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Aims: Improved long-term survival has widened the treatment goals for adults with congenital heart disease (ACHD) by addressing parameters that impact mental well-being and exercise capacity. Depression, a frequent co-morbidity in ACHD, is linked to both. Whether successful treatment of depression also affects cardiac parameters is a matter of debate. Methods: This prospective, cross-sectional, longitudinal study included N = 150 ACHD (mean age 35.2 ± 11.3 years, 57% male) at baseline (t0) and N = 114 at follow-up (mean follow-up: 4.8 ± 0.6 years; t1). Patients were interviewed using a structured clinical interview, and severity of depression was assessed using the Montgomery-Asperg Depression Scale (MADRS). Additional testing was performed using self-rating questionnaires concerning depression, anxiety and quality of life (QoL). Exercise capacity (VO2max) was assessed by symptom limited exercise testing. Results: Of N = 33 patients diagnosed with depression at t0, N = 18 patients remitted and N = 15 were non-remitters. Remitters displayed significantly decreased anxiety (P = 0.013), improved global QoL (P = 0.002), and preserved VO2max (P = 0.958) at t1 compared to t0. This was associated with favourable health behaviour at t1 and stable body-mass-index. Contrarily, non-remitters reported further increased anxiety (P = 0.021) and no significant improvement in QoL (P = 0.405). VO2max declined significantly (P = 0.006) and body-mass-index increased (P = 0.004). Never-depressed patients showed no significant changes in anxiety (P = 0.415) or QoL (P = 0.211). VO2max decreased significantly (P < 0.001). Conclusion: In ACHD, remission from depression is associated with better physical functioning, mental health, and QoL. The assessment and treatment of depression in ACHD emerges as an important clinical goal that should be included in a comprehensive multimodal treatment plan.
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AIMS: Adults with congenital heart disease (ACHD) constitute an ever-growing patient population characterized by high risks for cardiovascular- and mental disorders. Personality disorders (PDs) are associated with adverse physical and mental health. Studies assessing PD prevalence in ACHD are lacking. METHODS AND RESULTS: Personality disorder point prevalence was assessed in 210 ACHD by Structured Clinical Interview for Axis-II Personality Disorders (SCID-II) and compared to meta-analytical data from the general population (GP). Depression and anxiety were measured by self-report (Hospital Anxiety and Depression Scale, HADS) and clinician rating (Montgomery-Åsberg depression rating scale, MADRS). Childhood maltreatment was assessed with the Childhood Trauma Questionnaire and quality-of-life (QOL) with the World Health Organization QOL Scale. PD prevalence was markedly higher in ACHD compared to GP (28.1 vs. 7.7%). Particularly borderline (4.8 vs. 0.9%) and cluster C (i.e. anxious or fearful; 17.1 vs. 3.0%) PDs were overrepresented. PD diagnosis was associated with a surgery age ≤12 years (χ²(1) = 7.861, Ï = 0.195, P = 0.005) and higher childhood trauma levels (U = 2583.5, Z = -3.585, P < 0.001). ACHD with PD reported higher anxiety (HADS-A: U = 2116.0, Z = -5.723, P < 0.001) and depression (HADS-D: U = 2254.5, Z = -5.392, P < 0.001; MADRS: U = 2645.0, Z = -4.554, P < 0.001) levels and lower QOL (U = 2538.5, Z = -4.723, P < 0.001). CONCLUSION: Personality disorders, particularly borderline- and cluster C, are significantly more frequent in ACHD compared to GP and associated with depression, anxiety, and decreased QOL. Data from the GP suggest an association with adverse cardiometabolic and mental health. To ensure guideline-based treatment, clinicians should be aware of the increased PD risk in ACHD.
Adults with congenital heart disease (ACHD) constitute an ever-growing patient population characterized by an increased cardiovascular disease risk. Personality disorders (PDs) are associated with adverse mental and physical, in particular cardiovascular, health in the general population (GP). Studies assessing PD prevalence in ACHD have been lacking to date.Personality disorders, particularly borderline PD and cluster C (anxious or fearful) PDs, are highly prevalent in ACHD.Personality disorders are associated with heightened levels of anxiety and depression and decreased quality of life in ACHD.Heart surgery before puberty and increased levels of childhood maltreatment are associated with PD diagnosis.
