increased neprilysin activity (43, (40, 41). A previous study, which included 7,770 individuals 47). In postmenopausal women, hormone replacement therapy from the Framingham Heart Study and the Malmö Diet and administered for 3 months resulted in elevations in ANP and Cancer study, reported that obesity was associated with 6–20% BNP concentrations (48). Some research however hypothesized lower NT-proBNP levels, compared to normal-weight status, that free testosterone could increase lean mass and may directly and insulin resistance was associated with 10–30% lower levels decrease natriuretic peptide synthesis. This last statement goes of NT-proBNP, compared to insulin sensitive status (42). Age beyond the notion that estrogens are primarily responsible and sex are also important in modifying circulating levels of for gender differences in natriuretic peptides considering Frontiers in Cardiovascular Medicine | www.frontiersin.org 3 January 2021 | Volume 7 | Article 617705 Cediel et al. Heart Failure Biomarkers and Sex FIGURE 2 | Distribution of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in both sexes. Reproduced with permission from Suthahar et al. (43). that exogenous estrogen increased the sex hormone-binding noting that natriuretic peptide levels were similar or lower in globulin with a subsequent lower free testosterone (49). Of women compared to men (53, 54). However, this change in note, the profoundly different anthropometric characteristics tendency should be interpreted cautiously, because over the past and fat distributions found in males and females might also decade, one of the most robust findings across numerous HF play a role in natriuretic hormone levels. Recent evidence studies was that the gender distribution varied according to the from a general population study found that the relationship HF phenotype. Among individuals with HF, women significantly between NT-proBNP and obesity had a significant sex-associated outnumber men, and the gender ratio is ∼2:1 in HFpEF (6, 20). component. The inverse association between NT-proBNP and Numerous reports have shown that natriuretic peptide levels obesity was more pronounced among females than among males. are much lower in patients with HFpEF than in patients with Furthermore, among females, but not males, individuals with HFrEF (35, 55, 56). Consequently, when studies analyze the abdominal (visceral) obesity had lower NT-proBNP levels than convoluted relationship between sex, ejection fraction, and BNP individuals with peripheral (subcutaneous) obesity (50). Some levels in the setting of HF, the results show that women tend to studies propose at a molecular level a higher clearance of BNP have higher BNP levels than men (57, 58). However, despite the in obesity due to increased expression of natriuretic peptide gender-related differences in the levels of natriuretic peptides, receptor on adipose tissue, which binds BNP and leads to the performance of these peptides for diagnosing HF and their its internalization and degradation (51) A reduced release of prognostic utility are similar in both sexes, and sex specific cut-off natriuretic peptides from myocardial tissue in obese individuals points are not usually recommended. At this point, it should also have also been pustuled as an alternative hypothesis (52) be noted that there is a lack of coincidences between molecular Therefore, a combination of increased degradation and decreased mechanisms that affect HF progression and gender particularities release may contribute to relative deficiency of natriuretic in the context of biomarker levels’ variability (Figure 3). peptides in obesity. However, these sex-related dissimilarities observed in the Prediction of HF Incidence general population appeared to be less pronounced in HF NT-proBNP levels have shown clinical relevance in predicting and other disease populations associated with upregulated NT- the incidence of HF in the general population. High levels were proBNP levels. Some studies have reported the opposite findings, associated with a high risk of HF (59–61), which suggested Frontiers in Cardiovascular Medicine | www.frontiersin.org 4 January 2021 | Volume 7 | Article 617705 Cediel et al. Heart Failure Biomarkers and Sex FIGURE 3 | Representation of a lack of coincidences between mechanisms that affect heart failure progression and gender particularities in the context of biomarker levels’ variability. HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; NP, natriuretic peptide; Gal-3, Galectine 3; sST2, soluble interleukin-like receptor-like-1. that elevated baseline levels might reflect subclinical cardiac which leads to myocyte hypertrophy, fibrosis, and