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IMR Press / RCM / Volume 23 / Issue 1 / DOI: 10.31083/j.rcm2301019
Open Access Review
Sex beyond cardiovascular risk factors and clinical biomarkers of cardiovascular disease
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1 Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40138 Bologna, Italy
*Correspondence: olivia.manfrini@unibo.it (Olivia Manfrini)
Rev. Cardiovasc. Med. 2022 , 23(1), 19; https://doi.org/10.31083/j.rcm2301019
Submitted: 1 July 2021 | Revised: 4 August 2021 | Accepted: 3 September 2021 | Published: 14 January 2022
This is an open access article under the CC BY 4.0 license.
Abstract

In recent years, increasing attention has been reserved to the analysis of sex-related differences in pathophysiology and prognosis of ischemic heart disease (IHD). The traditional conventional cardiovascular risk factors (hypertension, hypercholesteremia, diabetes mellitus and cigarette smoking) are still considered the major risk factors for IHD in both sexes. Nevertheless, recent studies show that they may interact with male and female coronary anatomy in a different manner. The path to sex-specific risk stratification of IHD is also supported by differences in inflammation and necrosis biomarkers (such as C-reactive protein and troponins, respectively). Indeed, large cohort studies often show different mean values of these markers in men and women. The current review summarizes the state-of-art knowledge on sex-related differences in cardiovascular risk factors and cardiac biomarkers with a prognostic value.

Keywords
Ischemic heart disease
Sex differences
Women
Biomarkers
Risk factors
1. Sex differences in myocardial infarction and ischemia

Over the past decades, increasing attention has been reserved to the analysis of differences between men and women in the pathophysiology, diagnostic, and prognosis of cardiovascular diseases (CVD) [1, 2, 3, 4, 5]. This issue first acquired relevance in the early 90s, when it became apparent that the majority of randomized control trials (RCTs) excluded or included only a strict minority of women in their cohorts [6]. This phenomenon was partly based on the assumption that men are more frequently victims of CVD than women, and that the medications administered to men would automatically work, in the same proportion and with the same dosages, in the few women affected by the disease. These assumptions have been proven over time to be misconceptions. In fact, while it is true that women develop CVD approximately 10 years later than men, it has also been observed that female patients do have higher early case fatality rates and higher 1-year mortality rates, when affected by myocardial infarction [7, 8, 9]. The reasons behind this phenomenon are complex [10], and are still subject to studies and debates.

Gender and sex issues have been the main focus of research in the last years. Despite being considered similar enough to men to not being included in RCTs, women have been victim of undertreatment and underdiagnosis in many medical fields, especially in CVD. Focusing on ischemic heart disease (IHD) women have been reported to have longer delays from symptom onset to hospital presentation than men [11, 12]. In addition, women more commonly have symptoms such nausea, palpitations, and shortness of breath, rather than chest pain, thus when they arrive at the hospital, the atypical nature of their symptoms often proves to be misleading for physicians, bringing to further delays in the diagnosis of acute coronary syndromes (ACS). Moreover, even after a timely diagnosis, women do not always receive the same level of care as men do, as demonstrated by the lower rates of both medical and invasive treatment described in the female sex by several authors [11, 13].

Despite being undoubtedly worrying in their nature and extent, gender issues do not appear to be the sole cause of the differences between women and men in the survival and quality of life after an ACS. In a recent study by Cenko et al. [14] it was demonstrated that female patients, especially if younger than 60 years, have higher rates of 30-day mortality after ST-segment elevation myocardial infarction (STEMI) than younger men did even after adjustment for comorbidities and treatment covariates (odd ratio [OR], 1.88; 95% confidence interval [CI], 1.04–3.26). These data, supported by findings from other cohorts, clearly suggest that the differences in prognosis after an acute myocardial infarction (AMI) in men and women cannot be reconducted to gender-related disparities alone, but may be caused by intrinsic biological differences between the two sexes. Evidence supporting this hypothesis can be found in the pathophysiology of IHD. Women appear to present sex specific mechanisms underlying the clinical manifestations of IHD. Several studies showed that women have a less plaque burden than men, even despite the presence of higher rates of cardiovascular risk factors and even in the early stages of coronary atherosclerosis [15, 16]. In addition, women have more diffuse epicardial endothelial dysfunction than men.

