In the recent past, there has been a growing attention to sex-based differences in biology, genetics, biomedical sciences and general medicine, ranging from the cellular level to whole organs and organisms. As expected, this process quickly led to the generation of new insights into diagnostic, prognostic and therapeutic issues, from basic research to the clinical level . The overall message is indeed the one published by Nature in 2010, which summarizes old and new problems in the title “Putting gender on the agenda” . Starting from the fact that animals have a sex , well known differences in gene expression have to exist in male versus female mice . Based on the evidence that companies and scientists may have arbitrarily performed their preclinical tests on male models, the Editors of Nature concluded that “Medicine as it is currently applied to women is less evidence-based than that being applied to men” . The increasing attention towards sex and gender, along with the interest that emerges from this kind of aware research, are now beginning to bridge the gap . Thanks to the increased knowledge of the molecular, genomics and epigenomics bases of complex diseases, and thanks to the personalized pharmacogenetic/genomics approach to drug design/prescription, several diseases are now faced in a tailored fashion . However, while the inclusion of sex is a process already underway, with evident results from both preclinical and clinical trials, the impact of gender in medical/biomedical fields is still at an early stage, with difficulties and delays due to its intrinsic complexity. Ongoing efforts aim to include and understand the role of gender in pharmacology . To date, gender-related pharmacodynamic and pharmacokinetic differences have been reported with crucial implications on drugs effects . Overall, gender-specific pre-clinical models will increase the definition of gender-oriented therapeutic protocols, in turn accelerating the development of gender-specific drugs and the generation of gender-oriented and evidence-based guidelines .
2. Sex Disparity
Improvement in the acute treatment has led to a dramatic increasing in the number of acute myocardial infarction (AMI）survivors among those with damaged heart. These patients are at risk of developing severe complications, like left ventricular remodelling (LVR) and heart failure (HF), which are still considered orphans of specific prognostic tools and effective dedicated treatments 
. AMI is the most frequent cause of LVR and HF and patients often undergo to chronic and costly therapies, very frequent re-hospitalization and poor quality of life, with a significant gap among the two sexes 
. Recently it has been reported that “the incidence and prevalence of coronary artery disease in women has exceeded that in men over the past four decades” 
AMI takes place from a complex interrelationship among genetic/epigenetic and environmental risk factors, as it was revealed by several studies of pharmacogenetics and -genomics 
, and more extensively confirmed by omics investigations 
. In addition, a very recent study from the Multi-Analyte, Genetic, and Thrombogenic Markers of Atherosclerosis group (MAGMA) found that females with angina are more thrombogenic than males, and this difference may affect sex-related outcomes 
, also on the basis of undeniable genomics differences. Moreover, the Genetics of Subsequent Coronary Heart Disease consortium (GENIUS-CHD) was established to discover and validate genetic variants and biomarkers for the risk assessment of subsequent ischemic events along with novel drug targets for secondary prevention. It is considered a first-class initiative able to generate extraordinary results also in the field of sex-oriented cardiology 
Noteworthy, the incidence of AMI is much lower among females under the age of 50 years compared with males, but after the menopause, the rate in females dramatically increases, approaching that of males 
. For this reason, oestrogens were postulated to be cardioprotective but results coming from recent randomized clinical trials challenge this hypothesis 
. In addition, sex differences influence AMI pathophysiology, clinical presentation and clinical outcome. In detail, the mortality rate after one or five years is higher in females than in males, and the former more frequently experience heart wall remodelling, failure and stroke within five years from the first ischemic accident. This remains the poorest outcome, even considering several concomitant situations, like different age at presentation, genetic risk factors and comorbidities, as demonstrated by the higher in-hospital mortality, the readmission rate within the first thirty days or the longer follow-up 
. Interestingly, results coming from five Italian prospective registries conducted between 2001 and 2014, concluded that age and sex specific differences exist in the outcome of patients with ST-elevation myocardial infarction (STEMI) 
. Regardless of age, at discharge, females are at higher risk of re-hospitalization due to different causes. Strong disparities between the two sexes were confirmed also after adjustment for confounding factors 
. Accordingly, the in-hospital death was 3.2% for males and 8.4% for females, and the latter have been found significantly associated with in-hospital mortality. Finally, females continue to experience higher post-AMI mortality and global poorer outcome (Figure 1
) also despite the improvements in reperfusion therapy tools 
. In conclusion, despite a worldwide improvement in STEMI care, females continue to experience higher in-hospital mortality, which is not completely unexpected, as the most fundamental cardiovascular studies are primarily based on males 
Figure 1. Extreme clinical phenotypes and prognosis in male and female AMI patients. The increased AMI risk in males is balanced by a better prognosis, resulting in enhanced AMI outcome. Conversely, the reduced AMI risk in females is characterized by a worst prognosis, resulting in a poor AMI outcome.
