Multimodal Spatial Profiling Reveals Immune Suppression and Microenvironment Remodeling in Fallopian Tube Precursors to High-Grade Serous Ovarian Carcinoma.

High-Grade Serous Ovarian Cancer (HGSOC) originates from fallopian tube (FT) precursors. However, the molecular changes that occur as precancerous lesions progress to HGSOC are not well understood. To address this, we integrated high-plex imaging and spatial transcriptomics to analyze human tissue samples at different stages of HGSOC development, including p53 signatures, serous tubal intraepithelial carcinomas (STIC), and invasive HGSOC. Our findings reveal immune modulating mechanisms within precursor epithelium, characterized by chromosomal instability, persistent interferon (IFN) signaling, and dysregulated innate and adaptive immunity. FT precursors display elevated expression of MHC-class I, including HLA-E, and IFN-stimulated genes, typically linked to later-stage tumorigenesis. These molecular alterations coincide with progressive shifts in the tumor microenvironment, transitioning from immune surveillance in early STICs to immune suppression in advanced STICs and cancer. These insights identify potential biomarkers and therapeutic targets for HGSOC interception and clarify the molecular transitions from precancer to cancer.

PRAME expression in melanoma is negatively regulated by TET2-mediated DNA hydroxymethylation.

Preferentially Expressed Antigen in Melanoma (PRAME) and Ten-Eleven Translocation (TET) dioxygenase-mediated 5-hydroxymethylcytosine (5hmC) are emerging melanoma biomarkers. We observed an inverse correlation between PRAME expression and 5hmC levels in benign nevi, melanoma in situ, primary invasive melanoma, and metastatic melanomas via immunohistochemistry and multiplex immunofluorescence: nevi exhibited high 5hmC and low PRAME, whereas melanomas showed the opposite pattern. Single-cell multiplex imaging of melanoma precursors revealed that diminished 5hmC coincides with PRAME upregulation in premalignant cells. Analysis of TCGA and GTEx databases confirmed a negative relationship between TET2 and PRAME mRNA expression in melanoma. Additionally, 5hmC levels were reduced at the PRAME 5' promoter in melanoma compared to nevi, suggesting a role for 5hmC in PRAME transcription. Restoring 5hmC levels via TET2 overexpression notably reduced PRAME expression in melanoma cell lines. These findings establish a function of TET2-mediated DNA hydroxymethylation in regulating PRAME expression and demonstrate epigenetic reprogramming as pivotal in melanoma tumorigenesis. Teaser: Melanoma biomarker PRAME expression is negatively regulated epigenetically by TET2-mediated DNA hydroxymethylation.

Development and validation of time-to-event models to predict metastatic recurrence of localized cutaneous melanoma.

BACKGROUND: The recent expansion of immunotherapy for stage IIB/IIC melanoma highlights a growing clinical need to identify patients at high risk of metastatic recurrence and, therefore, most likely to benefit from this therapeutic modality. OBJECTIVE: To develop time-to-event risk prediction models for melanoma metastatic recurrence. METHODS: Patients diagnosed with stage I/II primary cutaneous melanoma between 2000 and 2020 at Mass General Brigham and Dana-Farber Cancer Institute were included. Melanoma recurrence date and type were determined by chart review. Thirty clinicopathologic factors were extracted from electronic health records. Three types of time-to-event machine-learning models were evaluated internally and externally in the distant versus locoregional/nonrecurrence prediction. RESULTS: This study included 954 melanomas (155 distant, 163 locoregional, and 636 1:2 matched nonrecurrences). Distant recurrences were associated with worse survival compared to locoregional/nonrecurrences (HR: 6.21, P < .001) and to locoregional recurrences only (HR: 5.79, P < .001). The Gradient Boosting Survival model achieved the best performance (concordance index: 0.816; time-dependent AUC: 0.842; Brier score: 0.103) in the external validation. LIMITATIONS: Retrospective nature and cohort from one geography. CONCLUSIONS: These results suggest that time-to-event machine-learning models can reliably predict the metastatic recurrence from localized melanoma and help identify high-risk patients who are most likely to benefit from immunotherapy.