a decline dysfunction that could subsequently manifest as overt HF. in left ventricular function (64). In contrast, sST2 acts Recent studies have explored sex-specific differences in using as a “decoy” receptor for IL-33; thus, sST2 inhibits the NT-proBNP to evaluate cardiac functional competence. Evidence cardioprotective effects mediated by the IL-33/ST2L interaction, from two community-based studies (44, 61) showed that the which indirectly promotes myocardial damage (65). With optimal cut-off point for detecting moderate to severe left the development of a highly sensitive ELISA method for ventricular disfunction was higher in women than in men. measuring sST2 (66), in the last decade, clinical evidence has The discriminatory ability of the biomarker was similar in highlighted the biological and clinical importance of plasma both sexes, but the strength of the association might be sST2 concentrations. Currently, sST2 is considered a strong, different between men and women. Indeed, a recent meta- independent prognostic biomarker in patients with myocardial analysis of prospective studies (62) found that NT-proBNP infarction and HF (67, 68). was more strongly associated with incident HF in men than Clinical data has suggested that sex has a potentially important in women. In the near future, the use of natriuretic peptides effect on sST2 concentrations. Women exhibited lower sST2 to assess risk in asymptomatic adults is expected to become levels than age-matched men (69). In a large population-based translated from clinical studies to routine clinical practice. study of ambulatory individuals, women had lower sST2 levels than men, but among older women, an age-associated rise in sST2 concentrations was observed. However, even among older adults, men had higher sST2 levels than women (69). These differences, SOLUBLE INTERLEUKIN-1 which seem to be evident beginning in late adolescence (70), RECEPTOR-LIKE 1 (ST2) were present both in patients with cardiovascular disease and in healthy subjects. Currently, the mechanism underlying these ST2 is a member of the interleukin-1 receptor family. ST2 differences has not been elucidated. The hypothesis that sex exists in both membrane-bound (ST2L) and soluble (sST2) hormones might be responsible for differences in sST2 levels forms. Interleukin-33 (IL-33) is the functional ligand for has not been adequately proven, and current evidence remains ST2L, and in the heart, the IL-33/ST2L interaction mitigates controversial. Some studies have supported this hypothesis by cellular responses to mechanical stress. This function is showing that elevated testosterone levels were linked to elevated thought to be mediated by the inhibition of apoptosis ST2 concentrations, and conversely, exogenous estrogen therapy and cell death (63). Loss of IL-33/ST2L signaling results was linked to lower sST2 levels. In contrast, another study did not in unchecked remodeling in the ventricular myocardium, find any significant correlation between sex hormones and sST2 Frontiers in Cardiovascular Medicine | www.frontiersin.org 5 January 2021 | Volume 7 | Article 617705 Cediel et al. Heart Failure Biomarkers and Sex levels (69, 71). Obesity is also an important factor to consider (HR 1.28 per 1 standard deviation increase in the log-Gal- in this setting, because sex hormones are produced by adipose 3 concentration). This association was clearly attenuated after tissue, and gender-related differences have been shown in the adjusting for kidney function (82). This “renal implication” association between obesity and metabolic diseases. A recent highlights the paramount relevance of cardio-renal interactions study by Zhao et al. revealed, in an animal model, that obesity in the setting of HF, and it suggests that HF might involve a induced sST2 expression and secretion in adipocytes (72). A deep common profibrotic process in the heart and kidneys. physiological understanding of the reasons and clinical relevance of gender-specific differences in sST2 concentrations requires future research. LESS COMMON BIOMARKERS IN Due to the prognostic value of ST2 (73–75) and its ability CLINICAL PRACTICE to predict incident HF (76), it has become part of the risk stratification strategy in HF clinical practice guidelines (77). In the last decade there has been an intensified interest in A cut-off point of 35 ng/ml ST2 has been universally adopted additional biomarkers as an objective alternative for diagnosis, as a good indicator of prognosis in both sexes; thus, to prognosis or personalized treatment in HF. Among them date, sex-specific cut-off points have not been needed for is the growth differentiation factor-15 (GDF-15), a