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Cardiopatías Congénitas , Trastornos de la Personalidad , Calidad de Vida , Humanos , Trastornos de la Personalidad/epidemiología , Trastornos de la Personalidad/psicología , Trastornos de la Personalidad/diagnóstico , Femenino , Masculino , Adulto , Cardiopatías Congénitas/epidemiología , Cardiopatías Congénitas/psicología , Prevalencia , Factores de Riesgo , Persona de Mediana Edad , Ansiedad/epidemiología , Ansiedad/diagnóstico , Ansiedad/psicología , Adulto Joven , Depresión/epidemiología , Depresión/diagnóstico , Depresión/psicología , Salud Mental , Escalas de Valoración PsiquiátricaRESUMEN
Objective: Adult congenital heart disease (ACHD) is a growing disease entity, posing questions concerning psychosocial outcomes across the lifespan. Spousal relationships were shown to benefit cardiovascular and mental health in the general population. We assessed the association of relationship status with anxiety and depression in ACHD patients and determined whether patients considered disease-related concerns potential mediators of relationship problems. Methods: N = 390 ACHD patients were included. Self-report questionnaires were used to assess relationship status, ACHD-related relationship problems, socio-demographic variables, and depression and anxiety scores. Further, clinical parameters concerning the heart condition were determined. Results: N = 278 (71%) patients were currently in a relationship, while N = 112 (29%) were not in a relationship. Groups did not significantly differ regarding age, sex, and cardiovascular parameters. Two-way MANCOVA with relationship status and sex as independent variables, controlling for age, NYHA class, and NT-proBNP, showed an association of relationship status with depression, while sex was associated with anxiety. N = 97 (25%) patients reported disease-related adverse effects on a current or prior relationship. In detail, worries about body image (N = 57, 61%), own fears (N = 51, 54%), problems arising from wish to have children (N = 33, 35%), fears regarding a joint future (N = 29, 31%), partner's fears or lack of understanding (N = 28, 30%), and sexual problems (N = 21, 22%) were cited. Conclusion: Relationships status was associated with depression, while sex was associated with anxiety in ACHD patients. Relationship status as well as potential relationship problems, and the importance of social support for mental and physical well-being, should be considered when treating ACHD patients.
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Enfermedades Cardiovasculares , Diabetes Mellitus , Humanos , Soledad/psicología , Corazón , Factores de RiesgoRESUMEN
BACKGROUND: Unipolar major depressive disorder (MDD) and bipolar disorder (BD) are associated with elevated mortality risk secondary to natural causes. Cardiovascular disease (CVD) constitutes the most prevalent underlying condition. Patients with BD display higher CVD-associated excess mortality than MDD patients. Epicardial adipose tissue (EAT) volume, a known predictor of premature CV morbidity and adrenal gland (AG) volume, an indicator for chronic hypothalamus-pituitary-adrenal (HPA) axis activation, were compared in BD and MDD patients. METHODS: Magnetic resonance imaging was performed to assess EAT and AG volume in age-, gender-, and body mass index (BMI)-matched MDD (N = 27) and BD (N = 27) patients. Ten-year CV mortality risk and diabetes risk were assessed by PROCAM, ESC-SCORE, and FINDRISK, respectively; metabolic syndrome (MetS) was determined following NCEP/ATP III criteria. RESULTS: Cardiometabolic risk scores and frequency of MetS were comparable, and scores of cardiometabolic risk indices did not significantly differ in both groups. After adjustment for age, BMI, and physical activity, EAT and AG volumes were significantly higher in BD compared to MDD. Partial correlation analyses showed a significant positive association of EAT and AG volumes in BD but not in the MDD. LIMITATIONS: The modest sample size warrants confirmation in a larger cohort and the cross-sectional design does not allow for temporal or causal inferences. CONCLUSION: Our study indicates increased EAT accumulation in BD patients. This was associated with HPA axis dysregulation. Therapeutic lifestyle interventions that reduce EAT volume should be considered in clinical BD management.
