Sex-specific differences in age-related aortic valve calcium load: A systematic review and meta-analysis

https://doi.org/10.1016/j.arr.2020.101077Get rights and content

Highlights

  • Aging of the aortic valve leads to thickening and calcification.

  • There are differences between CAVS in men and women.

  • With the same CAVS severity, women show lower AVC than men.

  • Age- and sex-specific prevention and pharmacological strategies are needed.

Abstract

Aging of the aortic valve, characterized by leaflet thickening and loss of extensibility, leads to progressive changes in valve function. These age-related mechanisms have not been evaluated yet in sex-specific calcific aortic valve stenosis (CAVS) onset and progression. Recent studies reported the association between high aortic valve calcification (AVC) load and male gender in patients with CAVS while women present faster progression than men. To evaluate these age- and sex-specific differences, we performed a systematic review and meta-analysis with meta-regression.

A systematic search related to AVC measured by computed tomography and gender-specific differences was conducted according to PRISMA guidelines. Seven studies, enrolling 1859 men and 1055 women, were included in the quantitative synthesis.

We found a significant difference between men and women both in AVC load and density. AVC load mean difference (MD), between men and women, was 1131 ± 243 AU (p < 0.0001; I2: 96.5 %, p < 0.001), while AVC density MD was 159 ± 20 AU/cm2 (p < 0.0001) without heterogeneity among the studies (I2: 23.5, p = 0.3). Meta-regression analyses showed that AVC load MD positively correlated with age and other cardiovascular risk factors such as diabetes, hypertension, and coronary artery disease presence.

Our meta-analysis shows a significant association of incremental AVC load with male gender, regardless of the individual anatomical characteristics and the cardiovascular risk factors. Further studies are needed: i) to clarify if there are different sex-related pathophysiological processes driving the development and the progression of age-related CAVS, and ii) to determine if a sex-specific therapeutic strategy should be applied for CAVS treatment and/or prevention.

Introduction

Significant increase in life expectancy, due to the improvement of lifestyle and clinical care, leads to advanced old age and the development of age-related disease (Fabbri et al., 2015; Oeppen and Vaupel, 2002). Calcific aortic valve stenosis (CAVS) is the most common valve disorder with a prevalence ranging from ∼1% in young adults to 13 % in people over 75 years of age (Carabello, 2002; Perrucci et al., 2017). Currently, there is no pharmacological treatment for CAVS and surgical or percutaneous interventions are the only available therapeutical options for patients affected by this debilitating and fatal disease (Myasoedova et al., 2018). CAVS is a multifactorial pathological process that starts with endothelial damage, lipid oxidation and accumulation, and inflammation that leads to fibroblasts aberrant activation, extracellular matrix remodeling, and finally ectopic calcification (Branchetti et al., 2013; Dweck et al., 2012; Poggio et al., 2014, 2013; Rajamannan et al., 2011).

Transthoracic echocardiography (TTE) is definitely the “gold standard” diagnostic tool for CAVS and the evaluation of its progression. However, TTE does not allow for an accurate aortic valve calcium (AVC) quantification and therefore computed tomography (CT) could be used to provide more specific and detailed quantification of CAVS severity and progression (Boulif et al., 2017; Nguyen et al., 2015; Tuncay et al., 2015). Furthermore, the AVC load was suggested as a surrogate marker of prognostic importance in CAVS patients (Clavel et al., 2014; Nchimi et al., 2018; Pradelli et al., 2013). Indeed, incremental values of AVC load are strongly associated with CAVS severity and worse morbidity and mortality (Di Minno et al., 2019).

Several studies, aimed to investigate the association between AVC load and CAVS, reported a possible influence of gender in the development and progression of CAVS (Aggarwal et al., 2013; Nguyen et al., 2016). Recently, it has been shown that women have less AVC load and faster CAVS progression than men (Tastet et al., 2017). Indeed, sex-specific AVC cut-off has been identified and they are strongly associated with CAVS hemodynamic severity and increase mortality (Clavel et al., 2013, 2014). However, it remains unclear if sex differences in AVC load and/or AVC density may underline different CAVS pathophysiological processes.

The increasing number of patients with age-related AVC is a significant public health problem and socioeconomic burden as the worldwide incidence of CAVS is expected to double in the next 20 years in developed countries (Beckmann et al., 2010). Thus, we need to better understand the mechanisms of valvular aging and thereby develop and implement novel targeted-preventive strategies. In order to better clarify this argument, we performed a systematic review and meta-analysis with meta-regression evaluating sex differences in age-related AVC.

Section snippets

Methods

In order to perform complete search and analysis, a detailed protocol for this review was prospectively developed, specifying objectives, criteria for study selection, outcomes, and statistical methods.