Also, there are important sex differences in the autonomic nervous control of the cardiovascular system are described as well. Men tend to have a higher sympathetic cardiac autonomic activity, whereas women tend to have a higher parasympathetic activity [17] (Fig. 1). Plaque erosion appears to be the most frequent substrate to the acute coronary event in women, whereas in men plaque rupture is more likely [18, 19]. This might impact the distribution of the types of IHD across sexes: female patients have lower rates of STEMI, but higher rates of non-ST segment elevation acute coronary syndromes (NSTE-ACS) and chronic coronary syndromes. Yet, in case of STEMI, women have a higher likelihood of developing severe complications like acute heart failure, with detrimental effects on prognosis [20].

Fig. 1.

Main differences in ischemic heart disease between men and women. Women have a higher prevalence of hypertension and hypercholesterolemia, but lower levels of abdominal obesity, lower plaque burden and obstructive coronary artery disease. Ischemic heart diasease in women occurs with plaque erosion and microvascular dysfunction more often than men. The higher vagal tone and estrogen levels (in the premenopausal state) postpone the development of the coronary artery disease by approximately 8 years compared with men. Nevertheless, women have worse outcomes, especially when they are smokers or affected by diabetes mellitus. All these differences may be contributing factors to the different expression of cardiovascular biomarkers between sexes.

The evidence of biological differences between sexes has consequences not only on the therapeutic strategies and medications administered to women with IHD, but also on the approaches used to evaluate patients’ risk of developing the disease or even diagnose IHD in the acute phase and its prognosis.

Sex differences in the role of cardiovascular risk factors are prone to translate into discrepancies in pathophysiologic mechanisms underlying myocardial ischemia and expression of serum CVD biomarkers between sexes (Fig. 1). The current review aims to report current evidence on these aspects.

2. Cardiovascular risk factors

Hypertension, hypercholesteremia, diabetes mellitus and cigarette smoking are the major cardiovascular factors for the development of significant coroanry artery disease (CAD) in the general population. However, there are only few data regarding the existence of any sex differences in the impact of these risk factors and how these differences could affect the severity of CAD or its relationship to outcomes. Huxley et al. [21] has suggested that smoking has a much larger harmful impact on women. Other studies have shown that smoking has a similar effect on increasing the risk of CHD in both men and women [22]. Recently, data coming from the ISACS-TC (International Survey of Acute Coronary Syndromes in Transitional Countries) shed light on the topic [23]. The study demonstrated that the harms of smoking differ by sex. Compared with nonsmokers, women (but not men) who were current smokers had a much greater risk of ACS with obstructive CAD than non-obstructive CAD. The study also showed that hypercholesterolemia and hypertension increased the risk of obstructive CAD without any differences between men and women, although the latter has a remarkably higher prevalence in the female sex [23]. These data are in line with other observational studies [23]. Moreover, hypertension particularly affects the coronary microcirculation, which therefore becomes extremely vulnerable in postmenopausal women, due to the drop in estrogen which plays a protective role [19, 24]. Many studies describe that women with diabetes mellitus face an increased cardiovascular risk compared to men [22, 23].

Obesity is a strong predictor of overall mortality, and especially abdominal obesity [25]. However, it seems that there is a significant interaction between body mass index (BMI) and sex in regard to the risk of AMI and cardiovascular death. Indeed, obese men have an increased risk of AMI and cardiovascular death, but, surprisingly, overweight women had a decreased risk of AMI compared with normal weighted women [25, 26].