The Spatial Landscape of Progression and Immunoediting in Primary Melanoma at Single-Cell Resolution.

Cutaneous melanoma is a highly immunogenic malignancy that is surgically curable at early stages but life-threatening when metastatic. Here we integrate high-plex imaging, 3D high-resolution microscopy, and spatially resolved microregion transcriptomics to study immune evasion and immunoediting in primary melanoma. We find that recurrent cellular neighborhoods involving tumor, immune, and stromal cells change significantly along a progression axis involving precursor states, melanoma in situ, and invasive tumor. Hallmarks of immunosuppression are already detectable in precursor regions. When tumors become locally invasive, a consolidated and spatially restricted suppressive environment forms along the tumor-stromal boundary. This environment is established by cytokine gradients that promote expression of MHC-II and IDO1, and by PD1-PDL1-mediated cell contacts involving macrophages, dendritic cells, and T cells. A few millimeters away, cytotoxic T cells synapse with melanoma cells in fields of tumor regression. Thus, invasion and immunoediting can coexist within a few millimeters of each other in a single specimen. SIGNIFICANCE: The reorganization of the tumor ecosystem in primary melanoma is an excellent setting in which to study immunoediting and immune evasion. Guided by classic histopathology, spatial profiling of proteins and mRNA reveals recurrent morphologic and molecular features of tumor evolution that involve localized paracrine cytokine signaling and direct cell-cell contact. This article is highlighted in the In This Issue feature, p. 1397.

A live cell reporter of exosome secretion and uptake reveals pathfinding behavior of migrating cells.

Small extracellular vesicles called exosomes affect multiple autocrine and paracrine cellular phenotypes. Understanding the function of exosomes requires a variety of tools, including live imaging. Our previous live-cell reporter, pHluorin-CD63, allows dynamic subcellular monitoring of exosome secretion in migrating and spreading cells. However, dim fluorescence and the inability to make stably-expressing cell lines limit its use. We incorporated a stabilizing mutation in the pHluorin moiety, M153R, which now exhibits higher, stable expression in cells and superior monitoring of exosome secretion. Using this improved construct, we visualize secreted exosomes in 3D culture and in vivo and identify a role for exosomes in promoting leader-follower behavior in 2D and 3D migration. Incorporating an additional non-pH-sensitive red fluorescent tag allows visualization of the exosome lifecycle, including multivesicular body (MVB) trafficking, MVB fusion, exosome uptake and endosome acidification. This reporter will be a useful tool for understanding both autocrine and paracrine roles of exosomes.

Relationship between antidepressant therapy and risk for cardiovascular events in patients with and without cardiovascular disease.

OBJECTIVE: The American Heart Association has endorsed depression as a cardiac risk factor and recommends screening as part of routine practice. This has been met with controversy due to inconsistencies in the data linking depression treatment to better cardiovascular outcomes. Our objective was to prospectively assess the association between depression treatment (defined as being prescribed antidepressant medication) and major adverse cardiovascular events (MACE) in patients referred for exercise stress tests. METHOD: Two thousand three hundred eighty-five consecutive patients presenting for myocardial perfusion exercise stress tests underwent a sociodemographic, medical, and psychiatric interview (Primary Care Evaluation of Mental Disorders [PRIME-MD]) and completed the Beck Depression Inventory (BDI). History of cardiovascular disease (CVD) and antidepressant use was self-reported and verified via chart review. Participants followed over an 8.8-year follow up, and information regarding MACE incidence (including cardiac mortality, nonfatal myocardial infarction, revascularization procedures, cerebrovascular events) was obtained from provincial administrative databases. RESULTS: 8% (n = 190) of the sample were taking antidepressants at baseline, 41% (n = 916) had a history of CVD, and 38.7% (n = 921) had depression according to the PRIME-MD or BDI. Antidepressant treatment was associated with a 30% reduced risk of MACE (Hazard ratio [HR] = 0.697; 95% confidence interval [CI] = [0.504, 0.964]; p = .029). A 46% reduction in risk was associated with antidepressant treatment among those without CVD (HR = 0.542; 95% CI [0.299, 0.981]; p = .043). In depressed patients, a 33% reduction in risk of MACE associated with antidepressant use was seen (adjusted HR = 0.674; 95% CI [0.440, 1.033]; p = .07). CONCLUSIONS: Antidepressants may be cardio-protective among patients presenting for stress testing independent of risk factors including CVD and depression. Results support treating depression with antidepressants in this population to reduce risk of MACE. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Factors associated with study completion in patients with premature acute coronary syndrome.

