Chronic thromboembolic pulmonary hypertension (CTEPH) is a chronic disease occurring as a possible complication after pulmonary embolism. There are several entities of pulmonary hypertension (PH), categorized into five groups by the World Health Organization (WHO). Of these, CTEPH is designated as WHO group 4.1 (1). In CTEPH, unresolved thromboembolic material leads to the occlusion of pulmonary arteries and progressive pulmonary vascular remodeling resulting in elevated pressure and resistance in the pulmonary vascular bed (2). As a consequence, patients are initially experiencing rather unspecific symptoms like progressive dyspnea on exertion and fatigue as well as syncope and signs of right heart failure in advanced disease (3). With pulmonary endarterectomy (PEA) as surgical treatment, CTEPH became a potentially curable disease for operable patients. The 3-year survival rate increased from estimated 40–90% in patients who underwent surgery. While the majority of operable patients can be cured or achieve functional improvement, residual or recurrent CTEPH might be present (4, 5). Further on, about one half of patients with CTEPH is considered inoperable and therefore receiving lifelong medical treatment and interventional therapy if possible (6, 7). Despite improvements in treatment and increased life expectancy, quality of life is impaired in comparison to the general population (8, 9), and concomitant mental disorders have shown to be associated with impaired physical health (10). Taking these results into account, other factors, increasing the risk of impaired quality of life, physical health and developing mental disorders, are of scientific interest. One of the factors potentially associated with disease coping and QoL is child maltreatment, which is associated with a various number of negative outcomes in adulthood. Child maltreatment is defined as abuse and neglect experienced by children through their parents or other caretakers potentially causing them harm. It is divided into five subtypes of sexual abuse, physical abuse, and neglect as well as emotional abuse and neglect (11). Global prevalence rates for subtypes of child maltreatment are being reported as 12.7% for sexual abuse, 22.6% for physical abuse, 36.3% for emotional abuse, 16.3% for physical neglect, and 18.4% for emotional neglect (12) as well as about one third of a German representative population sample experiencing at least one type of child maltreatment (13). The impact of child maltreatment on developing mental health issues was considered by various studies. Experiencing one or multiple types of child maltreatment is associated with a higher risk for developing depression (14–16), anxiety and eating disorders (14) as well as personality disorders (17–19). In particular, the association between borderline personality disorder and childhood maltreatment is reported in current literature (20), for instance the earlier onset of the disorder in adults who experienced maltreatment through childhood in comparison to those who did not report maltreatment experiences (21). Furthermore, Marchetti et al. (22) were able to identify two personality profiles mediating the association between childhood maltreatment and borderline personality disorder. With one profile being characterized by a high tendency of self-criticism and the other of self-criticism in combination with dependency, they were able to suggest therapy addressing the specific traits, for example cognitive behavioral therapy, compassion focused therapy and schema therapy. Different forms of general health risk factors were found to be associated as well. Experiencing child maltreatment increases the risk for obesity, smoking, and risky sexual behavior (14, 23, 24) as well as alcohol abuse (16). While all of the subtypes are associated with negative health outcomes, a dose-response relationship was shown in more severe health outcomes through co-occurrence of different subtypes (15, 18, 23, 25). In addition to the aforementioned impacted factors, child maltreatment increases the risk of developing physical health issues. The experience of child maltreatment is associated with a higher risk of developing type 2 diabetes (26) with its association being partly mediated by obesity, smoking and high blood pressure (27, 28). It is related with a higher risk of developing chronic obstructive pulmonary disease (COPD) as well (26, 29) and with respiratory diseases in general (30, 31). Furthermore, a higher risk of developing cardiovascular disease is described (32) with higher risk of heart failure (25) and mortality in general (33). Decreased quality of life, higher ratings for anxiety and depression, and a lower cardiac function were found in patients with congenital heart disease who had experienced child maltreatment (34). To the best of our knowledge, this is the first study assessing child maltreatment in patients with CTEPH and the association of its intensity with measures of CTEPH severity, mental well-being and quality of life. Additionally, we assessed the prevalence of child maltreatment using the Childhood Trauma Questionnaire (CTQ) and compared it with the prevalence of the general German population.

This cross-sectional observational study enrolled patients diagnosed with CTEPH in two German pulmonary hypertension referral centers (Hannover Medical School and University of Gießen and Marburg). Local institutional boards (Nr. 8540_BO_K_2019 for Hannover and Nr. 21119 for Giessen and Marburg) approved the study. Inclusion criteria were a diagnosis of CTEPH (WHO Group 4.1) (1, 35), age ≥ 18 years, and mental as well as physical capability of completing all questionnaires in German. Participants were excluded if they did not answer all questionnaires. A current or lifetime psychiatric diagnosis was not considered an exclusion criterium. Four hundred and ninety-three patients (309 from Hannover, 184 from Gießen) were contacted by mail after being identified for meeting the criteria from the databases of both referral centers. Recruitment took place from December 2019 until May 2021. One hundred and seven participants were recruited. All participants provided written informed consent (see Figure 1). The results presented here are part of a larger examining psychosocial factors in patients with CTEPH. We here focused on adverse childhood experiences and its impact on mental well-being and healthy lifestyle.

