In this large multicenter, international study of patients with HF-CS, compared to men, women tended to be older, exhibited fewer cardiovascular risk factors, and were more likely to present with de novo HF (e.g., lower prevalence of acute-on-chronic HF). Furthermore, women were less likely to present with a severely depressed LVEF or with renal dysfunction, resulting in a decreased requirement for dialysis. Nevertheless, use of treatments was comparable between women and men, and even after adjusting for relevant confounders, women and men faced similarly high mortality risk.

Sex-related differences in clinical presentation in HF-CS

Recent research findings indicate that a substantial proportion of patients with CS may be attributed to HF, independent of AMI as the underlying etiology, with a short-term mortality of around 50% [4,5,6,7,8, 24,25,26]. The heterogeneity of the underlying pathology in HF-CS poses significant clinical challenges in terms of risk-stratifying patients and tailoring CS treatments [14, 15]. Among the various factors that could contribute to this heterogeneity, sex potentially may be a significant factor in patients with HF-CS and thus was further investigated in this study.

In this context, we observed that sex influenced demographics and clinical presentation in patients with HF-CS. Specifically, women tended to be older than men and had a lower prevalence of typical cardiovascular risk factors such as diabetes and hypertension, as well as cardiac comorbidities like atrial fibrillation and renal dysfunction. As known from studies in chronic heart failure, female patients were less frequently treated with guideline-directed medical therapy [27]. Furthermore, our results indicated that women with HF-CS were less likely to present with a severely depressed LVEF, were more likely to present with de novo as compared to acute-on-chronic HF-CS, and were less likely to have had prior hospitalizations due to HF-CS. Although direct comparisons are limited, these findings contrast prior observations in patients with AMI-CS. These suggested that women had a worse cardiovascular risk profile compared to men, but consistently demonstrated an association between female sex and advanced age in CS [17, 18, 28, 29].

Overall, the observation that women are more likely to present with a higher LVEF, without prevalent HF, and with fewer comorbidities suggests the presence of different disease mechanisms in women vs. men presenting with HF-CS. Consequently, this might then also be translated into different treatment algorithms for women vs. men, e.g., introducing sex-tailored treatment strategies to the field of CS.

Sex-related differences in shock severity and end-organ failure in HF-CS

Evaluation of several parameters of CS severity, including SCAI CS risk class, indicated comparable clinical profiles between women and men presenting with HF-CS. However, previous research has highlighted the importance of short-term lactate kinetics as a prognostic indicator and a marker for end-organ failure in CS [30]. In our study, we observed a slightly faster clearance of serum lactate in women within the first few days after presentation, with a persistent trend over subsequent days. Additionally, we observed a significantly shorter duration of renal dysfunction in women compared to men over time, potentially indicating less subclinical end-organ damage. These findings suggest that women with HF-CS, although initially presenting with comparable CS severity, may have inherent physiological advantages that enable them to achieve quicker recovery from shock onset. This could be attributed to the higher rate of de novo HF-CS in women, e.g., lesser (sub-)clinical end-organ damage due to pre-existing HF, but also to their lower comorbidity burden [22]. Moreover, the role of systemic inflammation in patients with HF-CS, as well as their intersexual differences, is currently unclear and warrants further investigation [31]. Although further research is needed to elucidate the exact underlying mechanisms and to confirm these data, our observations might be used as a first step towards sex-tailored treatment strategies.

Sex-related differences in treatments of HF-CS

Currently, there is limited evidence for the tailored use of inotropics, vasopressors, MCS, and cause-specific therapeutic interventions in the management of HF-CS. The use of catecholamines in the treatment of CS remains the subject of debate, although there is a growing consensus on their short-term administration to stabilize patients for further therapeutic strategies [32,33,34]. It is noteworthy that most randomized controlled trials excluded patients with HF-CS (without AMI-CS), leading to a dearth of evidence-based therapeutic approaches [35,36,37]. The potential role of MCS devices to stabilize hemodynamic aberrations and bridge to native heart recovery is a promising option, supported by findings of a prior propensity-matched analysis from our registry [21]. However, the presence of complications with MCS remains a noteworthy concern [4, 21, 38,39,40,41,42].

In this study, we observed that vasopressors were administered to over 86% of the patients with HF-CS. Interestingly, despite limited evidence on the use of MCS in HF-CS, 39% of the patients in our cohort required MCS during their hospitalization. Importantly, there was no association between sex and the use of treatment modalities such as vasopressors, mechanical ventilation, and MCS. While we observed that women received slightly more ECMO therapy compared to men in this study, the utilization of MCS, including various MCS devices, was similar after adjusting for relevant confounders in women and men with HF-CS. These results contrast with previous studies in AMI-CS, where women were less likely to undergo MCS therapy [16, 18, 43, 44].

