What is the role of sex and gender in the future of precision cardiology?

Precision medicine is an ongoing cultural revolution in contemporary medicine, involving research and clinical practice at the same time (Figure 1). In contrast to the traditional reductionist approach, precision medicine aims to broaden the practical definition of disease beyond the mere association of signs and symptoms, to include the unique characteristics of individual patients, such as their genetic background, their history of environmental exposure, and their social interactions.1 The idea that the optimal strategy to restore and/or preserve the optimal health status should be tailored on individual characteristics is not novel and can be traced back in the ancient European humoral theory or the traditional Chinese medicine.2 However, during the 19th and 20th centuries, the embedding of the scientific method in medical research has favoured the adoption of a simplified approach, leading to immeasurable advances in medical knowledge and in the effectiveness of clinical interventions. Compared with the classical approach to medicine, based on a statistical definition of disease, precision medicine encompasses a personalized approach to diagnosis, treatment, and prevention. This envisages the comprehensive evaluation of different factors, ranging from a genetic level (genome) to an environmental and social level (exposome). Sex and gender differences express at each of these levels and should be considered when implementing a personalized approach to health and disease. Created with BioRender.com. The current epidemiological landscape, largely populated by chronic, non-communicable diseases with multifactorial origin, has highlighted the shortcomings of this approach. In the field of cardiovascular prevention, for instance, the evidence of a residual risk after optimization of all atherosclerotic risk factors underscores the relevance of the cumulative overtime effect of risk factors that should, therefore, be managed individually long before they reach the usually accepted risk thresholds, based on individual susceptibility to one or more specific risk factors. This can only be possible by the use of novel predictive tools, which allow tailored interventions using a broad range of potential predictors. Nowadays, modern technology has provided us with the tools to investigate the individual susceptibility to cardiovascular disorders and risk factors in depth, using a multi-omics approach; at the same time, advances in information technology and artificial intelligence allow us to integrate this heterogeneous amount of data with traditional clinical parameters.3 Under this perspective, the integration of genomic and epigenomic information could provide novel instruments for a refined risk prediction. Compared with other fields of modern medicine, such as oncology and rheumatology, acquisitions of precision medicine have a smaller practical application in cardiology and vascular medicine. This gap is mainly due to the terrific efficacy of traditional pharmacological and non-pharmacological interventions in the management of cardiovascular diseases (CVDs). At the same time, the weight of sex and gender disparity is emerging as a strong hindrance in modern management of cardiology and vascular medicine. Accumulating evidence suggests that, at the present time, CVDs are under-diagnosed and under-treated in women compared with men, and women are currently under-represented in epidemiological studies and clinical trials. For instance, women with non-ST-elevated myocardial infarction tend to receive fewer percutaneous coronary interventions.4 As a result, women may report higher mortality rates following coronary artery disease, even when coronary artery bypass graft is employed.5 Whether this disparity results from a cultural bias or from an epidemiological drift in CVDs is still a matter of debate. However, there is nowadays an increasing interest around sex differences in CVD, leading to the development of novel sex-specific prognostic tools, as well as novel acquisitions about biological determinants of sex differences.6,7 Indeed, the intrinsic complexity of biological sex is often overlooked in clinical research and sex differences are commonly reconducted to the pleiotropic effects of steroid sex hormones. Biological sex is instead a complex phenotype, determined by the concurrent effect of genomic, epigenomic, anatomic, hormonal, and metabolic factors. On top of this, social constructs and economic differences, collectively named as ‘gender’ features, contribute to the different health status between men and women. For instance, several genetic variants associated with the risk of developing CVDs show a sex-biased impact, influencing disease patterns, responses to treatment, and outcomes in a sex-specific manner.8 Furthermore, the two sexes differ from one another because of variations in gene expression independent from the underlying DNA sequence (epigenetic differences). Non-coding RNAs, including microRNAs and long non-coding RNAs, are integral components of epigenomic regulation, influencing gene expression without coding for proteins. Moreover, they are involved in the preservation of the chromatin structure, regulation of histone modifications, and control of transcriptional activity, thus playing key roles in cardiovascular health and disease.9 Micro-array analyses of human organ tissues revealed sex differences in microRNA transcriptome in both normal and diseased heart, with potential impact on susceptibility to CVD incidence and progression. Sex differences in the expression of non-coding RNAs are due to two main factors: (i) numerous gene promoters contain oestrogen-responsive elements, where the binding of oestrogen induces the expression of miRNAs; (ii) the X chromosome encodes 118 microRNAs, most of which are grouped into six regional clusters. Several of these X-linked microRNAs have been reported to escape X chromosome inactivation, resulting in higher expression levels in specific cell types such as endothelial cells, vascular smooth muscle cells, and cardiomyocytes. This sex-specific modulation of cell function can lead to different pathophysiological regulatory processes between men and women and may specifically explain sex-specific cardiovascular pathological features in women, such as in heart failure with preserved ejection fraction.10 Unravelling the complex interaction of sex and gender in CVDs requires a ‘precision medicine’ approach, as multiple levels of complexity need to be analysed. Could the expanding research in sex and gender differences help precision medicine grow within the field of cardiology and cardiovascular research? S.M. received financial support from the Swiss Heart Foundation, outside this project. T.P. is co-founder of the Spin-off Ivestatin Therapeutics S, unrelated to the content of this paper.