In this study, we investigated the prevalence of childhood maltreatment and its association with mental well-being, quality of life, and physical health in patients with CTEPH. More than half of the patients with CTEPH had experienced at least one subtype of childhood maltreatment with physical neglect being the most frequent subtype followed by emotional neglect and emotional abuse. While the prevalence of sexual abuse and physical neglect did not differ from prevalence rates in the general German population, the prevalence of emotional abuse, emotional neglect, and physical abuse were higher in patients with CTEPH. The relatively high rates of different kinds of childhood maltreatment in CTEPH could possibly be explained by changing parenting patterns during past decades. Parenting behavior, which is now considered abusive, was considered acceptable earlier on (47). Our patients had a mean age of 65 years, were born during the 1950s and educated by parents who themselves were survivors of the second world war. Being traumatized after experiencing a war was described to contribute to the next generations' childhood trauma (48, 49). In addition to that, parenting behavior was associated with being passed on from one generation to the other referred to as intergenerational transmission, increasing the likelihood of experiencing childhood maltreatment from former maltreated parents (47). Therefore, the experienced parental trauma and the parenting behavior based on old standards may have contributed to the higher prevalence rates of child maltreatment in this cohort. The high but not significantly different prevalence of physical neglect is reported to be especially apparent in the older German population due to growing up after the Second World War and suffering from privation (50).

Overall childhood maltreatment had a negative impact on general and physical QoL and was positively associated with anxiety symptoms. Furthermore, the subtypes emotional neglect and physical neglect were positively associated with anxiety symptoms as well. Emotional abuse and sexual abuse had a negative impact on overall QoL. Emotional neglect, physical neglect, and sexual abuse had a negative impact on physical QoL. A relationship between child maltreatment and the degree of physical impairment could not be identified.

The reported negative association between childhood maltreatment and overall and physical QoL is in line with other studies (51–53). Mechanistically, it has been suggested that child maltreatment leads to biological and behavioral maladaptation, which interfere with the development of necessary skills to cope with obstacles later in life (54). The behavioral changes are associated with the development of maladaptive schemas in reaction to child maltreatment (55, 56). These schemas are hypothesized to negatively impact the way of dealing with wearing situations in adulthood, with little or no improvement over time (57). In addition to the maladaptive schemas, childhood maltreatment is characterized as increasing the risk of the disrupted ability to recognize and verbalize one's emotions, called alexithymia, increasing the risk of psychopathology (19, 58, 59). Furthermore, emotional dysregulation in general is associated with the experience of childhood maltreatment (60, 61) affecting the psychological well-being negatively by maladaptive coping with obstacles (62). The latter is explained with the need of a primary caretaker as role model in order to learn adequate emotion regulation and problem oriented coping strategies, which children, who experience childhood maltreatment, most likely do not have (63). In contrast maltreatment increases the probability of learning emotional coping strategies through the maltreating caretaker, characterized as avoidance of stressful situations as well as the suppression of emotions in general and the expression of negative emotions already during childhood and adolescence (61, 64) and later in adulthood with increased risk of engaging in substance use (65). The possible presence of maladaptive schemas, the lack of functional coping strategies with stressful events and the resulting impact on self-esteem and interaction might be responsible for the negative association between childhood maltreatment and QoL (54, 55). The association between child maltreatment and anxiety symptoms in this cohort is supported by previous research (14, 34, 66, 67). The likelihood of developing anxiety after experiencing child maltreatment might be explained through an altered stress response. Changes in stress related systems [e.g., hypothalamus-pituitary-adrenal (HPA) axis, autonomic nervous system, serotonin transporter gene] tend to increase the anxiety sensitivity (68, 69). As CTEPH is a potentially life-threatening disease and debilitating symptoms as dyspnea are present, the increased anxiety sensitivity might be considered as a reason for the associations found in this study.

We did not find an association between child maltreatment of any kind and depressive symptoms as well as with other health risk factors such as BMI, smoking, low exercise and alcohol consumption. The result contrasts with the high prevalence rates of maltreatment found in this cohort and the strong association described between the aforementioned factors and child maltreatment in other cohorts (14, 16, 23, 54, 70). Additionally, we did not find an association between physical abuse and QoL, which is in contrast to other studies pointing out the influence of physical abuse on QoL (54). The lacking associations might be explained by the low number of participants in our study, masking the effects of childhood maltreatment on psychological and behavioral factors. A further possible explanation could be resilience as it was reported to lower the risk of developing depression after the experience of child maltreatment (71). Resilience is defined as adaptation to adverse experiences, showing at least average functioning in various domains and an absence of pathology (72). It is viewed as a dynamic process which therefore does not exclude the possibility of functioning in some domains while not in others (73). The absence of the association with common health risk factors and depressive symptoms in this study might be explainable by enough protective factors within the participants to cope in a functional way with the experienced trauma instead of engaging in maladaptive behavior as smoking, low exercise, and alcohol consumption. Further investigation on the effect of childhood maltreatment and resilience simultaneously might help to further elucidate the mechanism between resilience on the one hand and maladaptation on the other hand.