As indicated above, differences in clinical presentation in women vs. men (e.g., fewer comorbidities, lower rates of preexisting HF, and better LVEF) indicate sex-specific peculiarities in the pathomechanisms of CS. Most importantly, the higher LVEF observed in women suggests that they might respond differently to therapies targeting ventricular function. MCS, which specifically addresses this issue by providing cardiac output support until native heart recovery or durable replacement therapy, may be less effective in this subgroup, where depressed LVEF might not be the main problem. This suggests a more restrictive use of MCS in women with HF-CS, especially as the risk of MCS-related complications is similar, if not higher, in women vs. men. In addition, there are difficulties with regard to MCS access due to smaller vessels in women. Access size improvements are urgently needed to bridge the sex gap and allow women equal opportunities to benefit from these technologies while minimizing vascular complications. Ultimately, the decision to initiate MCS should be based on a comprehensive assessment of each patient’s clinical condition and hemodynamic profile, but most likely should also include the patients sex and the expected response to MCS use [45, 46].

Association between sex and 30-day all-cause mortality

In this study, despite women presenting with fewer cardiovascular risk factors, lesser comorbidities, a lower prevalence of pre-existing HF, better renal function, and higher LVEF as compared to men, 30-day all-cause mortality rate was comparable in women vs. men. Previous studies have indicated higher mortality rates among women compared to men in the context of CS and have often been attributed to factors such as older age, a greater burden of comorbidities, and a lower likelihood of early revascularization and MCS use. However, in this study, although they were more likely to be older, women tended to have less cardiovascular risk factors and comorbidities, and use of treatments was comparable in women vs. men, which might explain the lack of a sex-specific mortality risk. Also, previous studies on CS were mainly conducted in patients with AMI as the underlying etiology, and differences in pathomechanisms between AMI and HF as the cause of CS might contribute to explain the differences in mortality risks. Ultimately, based on the prior observation of differences in clinical presentation between women and men with HF-CS, it is tempting to speculate if the “true” mortality risk of women presenting with HF-CS might be even lower than in men if sex-specific treatment strategies had been used. Severe vascular complications, with subsequent interventions due to access-site-related ischemia or bleeding, may occur more frequently in women due to smaller vessel size. Access options for modern MCS devices, especially the still large ECMO cannulas, should be adapted and urgently improved to address anatomical differences in women, aiming to further enhance the risk–benefit ratio in women with HF-CS.

Limitations

The data used in this study were non-randomized, preventing us from establishing causal relationships between risk predictors and outcomes. Additionally, the assessment of patient characteristics may have been influenced by subjective judgments, particularly in challenging clinical environments such as intensive care units, emergency departments, or catheterization laboratories. Furthermore, this cohort did not collect invasive hemodynamic parameters, which could have provided additional insights and verification of sex-related differences. Although data were gathered from different hospitals in various countries, it is important to note that these hospitals were large tertiary care centers with significant experience in managing CS and utilizing MCS. This may have resulted in a higher use of MCS and a higher prevalence of severe CS in the cohort. It should be acknowledged that the use of MCS is a selective process, often favoring patients with higher physiological reserve. As a result, the generalizability of these findings may be limited, and there is a pressing need for randomized controlled trials specifically focusing on patients with HF-CS.

Another crucial aspect to consider is the potential for selective “healthiness” among women within the context of this study. It is conceivable that women with comparable comorbidities and preexisting HF might not be identified as HF-CS patients or included in the study’s registry. This potential for selection bias may contribute to the observed disparities in clinical characteristics and outcomes between sex.

Clinical implications

These findings suggest that healthcare providers should be aware of potential differences in clinical presentation and comorbidities between women and men with HF-CS. The higher LVEF, lower rates of preexisting heart failure, fewer comorbidities, and lower incidence of renal failure as well as faster lactate clearance observed in women with HF-CS indicate that they may follow a distinct trajectory and may benefit from tailored management strategies to optimize outcomes. One potential approach could be to adopt a more restrictive utilization of MCS in women. Given their higher inherent potential for stabilization, a less liberal MCS strategy may be considered.

Importantly, despite these disparities, both female and male patients with HF-CS face similar high mortality risks, emphasizing the need for adequate interventions to improve outcomes for all patients with this critically ill population. Further research is warranted to better understand the underlying mechanisms contributing to develop targeted interventions and sex-tailored treatment strategies that address the unique needs of female and male patients with HF-CS.