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Trastorno Bipolar , Enfermedades Cardiovasculares , Trastorno Depresivo Mayor , Síndrome Metabólico , Humanos , Trastorno Bipolar/complicaciones , Trastorno Depresivo Mayor/complicaciones , Sistema Hipotálamo-Hipofisario/metabolismo , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/complicaciones , Estudios Transversales , Factores de Riesgo , Sistema Hipófiso-Suprarrenal/metabolismo , Síndrome Metabólico/complicaciones , Factores de Riesgo de Enfermedad CardiacaRESUMEN
Objective: Major depressive disorder (MDD) constitutes a main risk factor for suicide. Suicide risk in psychiatric patients is primarily determined by often unreliable, self-reported information. We assessed serum levels of three microRNAs (miRNAs), previously demonstrated to be dysregulated in post-mortem brain samples of suicide victims, as potential peripheral biomarkers for suicidality. Methods: All study participants were diagnosed with MDD according to Diagnostic and Statistical Manual of Mental Disorders, 5th edition criteria. Suicidality, defined as acute suicide risk or suicide attempt within one week prior to study entry, was assessed by clinical interview. Relative serum levels of miR-30a, miR-30e, and miR-200a, normalized to U6, were measured by quantitative real-time PCR in MDD inpatients with (MDD/SI, N = 19) and without (MDD, N = 31) acute suicide risk. Median age and gender distribution were comparable in both groups. Results: Levels of miR-30a, miR-30e, and miR-200a were significantly elevated in MDD/SI compared to MDD. Subgroup analysis of the MDD/SI group showed that levels of miR-30e and miR-200a were significantly higher and miR-30a was increased by trend in patients admitted following a suicide attempt (N = 7) compared to patients with acute suicide risk but without recent suicide attempt (N = 12). Additionally, use of two databases for in silico transcription factor-miRNA interaction prediction indicated early growth response protein (EGR) 1 as potential transcriptional regulator for all three miRNAs. Conclusion: This study demonstrates suicide risk in MDD patients to be associated with increased levels of miR-30a, miR-30e, and miR-200a. Thus, these miRNAs might constitute potential biomarkers to predict suicidal behavior in MDD patients.
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Background and aim: Adverse childhood experiences (ACEs) are a major risk factor for unfavorable behavioral, mental and health outcomes later in life. However, the precise pathway via which ACEs convey these risks, in particular regarding health outcomes such as cardiovascular disease, remains unknown. Here, we combined psychiatric and cardiac methods to investigate the pathway via which childhood adversities may lead to adult adverse cardiovascular health, with a focus on epicardial adipose tissue (EAT) as a risk marker. Methods: 210 adult congenital heart disease outpatients (mean age 35.5 y, 43% female) completed a thorough cardiac and psychiatric evaluation. Psychiatric measurements included an expert interview, the childhood trauma questionnaire (CTQ), Beck's depression inventory II (BDI-II), quality of life and the global scale of functioning, amongst others. All patients completed a full cardiac workup including EAT assessment using echocardiography. We then computed bootstrapping mediation models using ACEs as a predictor, depression and physical activity as mediators and EAT as dependent variable in PROCESS. Results: CTQ scores had a significant indirect effect on EAT via a serial mediation of BDI and physical activity [a*b2*d = 0.0260, 95% BCa CI [0.0047, 0.0619]]. Conclusion: Using mediation analyses, we show that adverse childhood events are linked to increased depressive symptoms, which are linked to decreased physical activity, which in turn are linked to a higher amount of epicardial adipose tissue. While other pathways most certainly exist and replication is needed, this suggests a meaningful pathway via which ACEs lead to adverse cardiovascular health, with several potential targets for health interventions across time.
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Background: The prevalence of mental disorders, particularly adjustment disorder (AD), major depressive disorder (MDD) and panic disorder (PD) is increased in patients with pulmonary arterial hypertension (PAH). However, it is unclear which pathogenic mechanisms determine their development and could therefore be targeted in prevention or therapeutic interventions. Here, we assessed metacognitions in a sample of PAH patients with and without MDD and PD. Moreover, we reconstructed the course of mental illnesses following the PAH diagnosis. Methods: Two hundred seventeen PAH patients were included in this cross-sectional study. The prevalence of AD was assessed retrospectively using DSM-V criteria. Current mental disorders were assessed using the structured clinical interview for DSM-V. Additionally, metacognitive beliefs and processes were assessed using established questionnaires (MCQ-30, AnTI). Results: Patients with an AD consecutive to the PAH diagnosis more frequently developed MDD (37.5 vs. 13.9%, p < 0.001) and PD (26.3 vs. 8.8%, p = 0.001) later on compared to PAH patients without a former AD. Moreover, patients with current MDD/PD displayed more dysfunctional metacognitions than those without current MDD/PD (p < 0.001). Patients with current MDD/PD in the context of former AD had more dysfunctional metacognitive worries and beliefs compared to patients with current MDD/PD without former AD (p = 0.009). Conclusion: Our results suggest that in the context of PAH, dysfunctional metacognitions are associated with MDD and PD. Therefore, a metacognitive approach to treat and prevent those mental illnesses seems promising and should be investigated in future studies.