Another key element is that postmenopausal females tend to develop HF with preserved ejection fraction, characterized by diastolic dysfunction, whereas age-matching males develop HF with reduced ejection fraction, characterized by systolic dysfunction 
. These differences are important because most drugs used to treat HF have been developed to treat those with reduced ejection fraction, and there are few effective treatment options for HF with preserved ejection fraction 
. It is also possible that the aging process affects the heart of males and females differently, so that the latter are predisposed to problems of myocardial relaxation, while males mainly develop pump failure. As a result, males and females show a completely opposite trend in terms of hospitalization index for HF, which increases significantly with the age of the females compared with age-matching males 
. A recent long-term study on LVR after the first AMI reports that, of the total number of patients who experienced LVR after one-year follow-up (31–38% in the two cohorts of the study), females were significantly over-represented (43–46.5% vs 27–36.5% for females and males respectively in the two studies) 
. These data are extremely important since both cohorts of patients in that study had a very high rate of secondary prevention medications after one year (i.e., beta-blockers 90–95% and ACE inhibitors/angiotensin II R-blockers 93–97% respectively in the two studies). Interestingly, sex hormones are associated differently with the morphology of the remodelled heart wall, and a more androgenic profile is responsible for a greater imbalance in the heart mass/volume ratio in females than in males 
In summary, remodelling is the main determinant of survival after recovery from AMI. Observational clinical and post-mortem/experimental studies suggest important differences between females and males in the cardiac remodelling observed in response to different types of cardiac injuries including infarction. Recommended therapies for AMI in females are similar to those in males, but studies indicate that females are undertreated, which lead to worse outcomes 
. Interestingly, during the first few hours after AMI, complex local healing processes and inflammatory reactions are crucial in determining the risk of wall remodelling. Soluble molecules, resident and circulating cells and micro-RNAs finely mediate inflammation and regenerative progression by determining the fate of the heart after the infarction 
. Basically, imbalance in any healing process and unrestrained ECM proteolysis cause a delayed remedy, while lasting chronic lesions in any district may affect the normal organ/tissue functions with consequent failure and malfunction 
. Since these complex processes are in part genetically determined, molecular regenerative medicine, by providing molecular predictive indicators, might help clinicians to recognize at risk populations also in a sex- or gender-oriented direction 
. Reperfusion therapy and systematic use of evidence-based medications have effects on LVR or HF but they cannot be considered dedicated therapeutic approaches. Prognostic biomarkers able to score cases at higher risk to develop severe post-infarction complications (i.e., females) will allow the early identification of patients for whom the available standard care is not adequate. It is to be taken into account that groups of males at higher risk could also benefit from personalized approaches.
Overall, there is a mandatory need for a “holistic” sex specific approach (i.e., sex-oriented omics-investigations “sex/genderomics”), from the use of in vitro and in vivo preclinical models up to appropriate clinical studies with well-balanced male/female ratio cohorts. This will allow the identification of prognostic biomarkers to effectively counteract sex-disparities and help in designing sex-dedicated therapies 
. If appropriately addressed, these approaches will represent a significant improvement in the cardiovascular disease management, and the potential of sex-specific risk stratification tools will positively influence the worldwide National Health Care Systems.