In our study, men exhibited a higher prevalence of right ventricular dilation and experienced a significantly greater number of cardiovascular events compared to women, as also confirmed by Kaplan Meier curves (Log Rank χ2 10.664, p = 0.001).
Specifically, the median number of cardiovascular events was higher in men (Median: 2.00) compared to women (Median: 1.00; p = 0.031987), indicating greater cardiovascular vulnerability in male patients (17).
Although the difference in mortality between men and women was not statistically significant, (88.89% of men vs. 57.69% of women; p = 0.134426), Kaplan Meier curves demonstrated a significant lower survival in male patients (Log Rank χ2 5.986, p = 0.014) suggesting a trend that merits clinical attention [8]. These findings are consistent with current literature.
Men also showed a significantly higher prevalence of right ventricular dilation compared to women (100.00% vs. 44.23%; p = 0.002195), reflecting considerable cardiac impairment. The influence of sex hormones, particularly testosterone, is a critical factor in understanding these disparities. Testosterone has been shown to contribute to adverse cardiac remodeling, which may exacerbate right ventricular dilation and overall cardiac dysfunction in male patients. Jinzhi et al. (2024) emphasized that right ventricular dilation is a critical predictor of poor prognosis in male scleroderma patients, underscoring the importance of routine cardiac evaluations.(18)
Additionally, men had a higher prevalence of pericardial effusion, although it was not hemodynamically significant, compared to women (33.33% vs. 11.54%; p = 0.124605), which further complicates the clinical scenario. Cheron et al. (2021) suggest that recognizing gender differences in cardiac manifestations could facilitate the development of more effective, individualized treatment strategies (19).
The role of estrogens, or the lack thereof, is another crucial aspect. Estrogens are known to exert protective effects on the cardiovascular system, potentially mitigating some of the adverse effects seen in PAH. The absence of these protective hormones in men might explain the higher incidence of severe cardiovascular outcomes, including right ventricular dilation and pericardial effusion.
Moreover, recent research highlights the significant influence of sex on the pathophysiology and outcomes of pulmonary arterial hypertension (PAH), suggesting that women may have an intrinsic protective advantage due to estrogen's modulating effects on pulmonary vascular function. Dignam et al. (2024) emphasized the importance of sex in PAH pathogenesis and outcomes, further supporting the role of sex-specific therapies to address the increased cardiovascular risks observed in men (20).
Furthermore, hormonal therapies that modulate these pathways could represent a potential avenue for targeted treatments in male patients, particularly in reducing right ventricular strain and improving overall cardiac function.
Men also appeared to experience renal crises more frequently than women (11.11% vs. 1.92%; p = 0.275410), which negatively impacts prognosis. Cozzi et al. (2024) reported that scleroderma renal crises (SRC) are significantly associated with poor outcomes, particularly in men, with mortality rates as high as 59% at five years. This highlights the necessity of vigilant renal function monitoring and early intervention to improve prognosis. (21). Furthermore, men exhibited an active disease pattern more frequently than women (66.67% vs. 36.54%; p = 0.141794), suggesting higher disease activity
The increased disease activity in males may be further influenced by the pro-inflammatory effects of testosterone, which can exacerbate the progression of scleroderma and its complications. As discussed by Ketchem et al. (2024), testosterone and other male sex hormones have been shown to enhance inflammation, highlighting the need for a more aggressive therapeutic approach in male patients. (22)
Additionally, men were more likely to test positive for RNA polymerase III compared to women (11.11% vs. 0.00%; p = 0.147541), a marker strongly associated with severe complications, including renal crises and malignancies. Studies indicate that RNA polymerase III positivity is a significant indicator of disease severity, particularly in patients with diffuse cutaneous involvement, underscoring the need for close monitoring in men.(23)
Men were more likely to develop extensive ILD compared to women (66.67% vs. 42.31%; p = 0.278651), contributing to greater functional impairment. As described in ILD associated with connective tissue diseases, the link between extensive ILD and increased morbidity in males highlights the critical importance of regular pulmonary assessments to monitor disease progression and optimize treatment strategies. (24)
Furthermore, Sumner et al. (2017) have demonstrated the significant benefits of modern cardiac rehabilitation programs, particularly in patients who actively participate in these interventions. Their systematic review revealed that attenders of cardiac rehabilitation programs had significantly lower mortality rates and improved cardiovascular outcomes compared to non-attenders. This evidence further supports the need for structured exercise interventions in populations at high risk, such as male patients with scleroderma-associated PAH, who may benefit greatly from targeted rehabilitation programs that address both cardiovascular and pulmonary complications.
(25).
In this context, the importance of exercise-based interventions, such as those highlighted by McCormack et al. (2021), is increasingly recognized. Their feasibility study on home-based exercise interventions for patients with pulmonary hypertension emphasizes that structured physical activity can improve functional outcomes and quality of life, even in high-risk populations like those with scleroderma-associated PAH. Such interventions could be particularly beneficial for men, who often present more severe complications, by addressing both cardiovascular and pulmonary function deficits without exacerbating their condition. (26)
Spinella et al. (2018) highlighted the importance of managing cardiopulmonary disease in scleroderma patients through an integrated approach that involves standardized care in cardiorheumatology clinics. Their proposed patient care model emphasizes the need for early detection and management of cardiac complications, which are more prevalent and severe in male patients. This underscores the critical role of multidisciplinary care in improving patient outcomes.(27)
Research suggests that male patients with scleroderma are more prone to lung involvement, particularly pulmonary fibrosis, possibly due to differences in immune response, hormone levels, and genetic factors. The absence of estrogen, which has anti-fibrotic properties, may partly explain the greater severity of lung involvement in men. Genetic predispositions and differences in immune system function could also contribute to the increased susceptibility to pulmonary fibrosis in males. (19)
[Fig. II] Limitations
This study has several limitations that should be considered when interpreting the results.
First, the sample size, particularly of male patients (9 men compared to 52 women), is relatively small, which may limit the generalizability of our findings. The known gender disparity in the prevalence of scleroderma-associated pulmonary hypertension (PAH) contributes to this imbalance, but future studies with larger, multicenter cohorts are needed to validate these results.
Second, the retrospective design of the study may introduce inherent biases related to data collection and analysis. Retrospective data lack the precision of prospectively collected information, and there is a potential for missing or incomplete data, particularly in the long-term follow-up of these patients.
Third, while our comparison group included systemic sclerosis (SSc) patients without PAH, the exclusion of PAH was based on echocardiographic parameters according to the European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines. Although this method is standard, it does not entirely eliminate the risk of undiagnosed cases of early or subclinical PAH, potentially introducing a selection bias.
Finally, the study did not include a detailed longitudinal analysis, limiting the ability to fully assess the long-term impact of gender-specific factors on disease progression and outcomes. Prospective studies with extended follow-up would be beneficial to better understand the progression of PAH in male versus female patients and to assess the potential benefits of targeted interventions.