Moreover, the absence of a direct impact of child maltreatment on the severity of CTEPH might be explainable with resilience as well as the underlying mechanisms and risk factors for developing CTEPH. Wegman and Stetler (31) described the association of child maltreatment with cardiovascular and respiratory diseases with a greater risk to engage in health risking behavior as smoking and consuming alcohol. Other studies described this mediating effect as well (25, 26) which could be missing in this cohort due to the lack of association between childhood maltreatment and the aforementioned health risk behaviors. Another reason for the missing impact of childhood maltreatment on CTEPH severity might refer to the dose-response relationship. Studies who investigated on the mental and physical health outcome of participants who experienced child maltreatment reported an increased risk especially in association with the co-occurrence of different subtypes (15, 23, 25, 26). In contrast to that, more than half of the participants who reported child maltreatment in this study, had experienced not more than one subtype, and less than one third had experienced three or more subtypes. Further studies with a larger sample might be needed to further investigate on the relationship between child maltreatment and severity of CTEPH.

In comparison to the general German population, three out of five maltreatment subtypes were present with higher prevalence in our CTEPH cohort. This implies the question whether childhood maltreatment might be associated with the development of CTEPH later in life. A possible link between childhood maltreatment and thromboembolic events might be seen via alterations of the inflammatory response. In fact, inflammation is linked to the development of CTEPH besides other risk factors such as acute pulmonary embolism, medical interventions (e.g., splenectomy and ventriculoarterial shunt) and plasmatic factors (74). Inflammatory markers like the C-reactive protein (CRP) were shown to be increased in comparison to healthy controls (75). As CRP was found to be associated with childhood trauma as well (76), changes in the inflammatory response could mediate the effect between child maltreatment and developing CTEPH. Molecular changes in maltreated individuals are associated with epigenetic changes in response to the experienced trauma. Alterations in DNA methylation are associated with altered gene expression, influencing for example the stress response and inflammatory processes (77, 78). Further studies on the mediating effect of epigenetic alterations due to child maltreatment associating it with CTEPH patients may be needed to clarify the exact relationship.

Regarding the conception of this study, limitations have to be acknowledged. Child maltreatment was assessed with the CTQ, which is based on self-report and retrospection making a recall bias possible (13, 79). Furthermore, out of the contacted CTEPH patients, only 22% responded and were included into the assessment. Hence, the sample size was low in comparison to other studies focusing on the consequences of childhood maltreatment [e.g., (25, 33)]. One contributor to the low response rate may have been the higher age of our patient population compared to other studies. Furthermore, the motivation to participate might have been limited as many of the patients were no longer followed at their PH center (especially those who had undergone successful PEA surgery). In addition, the questionnaires had been sent out without personal advance notice from their PH physicians.

In conclusion, more than half of our patients with CTEPH had experienced at least one type of child maltreatment. A history of child maltreatment had a negative impact on QoL and was associated with anxiety symptoms. In order to improve the treatment of patients with CTEPH, the presence of experienced childhood maltreatment should be considered. Further studies are needed to assess tools that may help patients to cope better with the consequences of CTEPH.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Ethics Committee, Hannover Medical School, Hannover Germany and Ethics Committee, University Medical Center Gießen und Marburg, Marburg, Germany. The patients/participants provided their written informed consent to participate in this study.

NL, JF, MH, KK, KO, and M-RD were responsible for study design, implementation of the study, statistical analysis, data interpretation, and drafting the manuscript. NL and M-RD were responsible for conducting the interviews. NL, JF, and M-RD did data collection. JK, MR, and HGa implementation of the study. IH, D-HP, HGh, DE, JK, MR, HGa, TM, and H-DK were responsible for study design, data interpretation, and revising the manuscript. All authors contributed to the article and approved the submitted version.

This work was funded by the German Center for Lung Research (DZL).

MH has received honoraria for lectures and/or consultations from Acceleron, Actelion, Bayer, GSK, Janssen, MSD and Pfizer, and all outside the present study. D-HP has received honoraria for lectures and/or consultationsf rom Janssen. HGa has received personal fees from Actelion, personal fees from AstraZeneca, personal fees from Bayer, personal fees from BMS, personal fees from GSK, personal fees from Janssen-Cilag, personal fees from Lilly, personal fees from MSD, personal fees from Novartis, personal fees from OMT, personal fees from Pfizer, personal fees from United Therapeutics, outside the submitted work. HGh has received fees from Actelion, Bayer, Gilead, GSK, MSD, Pfizer and United Therapeutics, outside the present work. KK has received honoraria forconsultations and/or lectures from Eli Lilly, Janssen, Lundbeck, Neuraxpharm, Otsuka, Pfizer, Servier, Schwabe, Takeda and Trommsdorff/Ferrer, Alexion, and CannaXan (advisory board). KO has received honoraria for lectures and/or consultations from Acceleron, Actelion, Bayer, GSK, Janssen, MSD, United Therapeutics and Pfizer, and all outside the present study. H-DK was employed by Pulmonale Hypertonie eV. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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