Sedentary life is another risk factor for IHD. Several studies demonstrated that physical activity has a protective role both in primary and secondary prevention for men and women. Exercise training interventions have vasoprotective and antiatherosclerotic effects, likely due to the decrease of body fat, and the improvement of hypertension, dyslipidemia and diabetes. However, to enhance the complexity of interaction between sex and risk of IHD, no sex differences have been reported in the positive response of exercise training [27].

In conclusion, smoking and diabetes mellitus disproportionally increase the risk of obstructive CAD in women, and as so they are key factors in explaining sex differences in outcomes from ACS. Intense efforts to reduce tobacco use and increase screening for pre-diabetes mellitus have the potential to reduce the sex lag in cardiovascular disease mortality in women compared with men. Moreover, women would benefit more from strategies that prevent and treat hypertension at the population level and not at the individual one.

3. Markers of inflammation

Early and accurate CVD risk prediction and the subsequent implementation of prevention strategies determine a clear beneficial impact on patients’ health and quality of life, independently from sex. Considerable effort has been placed upon improving cardiovascular risk prediction with the use of biomarkers that play a key role in the pathogenesis of the disease or reflect atherosclerotic status. Still today, however, the most frequently discussed biomarkers in the primary prevention setting remain those index of systemic inflammation [28].

Systemic inflammation has been extensively demonstrated to be strictly related to the patient’s metabolic state and lipid profile. Increased levels of inflammation markers have also been associated with a higher risk of developing CVD, especially in women [29, 30].

One of the most extensively studied markers of inflammation in cardiology is C-reactive protein (CRP), a protein synthesized by the liver whose clinical use in cardiovascular prevention has been endorsed either by the current American Heart Association/American College of Cardiology (AHA/ACC) and European Society of Cardiology (ESC) guidelines, especially in regards to its high sensitivity quantification [28, 31, 32]. Current recommendations for CRP testing suggest uniform CRP thresholds to characterize the relative risk of CV events, but both sex and race- related differences in the expression of this biomarker have been reported [33, 34].

In a study by Khera et al. [32], female sex and black race were both associated with higher CRP levels (median, 3.3 vs. 1.8 mg/L in women versus men, and 3.0 vs. 2.3 mg/L in Caucasian vs. Black patients; p = 0.001). Sex difference was reported to be independent from the use of statins or oral estrogens, and was only partially attenuated by adjustment for traditional CV risk factors, BMI, statin, estrogen use, and sampling weights (OR, 1.6; 95% CI, 1.1–2.5 and OR, 1.7; 95% CI, 1.2–2.6, respectively). These findings were confirmed by a more recent analysis by Lau et al. [35], conducted on 7184 patients from the Framingham Heart Study. The authors observed marked differences in expression of biomarkers representing pathways of inflammation, including CRP. Interestingly, differently from what suggested in previous studies [36, 37], sex-related differences were not influenced by women’s menopausal state. These data suggest the potential usefulness of this biomarker in the evaluation of cardiovascular risk and in the stratification and personalization of said estimates based on sex. Such a possibility is further endorsed by the different relationship of CRP with the patient’s metabolic state that was observed across sexes. In fact, while other authors confirmed the persistence of sex differences in CRP levels independently from BMI [33], women with higher BMI were reported to have higher CRP levels than normal weighted women, whereas the phenomenon was not observed in men [32]. Table 1 (Ref. [32, 33, 38, 39, 40, 41]) reports some large observational studies exploring sex differences in CRP levels in individuals without history of IHD. Moreover, the use of alternative measures for patient’s weight status, such as distribution of body fat, suggested that the presence of increased subcutaneous adiposity was associated with higher CRP levels in women, but not in men [41]. Similar discrepancies were observed also in individuals with diabetes and metabolic syndrome [42, 43].

