We read with great interest the study by Tang et al,¹ published in this issue of Polish Archives of Internal Medicine, which assessed sex differences in cardiovascular diseases (CVDs) among patients with acute pancreatitis (AP) during long‑term follow‑up.

The relationships between AP and CVD, such as acute myocardial infarction or stroke, are not fully understood.² AP is an acute inflammatory process that affects the pancreatic parenchyma, with involvement of the surrounding regional tissues as well as distant organ systems in severe forms of the disease. The pathophysiological mechanism of the disease begins with inappropriate activation of trypsinogen that destroys secretory cells, leading to the systemic release of cytokines and inflammatory mediators and causing activation of inflammatory cells, fever, and multiorgan insufficiency. Extrapancreatic manifestations of the disease include systemic inflammatory response syndrome (SIRS), which leads to systemic multiorgan failure or exacerbation of a serious pre‑existing (most often cardiovascular) disease associated with AP.^3-5

Some studies have shown that AP is associated with an increased risk of CVD, but their interrelation remains insufficiently clarified. For example, CVD is associated with an increased risk of AP,⁶ but AP is also associated with cardiac injury and an increased risk of atherosclerotic CVD, making it sometimes unclear which is the cause and which is the consequence in this relationship.^6-9 Also, those few studies reporting that patients with AP have a higher risk of cardiovascular or cerebrovascular diseases (such as acute myocardial infarction and stroke) than individuals without AP were mostly heterogeneous studies, with significant limitations due to small sample size,⁷ inadequate control of confounding factors,^{2 6-9} or insufficiently elucidated impact of AP as the risk factor for acute atherosclerotic CVD.^2,10

Nevertheless, despite some disagreements, recent studies have shown an association between AP and an increased risk of acute atherosclerotic CVD and acute coronary syndrome. Given the possibility of a mutual relationship between AP and CVD, health care professionals should be aware of the potential correlation between these conditions to take preventive measures against complications.^1,2,6,11 However, it is not fully understood whether the risk depends on the sex of the patient and whether it varies between men and women. Sex differences in both normal and diseased exocrine pancreas are evident and should be considered in clinical and basic studies. Research on sex differences in pancreatic disease has mainly focused on etiology, clinical symptoms, effects of circulating sex hormones on the disease outcome, and effects of sex hormone derivatives on treatment of pancreatic disease. However, there are very few clinical and basic studies that have examined the mechanisms and outcomes of this disease, and have analyzed patient sex as an independent variable (side by side).¹²

Tang et al¹ conducted a large‑scale, population‑based prospective cohort study (enrolling 1371 participants with AP), which analyzed patient outcomes over an extended period since AP onset, and showed that men have a significantly increased risk of major CVD in comparison with women. The authors declared (and we confirmed this by examining the available scientific databases) that, to their knowledge, this is the first study to report the long‑term cardiovascular outcomes of patients with AP adjusted for sex. The authors presented findings that were consistent in a sensitivity analysis, which was limited to participants with AP, and showed a poorer prognosis in men with this disease. Their study highlights the need to improve current management strategies for patients with AP by taking into account their sex.

In the discussion section, the authors reported that the limitations of their study included a lack of information on the etiology and severity of AP, as well as data on the potential presence of abnormal glucose metabolism that could lead to development of type 3c diabetes. The authors also noted that they were unable to obtain information about comorbidities of the AP patients and, therefore, could not assess the influence of other diseases, such as CVD, chronic obstructive pulmonary disease, or peripheral arterial disease that could influence the relationship between AP and CVD.¹

We believe that the authors satisfactorily compensated for the issue of monitoring abnormal glucose metabolism and diabetes (in multivariate models that adjusted for baseline diabetes). However, the other 2 limitations undoubtedly reduce the significance of the study results. According to the revised Atlanta classification, AP is categorized into 3 levels of severity: mild, moderately severe, and severe, depending on organ failure and local as well as systemic complications.¹³ Severe forms of AP have a bimodal temporal distribution of complications: early complications are a consequence of SIRS, which leads to multisystem failure (frequently involving the cardiovascular and cerebrovascular systems), while late complications are caused by superinfection of pancreatic and peripancreatic necrosis, leading to sepsis and late multiorgan failure (which often involve the cardiovascular and / or cerebrovascular systems). In contrast, mild and moderately severe forms of the disease typically have a mild clinical course with almost no significant complications (regardless of sex). Likewise, the percentage of (especially early) complications of AP is much higher in patients with comorbidities than in individuals without comorbidities. Given that both of these limitations (severity of AP and patient comorbidities) have a confounding effect on the study design, they to some extent relativize the obtained results that showed a significant influence of sex distribution on cardiovascular complications in AP.^3,4,14,15

However, despite the aforementioned limitations, this is a valuable study that highlights significant sex differences in cardiovascular outcomes in patients with AP, providing useful information for both science and clinical practice, and certainly deserving publication in a reputable journal. As the authors stated, future research, preferably randomized trials or prospective collaborative studies, is required to increase understanding of the underlying mechanisms driving these sex differences and to develop targeted interventions.