BACKGROUND: Factors associated with study completion in younger adults are not well understood. This study sought to describe psychosocial, clinical, and demographic features associated with completion of a study of men and women with premature acute coronary syndrome. METHODS: As part of the GENdEr and Sex determInantS of cardiovascular disease: From bench to beyond-Premature Acute Coronary Syndrome (GENESIS-PRAXY) study, demographic, psychosocial, and clinical variables were assessed in 1213 patients hospitalized for acute coronary syndrome (≤ 55 years; 30% women). Patients were followed for 12 months. Dropouts withdrew from the study or were lost to follow-up after 12 months; completers were still enrolled after 12 months. RESULTS: Of 1213 patients initially enrolled, 777 (64.1%) completed 12-month follow-up. Fully adjusted models suggested that being older (OR = 1.04, 95% CI [1.01, 1.06]), higher subjective social status within one's country (OR = 1.11, 95% CI [1.01, 1.22]), being free of type II diabetes, (OR = 0.66, 95% CI [0.45, 0.97]), non-smoking status (OR = 0.70, 95% CI [0.51, 0.95]) and being free of depression (OR = 1.52, 95% CI [1.11, 2.07]) were independently associated with study completion. CONCLUSIONS: Recruitment/retention strategies targeting individuals who smoke, are younger, have low subjective social status within one's country, have diabetes, or have depression may improve participant follow-up in cardiovascular cohort studies.

Sex differences in prodromal symptoms in acute coronary syndrome in patients aged 55†years or younger.

BACKGROUND: Studies suggest that young women are at highest risk for failing to recognise early symptoms of acute coronary syndrome (ACS). OBJECTIVES: To examine sex differences in prodromal symptoms occurring days and weeks prior to the acute presentation of ACS. We also examined health-seeking behaviours and prehospital management in young patients. METHODS: Prospective cross-sectional analysis of 1145 patients (368 women) hospitalised for ACS, aged ≤55 years, from the GENdEr and Sex DetermInantS of Cardiovascular Disease: From Bench to Beyond Premature Acute Coronary SYndrome cohort study (January 2009-April 2013). Prodromal symptoms were determined using the McSweeney Acute and Prodromal Myocardial Infarction Symptom questionnaire. Health-seeking behaviour and prehospital care were determined by questionnaires. RESULTS: The median age was 49 years. The prevalence of prodromal symptoms was high and more women reported symptoms than men (85% vs 72%, p<0.0001). Symptoms were similar between sexes and included unusual fatigue, sleep disturbances, anxiety and arm weakness/discomfort. Chest pain was less common in both sexes (24%). Women were more likely to seek care (49% vs 42%, p=0.04). Among those who sought care, women were more likely to use an ambulance for their ACS compared with men (52% vs 39%). Cardiovascular risk-reduction therapy use was low (≤40%) in all patients and less than half perceived their care provider suspected a cardiac source. CONCLUSIONS: Prior to ACS, women were more likely to experience prodromal symptoms and seek medical attention than men. Prehospital care was generally similar between sexes but demonstrated underutilisation of risk-reduction therapies in at-risk young adults.