Table 1.Sex differences in C-reactive protein on large observational studies with individuals with no history of IHD.
 Authors Registry/Country Year Population Women Men p value Note (mg/L) (mg/L) Rutter et al. [39] Framingham Offspring Study 1991–1995 3037 1.6 1.3 0.002 Highest values in women with DM or MetS (0.2–5.1) (0.3–4.0) Khera et al. [32] Dallas Heart Study 2005 6101 3.3 1.8 0.001 Strong association with BMI Rogowski et al. [33] Israel 2004 938 2.1 $\pm$ 3.4 1.5 $\pm$ 2.8 $<$0.0005 Subjects with CV risk factors Rogowski et al. [33] Israel 2004 410 1.6 $\pm$ 3.4 1.0 $\pm$ 2.7 $<$0.0005 Subjects with no CV risk factors Cartier A et al. [41] Canada 2009 353 1.24 0.94 $<$0.05 Premenopausal women (0.54–3.04) (0.51–2.40) Metha NN et al. [40] Penn Diabetes Heart Study 2011 1299 2.8 1.4 $<$0.001 Diabetic subjects (1.4–6.6) (0.7–2.9) Metha NN et al. [40] Study of Inherited Risk of Coronary Atherosclerosis 2011 860 1.4 1.1 $<$0.001 Nondiabetic subjects (0.6–3.7) (0.5–2.1) Lakoski et al. [38] Multiethnic Study of Atherosclerosis 2006 6814 2.56 1.43 0.0001 Women on estrogen: median 3.90 (4.6) (2.5) Women not on estrogen: median 2.15 Data are mean $\pm$ SD or median (interquartile range). CV, cardiovascular; DM, diabetes mellitus; BMI, body mass index; MetS, Metabolic Syndrome.
4. Markers of cytonecrosis
4.1 Troponins

Since these proteins are part of the contractile system of the myocardium, increases in levels of cardiac troponin I (cTnI) and T (cTn) are quite specific indicators of cardiac injuries. For this reason, cardiac troponins and high-sensitivity cardiac troponins (hs-Tn) are the markers of myocardial injury most widely used in clinical practice and endorsed by current Guidelines on management and treatment of myocardial ischemia [44].

According to the Fourth Universal Definition of Myocardial Infarction, myocardial injury is defined as elevation of cTn values above the 99th percentile upper reference limit, with dynamic changes in level of this biomarker being indicative of an acute injury [44]. Still, there have been controversies regarding the optimal threshold to apply to each assay. In fact, baseline levels of cTn and hs-cTn have been demonstrated to be highly dependent on age, kidney injury, blood flow, timing of blood samples and biological variation. Sex differences in levels of this biomarker have also been observed, although the clinical importance of these differences has been subject to debate [45].

Either in animal and human models, women appear to present with lower levels of cTn levels than men do [42]. In a Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS-TIMI 18) substudy, Wiviott et al. [46] observed that, after adjustment for demographic characteristics, risk factors and history of CVD, women were less likely to have positive TnT than their male counterparts (OR, 0.53; 95% CI, 0.43–0.68). This has been attributed to intrinsic differences between the sexes: aside from the aforementioned differences in CAD extension (Fig. 1), which may bring to consequent discrepancies in the release of markers of cytonecrosis, troponin concentrations correlate with left ventricular mass, which is typically greater in men [45, 47].

In the TACTICS-TIMI 18 substudy, the presence of elevated troponins in female sex was also associated with higher recurrence rates of myocardial infarction at 180 days (OR for TnI, 0.30; 95% CI, 0.10–0.86). Eggers et al. [48] confirmed the previously observed sex-related difference in expression of this biomarker, as in their analysis median levels of cTnI were 4.1 (2.9–6.5) ng/L in men and 3.0 (2.3–3.9) ng/L in women (p $<$ 0.001), but terms for sex interaction on the association between cTnI levels and all-cause mortality and incident CVD were not significant in a median follow-up of 10 years.

