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