The Contribution of Gender to Apparent Sex Differences in Health Status Among Patients with Coronary Artery Disease.

BACKGROUND: While it has been identified that gender (socially manufactured roles, behaviors, expressions, and identities) plays a central role in men's and women's health, the distinction between gender and sex (biological attributes) has largely been ignored in health science research. The purpose of this study was to look at the unique contributions of sex, age, and the Gender Index (GI) to baseline health status in a cohort of patients with coronary artery disease (CAD). PARTICIPANTS AND METHODS: Questions that comprised the GI were included in the follow-up questionnaire sent to patients in the APPROACH registry. To examine the relationship between sex, gender, and health status, a sequential linear regression modeling approach was used. RESULTS: A total of 632 patients completed the GI between July and August 2015. The women were significantly older (68 years vs. 66 years, p = 0.02) and significantly more likely to have hypertension (50.8% vs. 38.8%, p = 0.02) compared to the men. Women reported significantly lower mean Seattle Angina Questionnaire (SAQ) scores compared to men. The inclusion of age into the models did not change the relationship between sex and the SAQ scales. However, the inclusion of the GI attenuated the relationship between sex and the SAQ scale scores. CONCLUSIONS: Our results support the concept that sex differences in health status outcomes may be better explained by patient's gender-related characteristics, than biological sex characteristics. More importantly, the GI offers a pragmatic composite score to assess the effects of psychosocial factors that researchers interested in measuring gender could use in studies of subjects with CAD.

Sex Differences in Clinical Outcomes After Premature Acute Coronary Syndrome.

BACKGROUND: Over past decades, the incidence of acute coronary syndrome (ACS) has increased in young women, and greater mortality rates after discharge were observed among young women vs men. We revisited this issue with contemporary data from the Gender and Sex Determinants of Cardiovascular Disease: From Bench to Beyond Premature Acute Coronary Syndrome (GENESIS-PRAXY), a multicentre prospective cohort study. METHODS: One thousand two hundred thirteen patients were enrolled in GENESIS-PRAXY from 26 centres across Canada, the United States, and Switzerland between January 2009 and April 2013. We assessed major adverse cardiac events (MACE) and mortality over 12 months after ACS. The role of sex as a predictor of outcomes was determined with Cox proportional hazard regression analysis. RESULTS: We included 1163 patients with complete data. The occurrence of MACE was 9% and 8% in women and men, respectively (P = 0.75), and 1% of women and men died during follow-up. In adjusted models, there was no sex difference in the risk of MACE or mortality. The proportion of patients with all-cause rehospitalization was higher in women (13%) compared with men (9%; P = 0.006), but cardiac rehospitalization rates were similar in both sexes regardless of ACS type. Among first rehospitalizations, the majority was classified as cardiac related (69%), with chest pain or angina (28%) and myocardial infarction (19%) reported as the most common reasons for first rehospitalization. CONCLUSIONS: Women were more likely than men to be rehospitalized for all causes but not for a cardiac cause. In contrast to earlier studies, men and women had similar mortality and MACE outcomes at 1 year.

Premature cardiovascular disease following a history of hypertensive disorder of pregnancy.