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Major depressive disorder (MDD) is frequently associated with poor response to treatment. Common antidepressants target neurotransmission and neuronal plasticity, which require adequate energy supply. As imaging studies indicate disturbances in central energy metabolism, and caloric restriction improves neuroplasticity and impacts mood and cognition, correction of energy status might increase the effectiveness of antidepressant treatments and reduce the psychopathological symptoms of depression. Metabolic parameters, stress hormones, and brain-derived neurotrophic factor (BDNF) levels were assessed in serum of depressed inpatients (MDD, N = 21) and healthy volunteers (Ctrl, N = 28) before and after a 72 h fasting period during which only water was consumed. Depression severity was assessed by Beck's Depression Inventory (BDI)-2 sum-score and cognitive-affective and somatic sub-scores. Fasting similarly impacted metabolic parameters and stress systems in both groups. Fasting elevated BDI-2 sum-scores and somatic sub-scores in Ctrl. In MDD, fasting increased somatic-, but decreased cognitive-affective symptoms. Sub-group analyses based on BDI-2 sum-scores pre-fasting showed that cognitive-affective symptoms decreased in patients with moderate/severe but not in those with mild symptoms. This was associated with differential changes in BDNF levels. In conclusion, fasting improved cognitive-affective sub-scores in MDD patients with moderate/severe symptoms that had not responded to prior therapy. Interventions that modulate energy metabolism might directly improve cognitive-affective symptoms and/or augment therapeutic efficacy in moderate-to-severely depressed patients.
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Trastorno Depresivo Mayor , Antidepresivos/uso terapéutico , Factor Neurotrófico Derivado del Encéfalo , Estudios Transversales , Depresión , Trastorno Depresivo Mayor/psicología , Ayuno , HumanosRESUMEN
The neurobiological and behavioral underpinnings linking mental disorders, in particular, major depressive disorder (MDD), with cardiovascular disorders are a matter of debate. Recent research focuses on visceral (intra-abdominal and epicardial) adipose tissue and inflammation and their impact on the development of cardiometabolic disorders. Intra-abdominal adipose tissue is defined as an endocrine active fat compartment surrounding inner organs and is associated with type 2 diabetes mellitus, a risk factor for the later development of cardiovascular disorders. Epicardial (pericardial) adipose tissue is a fat compartment surrounding the heart with close proximity to the arteries supporting the heart. Visceral adipose tissue (VAT) is an important source of inflammatory mediators that, in concert with other risk factors, plays a leading role in cardiovascular diseases. In conjunction with the behavioral (physical inactivity, sedentary lifestyle), psychological (adherence problems), and hormonal (dysfunction of the hypothalamus-pituitary-adrenal axis with subsequent hypercortisolism) alterations frequently accompanying MDD, an enhanced risk for cardiovascular disorders results.
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Background: Mental disorders are common among patients with severe cardiovascular diseases (CVD). Yet, there is a lack of easily accessible evidence-based treatments. Recent research indicates elevated prevalence of dysfunctional metacognitions in patients with mental disorders following cardiovascular events. As metacognitive therapy (MCT) is an established treatment to modify metacognitions, we tested if a brief metacognitive intervention via videotelephony is effective in this patient group. Methods: A brief MCT treatment was tailored to CVD patients and designed as a face-to-face internet-based intervention. Five patients with CVDs and comorbid mental disorders underwent a psychocardiological examination and diagnostic approach. Each patient participated in eight 50 min sessions via encrypted video messenger service. Metacognitions, depression and anxiety symptoms and quality of life were assessed by self-report measures pre- and post-treatment. Patients rated dysfunctional thought processes, current psychological impairment, and treatment satisfaction after each session. Intended follow-up measures were not reported due to missing data. Results: For most patients, the brief metacognitive intervention was associated with a decrease in dysfunctional metacognitions and a reduction of symptoms of anxiety and depression post-treatment. Psychological and physiological quality of life improved. Patients reported high satisfaction with the tailored treatment. Conclusion: Our results suggest that a brief internet-based metacognitive treatment may be a promising tool for patients with CVDs and comorbid mental disorders. Feasibility and acceptance of the intervention was rated high by the patients. Further research is necessary to support the preliminary findings and to adapt and evaluate the intervention in a controlled clinical trial setting.
