Gender Medicine in Dilated Cardiomyopathy: Pride and Prejudice

This article refers to ‘Sex- and age-based differences in the natural history and outcome of dilated cardiomyopathy’ by B.P. Halliday et al., published in this issue on pages 1392–1400. Non-ischaemic dilated cardiomyopathy (DCM), despite its apparently simple definition, incorporates several aetiologies. Currently, the advent of next-generation sequencing techniques has demonstrated that genetic mutations are responsible for approximately 50% of DCM. In the remaining cases, a complex interaction between environmental triggers (e.g. inflammation, tachyarrhythmias, alcohol, chemotherapy) and specific genetic backgrounds lead to the dilated phenotype.1 Although the prognosis of DCM has improved significantly over the past decades with advances in pharmacological and non-pharmacological treatments,2 DCM still remains the leading cause of heart transplantation. Therefore, clinical presentation and subsequent outcomes are barely generalizable; furthermore, management of DCM is difficult and needs to be implemented. Affected patients are generally relatively young, with a low co-morbidity profile and thus low event rates during the follow-up. This scenario dramatically limits the statistical power of focused studies, which require enrolment of a large number of patients before definitive conclusions can be made. In this issue of the Journal, Halliday et al.3 pointed out all the above-mentioned critical issues. Furthermore, and most importantly, they eloquently evaluated the prognostic role of gender differences in the natural history of DCM patients. Over 10 years of follow-up, they enrolled almost 900 well-characterized DCM patients. The main result of their study is the better long-term outcome of women compared to men, even after adjustment for the major prognostic determinants of the disease. Besides gender, older age emerged, as expected, as an important prognostic predictor, since after 60 years of age the competitive risk of non-cardiac death progressively increases, as stated by the same authors.3 Up until now, the role of gender differences in DCM has been only loosely considered as a significant outcome modifier. Data from this registry3 confirm previous findings from a similar Italian registry regarding the different clinical presentation and the natural history of DCM in women4 (Figure 1), who appear to have a particular morpho-functional phenotype of DCM even after adjusting for several key prognostic variables. Indeed, the higher prevalence of left bundle branch block and a more advanced New York Heart Association class at presentation suggest a more advanced disease state in women. However, female DCM patients show smaller left ventricular volumes and higher ejection fraction and less frequently late gadolinium enhancement at cardiac magnetic resonance, a feature of less severe disease.4 The natural history of DCM in women clearly appears more favourable if compared to men. The higher survival rate reflects a better response to treatment in women4 and also the more favourable milieu, which preserves women's functional status, confirming the uniqueness of their disease compared to their male counterparts.3-5 However, because of the limited number of events, further analyses are warranted, in addition to those conducted by Halliday et al., to draw definitive conclusions on the influence of gender differences on specific critical issues, including (i) arrhythmic event rates, (ii) prognosis of patients with reduced vs. mid-range ejection fraction, and (iii) prognosis of patients with different DCM aetiologies. Randomized clinical trials provided controversial data on different gender-related outcomes of patients with heart failure, and those conclusions have been derived only from post-hoc analyses. Although in recent years the most relevant clinical trials on heart failure included larger numbers of women compared to the past, the proportion of females was still low (30–40%), likely because of social and cultural factors. In the CHARM and MADIT-CRT trials, outcomes of female patients were more favourable than in men.4 Conversely, no prognostic differences between men and women were reported in the PARADIGM-HF and DANISH trials, and post-hoc analyses, despite their limitations, are still warranted.6, 7 Furthermore, prognosis does not differ between women and men with acute heart failure, making gender-specific risk models useless for predicting prognosis of these patients.8 Therefore, although clinically focused prospective trials are the best tool for elucidating DCM outcomes in women, their feasibility is very limited due to the specific characteristics of DCM, which affects women and men with a ratio of 1:3. Moreover, meta-analyses are also limited by heterogeneity in enrolment era, treatment, and patient characteristics of the evaluated studies.9 It is likely that a more definitive answer as to the role of gender medicine in DCM could be derived from large registry data. Indeed, registries provide a ‘closer to the real-world’ analysis of more homogeneous populations. The very best way to address these issues appears to be the establishment of international networks and consortia, which gather multiple different size registries and overcome the limitation of low event rates. In everyday clinical practice, gender medicine has progressively gained in importance for the evaluation of patients with cardiovascular disease and for cardiovascular disease prevention.10-12 From the bench, sex hormones play a pivotal role in organism development and healthy aging.13 Oestrogens, and in particular 17β-oestradiol, have cardioprotective effects.14 In addition, gender-specific transcriptomic differences can be found in patients with new-onset heart failure.15 Back to the bedside, alcohol consumption is still unacceptably high in males, whereas the incidence of post-inflammatory DCM or cardiotoxicity from chemotherapeutic agents is more prevalent in women.3 So far, clinicians approached DCM looking at the heart with the prejudice that gender differences may play a role in the epidemiology, and sometimes even in the pathophysiology, of the disease, but rarely bearing in mind the critical prognostic differences between men and women. Also psychological and cultural factors (e.g. disease acceptance or reluctance), resistance to device treatment, or everyday life approach may differ between men and women, and all this should be taken into consideration. With the availability of more advanced diagnostic techniques, modern medicine is currently moving from disease-specific medicine towards personalized medicine. Patient-specific assays could provide individualized disease management that includes specific genetic background, epigenetic modification, drug response, and environmental factors.16 Developing a more targeted risk stratification approach and a more personalized treatment is pivotal to drive therapeutic regimens and device therapies, reduce inappropriate treatments and optimize cost-effectiveness. Gender medicine should be seen, therefore, as a step towards personalized medicine, considering not only differences between young and old patients with DCM but also between men and women as significant prognostic factors. Personalized medicine should convey the global assessment of patients, in their uniqueness as a whole made by several singular components, which in turn may modify the prognostic outcome. Conflict of interest: none declared.