member risk predictions. of the transforming growth factor-?? cytokine superfamily with anti-apoptotic, anti-hypertrophic, and anti-inflammatory properties. GDF-15 is weakly expressed in tissues under normal conditions. Although its pathobiology is not fully understood, it is strongly induced by macrophages in response GALECTIN-3 to inflammation and tissue injury. It appears to be only Galectin-3 (Gal-3), a unique member of the chimera-type moderately expressed in the heart (81). Despite GDF-15 have galectins, is involved in a large number of disease processes. It been identified as an inflammatory biomarker with prognostic is widely expressed in human tissues, including epithelial, value in several conditions, particularly in cardiovascular diseases endothelial, and immune cells (78). Gal-3 plays a role (91, 92), with strong association with incident HF (93), in both acute and chronic inflammation, and its effects sex differences in plasma levels of this biomarker have not on cell function include the activation of fibroblasts and been clearly established (94, 95). It has been showed that macrophages, which lead to fibrosis in various organs, testosterone together with estradiol significantly decreased GDF- including the heart (79). As a biomarker, Gal-3 has been 15 levels through an androgren receptor/estrogen receptor- associated with cardiac function (80); several studies have mediated pathway (96). Osteopontin, a glycoprotein expressed demonstrated significantly higher Gal-3 levels in patients with in various cell types, including cardiomyocytes and fibroblasts HF, particularly those with HFpEF, compared to controls has also gained interest as a prognostic marker in HF. It (80). Nevertheless, this biomarker is not predominantly had been found to be significantly elevated in patients with produced in the heart; non-cardiac sources appear to systolic HF (97). Its cardiac expression promotes myocardial be responsible for high Gal-3 levels in patients with fibrosis and increases left ventricular stiffness (98). It appears HF (81). that plasma osteopontin levels are higher in men than in Recent data from population-based studies (82–84) have women as evidence in the study by Arnlöv et al. (99), indicated that plasma Gal-3 levels were slightly higher in women however there are lacking evidence in the literature of than in men. The physiological explanation for this gender- sex differences in osteopontin expression, and this requires specific difference is not fully understood, but differences in further investigation. fat mass might play a role, considering that, for the same body mass index, women typically have 10% more body CONCLUSIONS AND PERSPECTIVES fat than men (85). Indeed, prior studies have observed an association between total body fat and Gal-3 levels (86). Although Most circulating HF biomarkers are used daily by clinicians the sex-specific prognostic value of Gal-3 in HF remains without taking sex into account. Nevertheless, multiple unknown, baseline Gal-3 concentrations were associated with gender-related differences have been observed in the plasma adverse outcomes during follow-up in patients with acute and concentrations of several biomarkers. In the healthy population, chronic HF (87–89). However, the prognostic value of Gal- women tend to exhibit higher levels of natriuretic peptides 3 in the setting of chronic HF remains controversial; other and Gal-3 and lower levels of cTn and sST2, compared to biomarkers, such as NT-proBNP or sST2, have frequently men. Plausible biological explanations for these sex-related exhibited superior predictive value (90). Moreover, other studies differences have been postulated, like differences in body have shown that the predictive value of Gal-3 in HF was composition, fat distribution, or sex hormones. Nonetheless, less pronounced when the analysis was adjusted for renal several clinical studies have shown that these differences were function (87). attenuated in patients with HF, despite the fact that distinct In the Framingham Heart Study, an analysis of more than gender distributions have been extensively described for different 3,000 participants showed that elevated Gal-3 concentrations HF phenotypes. Moreover, these sex-related differences do were associated with increases in the risk of new-onset HF not necessarily translate into a need to use different cut-off Frontiers in Cardiovascular Medicine | www.frontiersin.org 6 January 2021 | Volume 7 | Article 617705 Cediel et al. Heart Failure Biomarkers and Sex points for men and women, either for HF diagnosis or HF AUTHOR CONTRIBUTIONS prognosis, in clinical practice. 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