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Patients with mental disorders have an increased risk to develop cardiovascular disease (CVD), and CVD are frequently comorbid with especially adjustment, anxiety and depressive disorders. Therefore, clinicians need to be aware of effective and safe psychological and pharmacological treatment strategies for patients with comorbid CVD and mental disorders. Cognitive behavioral therapy and third-wave of cognitive-behavioral therapy are effective for patients with CVD and mental disorders. Internet-based psychological treatments may also be considered. In more severe cases, psychopharmacological drugs are frequently used. Although generally well tolerated and efficacious, drug- and dose-dependent side effects require consideration. Among antidepressants, selective serotonin reuptake inhibitors, selective serotonin and noradrenalin reuptake inhibitors, and newer antidepressants, such as mirtazapine, bupropion, agomelatine, and vortioxetine, can be considered, while tricyclic antidepressants should be avoided due to their cardiac side effects. Mood stabilizers have been associated with arrhythmias, and some first- and second-generation antipsychotics can increase QTc and metabolic side effects, although substantial differences exist between drugs. Benzodiazepines are generally safe in patients with CVD when administered short-term, and may mitigate symptoms of acute coronary syndrome. Laboratory and ECG monitoring is always recommended in psychopharmacological drug-treated patients with CVD. Presence of a heart disease should not exclude patients from necessary interventions, but may require careful risk-benefit evaluations. Effectively and safely addressing mental disorders in patients with CVD helps to improve both conditions. Since CVD increase the risk for mental disorders and vice versa, care providers need to screen for these common comorbidities to comprehensively address the patients' needs.
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Breast cancer is the most prevalent malignancy amongst women worldwide while ovarian cancer represents the leading cause of death among gynecological malignancies. Women suffering from these cancers displayed heightened rates of major depressive disorder, and antidepressant treatment with selective serotonin reuptake inhibitors (SSRIs) is frequently recommended. Recently, narrative reviews and meta-analyses showed increased recurrence risks and mortality rates in SSRI-treated women with breast and ovarian cancer. We therefore examined whether three commonly prescribed SSRIs, fluoxetine, sertraline and citalopram, affect proliferation or glucose uptake of human breast and ovarian cancer cell lines characterized by different malignancies and metastatic potential. SSRI treatment or serotonin stimulation with therapeutically relevant concentrations over various time periods revealed no consistent dose- or time-dependent effect on proliferation rates. A marginal, but significant increase in glucose uptake was observed in SK-OV-3 ovarian cancer cells upon fluoxetine or sertraline, but not citalopram treatment. In three breast cancer cell lines and in two additional ovarian cancer cell lines no significant effect of SSRIs on glucose uptake was observed. Our data suggest that the observed increase in recurrence- and mortality rates in SSRI-treated cancer patients is unlikely to be linked to antidepressant therapies.
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Neoplasias de la Mama/metabolismo , Proliferación Celular/efectos de los fármacos , Glucosa/metabolismo , Neoplasias Ováricas/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Femenino , Humanos , Células MCF-7 , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patologíaRESUMEN