To identify all available studies, a systematic search was evaluated in the electronic databases (PubMed, Web of Science, and Scopus). A detailed search relating to AVC load, measuring by CT scan, and the gender-specific difference was conducted according to PRISMA guidelines (Moher et al., 2009

Results

The search strategy identifies 73 articles (Fig. 1). Duplicate results were excluded and after a screening of the titles and the abstracts, thirty-four articles were selected for full-text evaluation. The revision of full-length papers allows the exclusion of twenty-seven articles due to wrong study design (n = 11) or lacked data of interest (n = 16). Thus, seven studies (Abramowitz et al., 2017; Aggarwal et al., 2013; Clavel et al., 2013, 2014; Nguyen et al., 2016; Simard et al., 2017; Thaden

Discussion

The present systemic review and meta-analysis included more than 2900 patients with several degrees of AVC. To the best of our knowledge, this is the first meta-analysis focused on gender difference and AVC in CAVS patients. The main result of our study shows a significant gender difference in AVC load and AVC density. Meta-regression analysis indicated that the differences in AVC load, between men and women, are directly associated with cardiovascular risk factors, such as hypertension,

Conclusions

Summarizing all these evidence, we can conclude that AVC density is definitely lower in women compared to men, regardless of the individual anatomical characteristics and their cardiovascular risk factors. Indeed, in the last European Guidelines for the management of valve diseases, sex-specific AVC cut-off has been included (Baumgartner et al., 2017).

In conclusion, aging of the aortic valve, characterized by leaflet thickening (Sahasakul et al., 1988) and loss of extensibility (Christie and

Financial support

This work was supported by the Fondazione Gigi e Pupa Ferrari ONLUS.

Declaration of Competing Interest

None of the authors declares a conflict of interest.

Acknowledgments

The Authors thank the Cardiac Surgery Unit and the Echocardiography Unit at Centro Cardiologico Monzino IRCCS, Milan, Italy.

References (48)

  • M. Eberhard et al.

    Reproducibility of aortic valve calcification scoring with computed tomography - an interplatform analysis

    J. Cardiovasc. Comput. Tomogr.

    (2019)
  • P. Genereux et al.

    Natural history, diagnostic approaches, and therapeutic strategies for patients with asymptomatic severe aortic stenosis

    J. Am. Coll. Cardiol.

    (2016)
  • V.A. Myasoedova et al.

    Novel pharmacological targets for calcific aortic valve disease: prevention and treatments

    Pharmacol. Res.

    (2018)
  • V. Nguyen et al.

    Sex differences in the progression of aortic stenosis and prognostic implication: the COFRASA-GENERAC study

    JACC Cardiovasc. Imaging

    (2016)
  • Y. Sahasakul et al.

    Age-related changes in aortic and mitral valve thickness: implications for two-dimensional echocardiography based on an autopsy study of 200 normal human hearts

    Am. J. Cardiol.

    (1988)
  • B.F. Stewart et al.

    Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study

    J. Am. Coll. Cardiol.

    (1997)
  • L. Tastet et al.

    Impact of aortic valve calcification and sex on hemodynamic progression and clinical outcomes in AS

    J. Am. Coll. Cardiol.

    (2017)
  • Y. Abramowitz et al.

    Severe aortic stenosis with low aortic valve calcification: characteristics and outcome following transcatheter aortic valve implantation

    Eur. Heart J. Cardiovasc. Imaging

    (2017)
  • S.R. Aggarwal et al.

    Sex differences in aortic valve calcification measured by multidetector computed tomography in aortic stenosis

    Circ. Cardiovasc. Imaging

    (2013)
  • H. Baumgartner et al.

    2017 ESC/EACTS Guidelines for the management of valvular heart disease

    Eur. Heart J.

    (2017)
  • E. Beckmann et al.

    Insights into the use of biomarkers in calcific aortic valve disease

    J. Heart Valve Dis.

    (2010)
  • E. Branchetti et al.

    Antioxidant enzymes reduce DNA damage and early activation of valvular interstitial cells in aortic valve sclerosis

    Arterioscler. Thromb. Vasc. Biol.

    (2013)
  • B.A. Carabello

    Clinical practice. Aortic stenosis

    N. Engl. J. Med.

    (2002)
  • B.H. Choi et al.

    Association between aortic valvular calcification and characteristics of the aortic valve in patients with bicuspid aortic valve stenosis

    Acta Radiol.

    (2019)
  • Cited by (25)

    • Matters of the heart: Cellular sex differences

      2021, Journal of Molecular and Cellular Cardiology
      Citation Excerpt :

      Female sex is further associated with more mitral valve leaflet thickening, and postmenopausal osteoporosis is considered a risk factor in mitral valve calcification [14,15,25]. Aortic valve stenosis (AVS) presents later in women [16], where symptoms are more severe with a lesser amount of calcification [17,18]. Interestingly, the mineralization that occurs during aortic valve calcification (AVC) develops more slowly in females relative to males [162].

    View all citing articles on Scopus
    View full text