Despite these evidences, the suboptimal analytical precision at low concentrations of cTn does not allow the definition of sex-specific cTn 99th percentiles for conventional assays. This issue has been partly solved with the development of high-sensitivity assays, which have further highlighted the aforementioned sex-related discrepancies [45]. In this regard, in a cross-sectional analysis performed in three independent community-based cohorts, Gore et al. [49] observed higher 99th percentile cutpoints of hs-cTnT in men compared with women, with median values ranging from 17 to 39 ng/L and from 11 to 34 ng/L in men versus women, respectively, depending from the cohort and sub-populations considered. Shah et al. [47] provided further insight into this phenomenon. In their study, the use of a high sensitivity assay (Abbott), significantly increased the number of diagnoses of type I myocardial infarction in women, especially if a sex-specific threshold was applied. This increase was observed only marginally in men. The use of a sex-specific threshold (34 ng/L in men and 16 ng/L in women) proved also to be a more accurate predictor of recurrent myocardial infarction in women, suggesting that acknowledging these differences in biomarkers expression would prove to be beneficial in clinical practice, especially in terms of diagnostic accuracy for female patients. Following these observations, and despite the presence of dissenting voices regarding the clinical impact of different hs-cTn thresholds in men and women [50], the identification of sex-specific cutoffs for hs-cTn assays has been suggested by the Global Task Force for the Diagnosis of MI and the IFCC (International Federation of Clinical Chemistry and Laboratory Medicine) Task Force on Cardiac Biomarkers [51]. Still, while the most recent ESC Guidelines for management of ACS without persistent ST segment elevation did provide assay-specific cut-offs for hs-Tn evaluation according to the 0/1 h or 0/2 h algorithms, they did not differentiate these thresholds by sex. Indeed, it was deemed necessary to wait for the development of a stratification tool that could take into consideration also patient’s age, renal function and time of chest pain onset [52].

4.2 Other biomarkers of cytonecrosis

Aside from cardiac troponins, among the remaining biomarkers of myocardial cytonecrosis those with the highest clinical impact are creatine phosphokinase (CK) and copeptin, although they all present levels of specificity and sensitivity markedly inferior to cTn [52].

CK is an enzyme apt at promoting the transfer of high-energy phosphate into and out of mithocondria. The isoenzyme CK-MB (combination of brain and muscle subunits) is expressed in high concentrations in the myocardium. Consequently, myocardial injury of any type usually leads to an increase in CK-MB plasma levels. Dosing this biomarker has been for decades an essential aid in the diagnosis of myocardial infarction, right before cTn assays were introduced to clinical practice. Still, as CK-MB shows a more rapid decline after myocardial infarction than cTn, its use is still endorsed as further evidence to establish the timing of myocardial injury and detection of early infarction. CK-MB is considered the best alternative to cTn in case of unavailability of the latter [44, 52]. As even in this case women tend to present lower serum level of CK-MB than men do, sex-specific thresholds are available and recommended for use [44].

In regards to copeptin, a neuropeptide of yet undetermined pathophysiological function, its use is emerging as an additional biomarker for rapid rule-out of myocardial infarction in case of absence of hs-cTn assays [52]. Data regarding potential sex differences in the expression of this biomarker are scarce, although in a recent analysis by Vargas et al. [53] male sex was associated with higher levels of this biomarker (OR, 2.37; 95% CI, 1.61–3.49; p $<$ 0.001).