Cardiac levels of the signal transducer and activator of transcription factor-3 (STAT3) decline with age, and male but not female mice with a cardiomyocyte-specific STAT3 deficiency conditional knockout (CKO) display premature age-related heart failure associated with reduced cardiac capillary density. In the present study, isolated male and female CKO-cardiomyocytes exhibit increased prostaglandin (PG)-generating cyclooxygenase-2 (COX-2) expression. The PG-degrading hydroxyprostaglandin-dehydrogenase-15 (HPGD) expression is only reduced in male cardiomyocytes, which is associated with increased prostaglandin D2 (PGD2) secretion from isolated male but not female CKO-cardiomyocytes. Reduced HPGD expression in male cardiomyocytes derive from impaired androgen receptor (AR)-signaling due to loss of its cofactor STAT3. Elevated PGD2 secretion in males is associated with increased white adipocyte accumulation in aged male but not female hearts. Adipocyte differentiation is enhanced in isolated stem cell antigen-1 (SCA-1)+ cardiac progenitor cells (CPC) from young male CKO-mice compared with the adipocyte differentiation of male wild-type (WT)-CPC and CPC isolated from female mice. Epigenetic analysis in freshly isolated male CKO-CPC display hypermethylation in pro-angiogenic genes (Fgfr2, Epas1) and hypomethylation in the white adipocyte differentiation gene Zfp423 associated with up-regulated ZFP423 expression and a shift from endothelial to white adipocyte differentiation compared with WT-CPC. The expression of the histone-methyltransferase EZH2 is reduced in male CKO-CPC compared with male WT-CPC, whereas no differences in the EZH2 expression in female CPC were observed. Clonally expanded CPC can differentiate into endothelial cells or into adipocytes depending on the differentiation conditions. ZFP423 overexpression is sufficient to induce white adipocyte differentiation of clonal CPC. In isolated WT-CPC, PGD2 stimulation reduces the expression of EZH2, thereby up-regulating ZFP423 expression and promoting white adipocyte differentiation. The treatment of young male CKO mice with the COX inhibitor Ibuprofen or the PGD2 receptor (DP)2 receptor antagonist BAY-u 3405 in vivo increased EZH2 expression and reduced ZFP423 expression and adipocyte differentiation in CKO-CPC. Thus, cardiomyocyte STAT3 deficiency leads to age-related and sex-specific cardiac remodeling and failure in part due to sex-specific alterations in PGD2 secretion and subsequent epigenetic impairment of the differentiation potential of CPC. Causally involved is the impaired AR signaling in absence of STAT3, which reduces the expression of the PG-degrading enzyme HPGD.
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Miocitos Cardíacos/metabolismo , Prostaglandina D2/metabolismo , Factor de Transcripción STAT3/metabolismo , Adipocitos Blancos/metabolismo , Animales , Diferenciación Celular/genética , Células Cultivadas , Ciclooxigenasa 2/metabolismo , Células Endoteliales/metabolismo , Femenino , Insuficiencia Cardíaca/genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Madre Multipotentes/metabolismo , Prostaglandina D2/fisiología , Factor de Transcripción STAT3/genética , Transducción de Señal/genética , Células Madre/metabolismoRESUMEN
Peritoneal dialysis (PD) is limited by glucose-mediated peritoneal membrane (PM) fibrosis, angiogenesis, and ultrafiltration failure. Influencing PM integrity by pharmacologically targeting sodium-dependent glucose transporter (SGLT)-mediated glucose uptake has not been studied. In this study, wildtype C57Bl/6N mice were treated with high-glucose dialysate via an intraperitoneal catheter, with or without addition of selective SGLT2 inhibitor dapagliflozin. PM structural changes, ultrafiltration capacity, and peritoneal equilibration testing (PET) status for glucose, urea, and creatinine were analyzed. Expression of SGLT and facilitative glucose transporters (GLUT) was analyzed by real-time PCR, immunofluorescence, and immunohistochemistry. Peritoneal effluents were analyzed for cellular and cytokine composition. We found that peritoneal SGLT2 was expressed in mesothelial cells and in skeletal muscle. Dapagliflozin significantly reduced effluent transforming growth factor (TGF-ß) concentrations, peritoneal thickening, and fibrosis, as well as microvessel density, resulting in improved ultrafiltration, despite the fact that it did not affect development of high-glucose transporter status. In vitro, dapagliflozin reduced monocyte chemoattractant protein-1 release under high-glucose conditions in human and murine peritoneal mesothelial cells. Proinflammatory cytokine release in macrophages was reduced only when cultured in high-glucose conditions with an additional inflammatory stimulus. In summary, dapagliflozin improved structural and functional peritoneal health in the context of high-glucose PD.