BACKGROUND: Following an episode of hypertensive disorder of pregnancy (HDP) women have an increased risk of cardiovascular disease over their lifetime. At the time of acute coronary syndrome we compared clinical information between women with and without a history of hypertension in pregnancy to gain further insight into the pathophysiology of cardiovascular disease in this population. METHODS: GENESIS-PRAXY (GENdEr and Sex determInantS of cardiovascular disease: from bench to beyond-PRemature Acute Coronary SYdrome) is a prospective multicenter study, with recruitment between January 2009 and April 2013, including 242 parous women with premature acute coronary syndrome. RESULTS: The median age was 50years (IQR 6) and HDP was common; 43 (17.8%) women had prior gestational hypertension, 33 (13.6%) preeclampsia and 166 (68.6%) a prior normotensive pregnancy. Women with a history of HDP commonly had chronic hypertension and diabetes and those presenting with ST-elevation myocardial infarction were more likely to have a history of preeclampsia (aOR 3.12, 95% CI 1.22-8.01) than were women with prior normotensive pregnancies. Neither gestational hypertension (aOR 1.40, 95% CI 0.60-3.26) nor preeclampsia (aOR 0.63, 95% CI 0.23-1.74) was associated with a higher composite risk of three-vessel, left main or proximal left anterior descending coronary disease. CONCLUSION: In this study of women with premature cardiovascular disease, ST-elevation myocardial infarction was associated with a history of preeclampsia possibly because of persistent endothelial dysfunction. High-risk coronary lesions on angiography did not appear to have an association with preeclampsia or gestational hypertension despite a high burden of traditional risk factors.

Do Women With Anxiety or Depression Have Higher Rates of Myocardial Ischemia During Exercise Testing Than Men?

BACKGROUND: Women diagnosed with coronary artery disease (CAD) typically experience worse outcomes relative to men, possibly through diagnosis and treatment delays. Reasons for these delays may be influenced by mood and anxiety disorders, which are more prevalent in women and have symptoms (eg, palpitations and fatigue) that may be confounded with CAD. Our study examined sex differences in the association between mood and anxiety disorders and myocardial ischemia in patients with and without a CAD history presenting for exercise stress tests. METHODS AND RESULTS: A total of 2342 patients (women n=760) completed a single photon emission computed tomographic exercise stress test (standard Bruce Protocol) and underwent a psychiatric interview (The Primary Care Evaluation of Mental Disorders) to assess mood and anxiety disorders. Ischemia was assessed using single photon emission computed tomography, with odds ratio used to calculate the effect of sex and mood/anxiety on the presence of ischemia during stress testing by CAD history in a stratified analyses, adjusted for relevant covariates. There was a sex by anxiety interaction with ischemia in those without a CAD history (P=0.015): women with anxiety were more likely to exhibit ischemia during exercise than women without anxiety (odds ratio, 1.75; 95% confidence interval, 1.05-2.89). No significant effects were observed for men nor mood. CONCLUSIONS: Women with anxiety and no CAD history had higher rates of ischemia than women without anxiety. Results suggest that anxiety symptoms, many of which overlap with those of CAD, might mask CAD symptoms among women (but not men) and contribute to referral and diagnostic delays. Further research is needed to confirm this hypothesis.

Sex Versus Gender-Related Characteristics: Which Predicts Outcome After Acute Coronary Syndrome in the Young?

BACKGROUND: "Gender" reflects social norms for women and men, whereas "sex" defines biological characteristics. Gender-related characteristics explain some differences in access to care for premature acute coronary syndrome (ACS); whether they are associated with cardiovascular outcomes is unknown. OBJECTIVES: This study estimated associations between gender and sex with recurrent ACS and major adverse cardiac events (MACE) (e.g., ACS, cardiac mortality, revascularization) over 12 months in patients with ACS. METHODS: We studied 273 women and 636 men age 18 to 55 years from GENESIS-PRAXY (GENdEr and Sex determInantS of cardiovascular disease: from bench to beyond-Premature Acute Coronary SYndrome), a prospective observational cohort study, who were hospitalized for ACS between January 2009 and April 2013. Gender-related characteristics (e.g., social roles) were assessed using a self-administered questionnaire, and a composite measure of gender was derived. Outcomes included recurrent ACS and MACE over 12 months. RESULTS: Feminine roles and personality traits were associated with higher rates of recurrent ACS and MACE compared with masculine characteristics. This difference persisted for recurrent ACS, after multivariable adjustment (hazard ratio from score 0 to 100: 4.50; 95% confidence interval: 1.05 to 19.27), and was a nonstatistically significant trend for MACE (hazard ratio: 1.54; 95% confidence interval: 0.90 to 2.66). A possible explanation is increased anxiety, the only condition that was more prevalent in patients with feminine characteristics and that rendered the association between gender and recurrent ACS nonstatistically significant (hazard ratio: 3.56; 95% confidence interval: 0.81 to 15.61). Female sex was not associated with outcomes post-ACS. CONCLUSIONS: Younger adults with ACS with feminine gender are at an increased risk of recurrent ACS over 12 months, independent of female sex.