5. Markers of myocardial dysfunction

Acute heart failure is one of the most common and dangerous complications of myocardial ischemia, with a deep impact on a patient’s prognosis and quality of life. The most renown biomarkers for this condition are B-type natriuretic peptide (BNP) and N-terminal pro-BNP peptide (NT-pro-BNP). BNP is a hormone released by the myocardium in response to excessive stretching of cardiomyocytes, and NT-pro-BNP is its degradation derivative. BNP exhibits the biological activity, whereas no defined biological function has been found to be associated with NT-proBNP. The calculated biological half-lives of BNP range from 13 to 20 minutes and of NT-proBNP from 25 to 70 minutes. These molecules are widely used in clinical practice to ascertain presence of clinically suspected heart failure. Similarly to the other biomarkers mentioned so far, both BNP and NT-proBNP levels often vary according to comorbidities (i.e., atrial fibrillation, pericardial disease) and demographic characteristics like age, race and sex [54]. In 2002, Redfield et al. [55] observed that BNP levels were on average 32% higher in women with ejection fraction $>$50% if compared with their male counterparts. A more recent analysis confirmed these findings by evaluating levels of NT-pro-BNP, and additionally stratifying results for menopausal state of female participants [56]. In particular, men presented with lower NT-pro-BNP than women, and this relationship did not change after menopause, although pre-menopausal women administered with hormone replacement therapy did show higher levels of the biomarker if compared with those receiving no treatment. In both sexes, however, increasing NT-pro-BNP levels were related to decreasing free testosterone and increasing sex hormone binding protein concentrations. When accounting for these factors, all differences related to sex or hormone levels decreased considerably, suggesting that interaction between androgen levels and NT-pro BNP may explain the observed sex differences, a hypothesis formulated also in the Dallas Heart Study [57]. However, it should be noted that the most significant sex-related differences in terms of BNP levels were observed in the general population, whereas studies including acute patients reported only slight differences in the concentrations of this biomarker [58, 59]. In general, women have been shown to present a tendency to lower increases of BNP and NT-pro-BNP in the acute setting when compared to their male counterparts. This phenomenon was confirmed in a meta-analysis by Mangussen et al. [60], which concluded that higher NT-pro-BNP levels were actually more strictly associated with incidence of heart failure in men than in women (hazard ratio [HR], 1.89; 95% CI, 1.75–2.05) in men versus 1.54; 95% CI, 1.37–1.74) in women) [60]. It follows that further research is warranted to better define the clinical relevance of differences in BNP and NT- pro-BNP concentrations across sexes, and to establish whether the application of sex-specific thresholds would actually improve management and prognosis of patients in day- to day practice.

Similar observations can be made on other biomarkers whose variations have been associated with an increased risk of heart failure. For instance, galectin-3 is a pro-fibrotic protein that has been found to be significantly increased in patients with heart failure [61], and some levels of sex-related differences in its concentrations have been observed at baseline. Moreover, in a recent study conducted on data from 4 community-based cohorts with 12.5 years of follow-up, galectin-3 was significantly associated with incident heart failure only in women (HR: 1.13; 95% CI: 1.05–1.22), suggesting differences in the development of cardiac fibrosis as potential pathophysiological mechanisms underlying sex-related discrepancies in incidence and prognosis from heart failure [62]. More analyses still need to be conducted in order to definitely to assess differences in its prognostic value between men and women [63].

6. Conclusions

With the rightful evolution of clinical and research perspective on women in cardiovascular diseases, female patients have gradually emerged as individuals, with pathophysiological characteristics and responses to treatment that differ profoundly to what has been observed in men and cannot simply be assumed on the basis of studies conducted on mostly or only male participants. The present review summarized the state-of-art knowledge on sex-related differences in cardiovascular risk factors and biomarkers expression of myocardial necrosis and dysfunction. What emerged is that while women do present significant differences either in indicators of inflammation, necrosis and ventricular disfunction, the clinical and prognostic implications of these differences are less extensively characterized, a phenomenon that has prevented international organizations from adopting clear and standardized sex-specific thresholds for these indicators. Smoking and diabetes mellitus disproportionally increase the risk of obstructive CAD in women compared to men, and as so it may contribute to sex differences in outcomes from ACS. New studies conducted on contemporary, more inclusive cohorts are warranted to shed light on these issues and to bring us closer to a personalized and equal standard of care.

Author contributions

MB and OM conceived and designed the manuscript, drafted the manuscript, and revised it for important intellectual content. MS, RB and EC made substantial contributions to the conception and design of the manuscript, drafted the manuscript, and revised it for important intellectual content. All authors approved the final version of the manuscript.

Ethics approval and consent to participate

Not applicable.

Acknowledgment

We thank Natalia Fabin for helping us make pictures and fix the style of references.

Funding

This research received no external funding.

Conflict of interest

The authors declare no conflict of interest.

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