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Compuestos de Bencidrilo/uso terapéutico , Soluciones para Diálisis/toxicidad , Glucosa/toxicidad , Glucósidos/uso terapéutico , Fibrosis Peritoneal/tratamiento farmacológico , Peritoneo/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Transportador 2 de Sodio-Glucosa/biosíntesis , Adolescente , Animales , Compuestos de Bencidrilo/farmacología , Línea Celular Transformada , Células Cultivadas , Femenino , Glucósidos/farmacología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Fibrosis Peritoneal/metabolismo , Fibrosis Peritoneal/patología , Peritoneo/metabolismo , Peritoneo/patología , Células RAW 264.7 , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Ultrafiltración/métodosRESUMEN
BACKGROUND: Advanced cancer induces fundamental cardiac changes and promotes body wasting and heart failure. We evaluated the impact of cancer on major cardiac signalling pathways, and resulting consequences for the heart. METHODS AND RESULTS: Metastatic melanoma disease was induced in male C57BL/6â¯N mice by intraperitoneal injection of the melanoma cell line B16F10 and lead to cardiac atrophy and heart failure. Analyses of key cardiac signalling pathways in left ventricular tissue revealed increased activation of STAT3 and reduced activation of AKT, p38 and ERK1/2. Markers of the ubiquitin proteasomal system (UPS: Atrogin-1) and of mitophagy/autophagy (LC3b, BNIP3) were upregulated. Tumour-bearing C57BL/6â¯N mice with a cardiomyocyte-specific overexpression of a constitutively active AKT transgene (AKTtg) displayed less cardiac atrophy and dysfunction and normalized Atrogin-1, LC3b and BNIP3 expression while the cardiomyocyte-specific knockout of STAT3 (CKO) had no major effect on these parameters compared to WT. CONCLUSION: Cancer alters major cardiac signalling pathways and subsequently the UPS, mitophagy and autophagy. The present study suggests that cancer-induced reduction of cardiomyocyte AKT contributes to these alterations as they were attenuated in tumour-bearing AKTtg mice. In turn, increased cardiomyocyte STAT3 activation appears less relevant, as tumour-induced impairment on the heart was largely similar in CKO and WT mice. Since oncologic therapies frequently target AKT and/or STAT3, their impact on the heart might be different in tumour-bearing mice compared to healthy mice, a feature suggesting to test tumour therapies also in tumour disease models and not only under healthy conditions. This article is part of a Special Issue entitled: Cardiomyocyte biology: new pathways of differentiation and regeneration edited by Marijke Brink, Marcus C. Schaub, and Christian Zuppinger.
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Insuficiencia Cardíaca/genética , Corazón/fisiopatología , Melanoma Experimental/genética , Proteínas Proto-Oncogénicas c-akt/genética , Factor de Transcripción STAT3/genética , Animales , Autofagia/genética , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/patología , Humanos , Melanoma Experimental/complicaciones , Melanoma Experimental/patología , Ratones , Ratones Transgénicos , Mitofagia/genética , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Complejo de la Endopetidasa Proteasomal/genética , Transducción de Señal/genética , Ubiquitina/genéticaRESUMEN
AIMS: Peripartum cardiomyopathy (PPCM) is a life-threatening heart disease occurring in previously heart-healthy women. A common pathomechanism in PPCM involves the angiostatic 16 kDa-prolactin (16 kDa-PRL) fragment, which via NF-κB-mediated up-regulation of microRNA-(miR)-146a induces vascular damage and heart failure. We analyse whether the plasminogen activator inhibitor-1 (PAI-1) is involved in the pathophysiology of PPCM. METHODS AND RESULTS: In healthy age-matched postpartum women (PP-Ctrl, n = 53, left ventricular ejection fraction, LVEF > 55%), PAI-1 plasma levels were within the normal range (21 ± 10 ng/mL), but significantly elevated (64 ± 38 ng/mL, P < 0.01) in postpartum PPCM patients at baseline (BL, n = 64, mean LVEF: 23 ± 8%). At 6-month follow-up (n = 23), PAI-1 levels decreased (36 ± 14 ng/mL, P < 0.01 vs. BL) and LVEF (49 ± 11%) improved. Increased N-terminal pro-brain natriuretic peptide and Troponin T did not correlate with PAI-1. C-reactive protein, interleukin (IL)-6 and IL-1ß did not differ between PPCM patients and PP-Ctrl. MiR-146a was 3.6-fold (P < 0.001) higher in BL-PPCM plasma compared with PP-Ctrl and correlated positively with PAI-1. In BL-PPCM serum, 16 kDa-PRL coprecipitated with PAI-1, which was associated with higher (P < 0.05) uPAR-mediated NF-κB activation in endothelial cells compared with PP-Ctrl serum. Cardiac biopsies and dermal fibroblasts from PPCM patients displayed higher PAI-1 mRNA levels (P < 0.05) than healthy controls. In PPCM mice (due to a cardiomyocyte-specific-knockout for STAT3, CKO), cardiac PAI-1 expression was higher than in postpartum wild-type controls, whereas a systemic PAI-1-knockout in CKO mice accelerated peripartum cardiac fibrosis, inflammation, heart failure, and mortality. CONCLUSION: In PPCM patients, circulating and cardiac PAI-1 expression are up-regulated. While circulating PAI-1 may add 16 kDa-PRL to induce vascular impairment via the uPAR/NF-κB/miR-146a pathway, experimental data suggest that cardiac PAI-1 expression seems to protect the PPCM heart from fibrosis. Thus, measuring circulating PAI-1 and miR-146a, together with an uPAR/NF-κB-activity assay could be developed into a specific diagnostic marker assay for PPCM, but unrestricted reduction of PAI-1 for therapy may not be advised.
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Cardiomiopatías/sangre , Periodo Periparto/sangre , Inhibidor 1 de Activador Plasminogénico/sangre , Trastornos Puerperales/sangre , Adulto , Animales , Biomarcadores/sangre , Cardiomiopatías/diagnóstico por imagen , Cardiomiopatías/fisiopatología , Estudios de Casos y Controles , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones Noqueados , Miocitos Cardíacos/metabolismo , Paridad , Inhibidor 1 de Activador Plasminogénico/genética , Embarazo , Pronóstico , Trastornos Puerperales/diagnóstico por imagen , Trastornos Puerperales/fisiopatología , Recuperación de la Función , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Volumen Sistólico , Factores de Tiempo , Regulación hacia Arriba , Función Ventricular IzquierdaRESUMEN
The dataset describes protein expression of phosphorylated and total signal transducer and activator of transcription 3 (STAT3), protein kinase B (AKT) and suppressor of cytokine signalling 3 (SOCS3) in left ventricular tissue (LV) from healthy and B16F10 melanoma tumour-bearing (B16F10-TM) wildtype (WT) mice, mice with cardiomyocyte-specific constitutively active AKT transgene (AKTtg) and mice with cardiomyocyte-restricted deletion of STAT3 (CKO) analysed in Western blot and/or fluorescence microscopy experiments. The data presented in this article are related to the research paper entitled "Modulation of cardiac AKT and STAT3 signalling in preclinical cancer models and their impact on the heart", available in Biochim. Biophys. Acta Mol. Cell Res. (1).
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Introduction: In line with the monoamine hypothesis of major depressive disorder (MDD), the clinical efficacy of the selective serotonin reuptake inhibitor fluoxetine has classically been ascribed to central serotonin enhancing properties. Current research described disturbances in brain energy metabolism in MDD. Additionally, fluoxetine showed beneficial effects in neuropsychiatric disorders associated with central energy imbalance. Areas covered: The effect of in vitro fluoxetine exposure on cellular glucose uptake and cerebral glucose transporter function was assessed in human peripheral blood mononuclear cells (PBMC) and murine neuroblastoma N2a cells. Fluoxetine augmented glucose uptake, measured by utilizing the radionuclide-labled glucose analog [18]F-fluorodeoxyglucose, in PBMC without affecting glucose transporter protein content. Analysis of protein palmitoylation using the acyl-biotinyl exchange method revealed GLUT3 to be palmitoylated in PBMC and N2a cells, while palmitoylation of GLUT1 was detected only in N2a cells. Treatment with fluoxetine significantly increased palmitoylation of GLUT3 in PBMC and strongly induced palmitoylation of GLUT1 in PBMC and N2a cells. Expert opinion: Our findings suggest a novel mechanism exerted by fluoxetine targeting glucose metabolism by regulating glucose transporter palmitoylation. Thus, fluoxetine might evoke its therapeutic effects in neuropsychiatric diseases characterized by disturbances in central energy metabolism at least partly by improving cerebral glucose uptake.
Asunto(s)
Metabolismo Energético/efectos de los fármacos , Fluoxetina/farmacología , Glucosa/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Adulto , Animales , Proteínas Facilitadoras del Transporte de la Glucosa/efectos de los fármacos , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Lipoilación/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Neuroblastoma/metabolismoRESUMEN
Major depression is the most common mental disorder and a leading cause of years lived with disability. In addition to the burden attributed to depressive symptoms and reduced daily life functioning, people with major depression are at increased risk of premature mortality, particularly due to cardiovascular diseases. Several studies point to a bi-directional relation between major depression and cardiovascular diseases, thereby indicating that both diseases may share common pathophysiological pathways. These include lifestyle factors (e.g. physical activity, smoking behavior), dysfunctions of endocrine systems (e.g. hypothalamus-pituitary adrenal axis), and a dysbalance of pro- and anti-inflammatory factors. Furthermore, recent research point to the role of epigenomic and proteomic factors, that are reviewed here with a particular focus on the mitochondrial energy metabolism.