Relative associations between depression and anxiety on adverse cardiovascular events: does a history of coronary artery disease matter? A prospective observational study.

OBJECTIVES: To assess whether depression and anxiety increase the risk of mortality and major adverse cardiovascular events (MACE), among patients with and without coronary artery disease (CAD). DESIGN AND SETTING, AND PATIENTS: DECADE (Depression Effects on Coronary Artery Disease Events) is a prospective observational study of 2390 patients referred at the Montreal Heart Institute. Patients were followed for 8.8 years, between 1998 and 2009. Depression and anxiety were assessed using a psychiatric interview (Primary Care Evaluation of Mental Disorders, PRIME-MD). Outcomes data were obtained from Quebec provincial databases. MAIN OUTCOME MEASURES: All-cause mortality and MACE. RESULTS: After adjustment for covariates, patients with depression were at increased risks of all-cause mortality (relative risk (RR)=2.84; 95% CI 1.25 to 6.49) compared with patients without depression. Anxiety was not associated with increased mortality risks (RR=0.86; 95% CI 0.31 to 2.36). When patients were stratified according to CAD status, depression increased the risk of mortality among patients with no CAD (RR=4.39; 95% CI 1.12 to 17.21), but not among patients with CAD (RR=2.32; 95% CI 0.78 to 6.88). Neither depression nor anxiety was associated with MACE among patients with or without CAD. CONCLUSIONS AND RELEVANCE: Depression, but not anxiety, was an independent risk factor for all-cause mortality in patients without CAD. The present study contributes to a better understanding of the relative and unique role of depression versus anxiety among patients with versus without CAD.

Potential factors associated with fruit and vegetable intake after premature acute coronary syndrome: a prospective cohort study.

Studies on dietary changes and their associated factors are limited, particularly with respect to younger cardiovascular patients. Our objective was to evaluate the factors associated with fruit and vegetable intake among adults with premature acute coronary syndrome (ACS) 1 year after the event. We used data from GENESIS-PRAXY, a multicentre prospective study of adults aged 18-55 years, hospitalised for ACS. Participants were 704 adults from 24 centres in Canada, 1 in USA and 1 in Switzerland. Data were collected through questionnaires and chart reviews at baseline and 1 year post-ACS. Fruit and vegetable intake was low among adults with premature ACS, and remained suboptimal at 1 year post-ACS, with only 21% meeting the minimum recommendations of at least 5 daily servings. The findings suggest that patient lifestyle characteristics, such as the number of hours spent at work and baseline intake are factors that may be associated with the intake of fruits and vegetables. More research is needed to assess effective strategies to increase fruit and vegetable intake among patients with premature ACS so that they meet dietary recommendations.

Sex differences in health behavior change after premature acute coronary syndrome.

BACKGROUND: Limited information is available on the health behavior profile of patients with premature acute coronary syndrome (ACS). The purpose of this study is to desribe the health bahvior of young patients with ACS at the baseline and 1 year post-ACS and examine sex differences. METHODS: GENESIS-PRAXY is a prospective cohort study of adults (18-55 years old) hospitalized with ACS from 26 centers located in Canada, United States, and Switzerland. Data on diet, physical activity, smoking, alcohol consumption, and recreational drug use were collected through self-administered questionnaires at baseline and 1 year post-ACS. RESULTS: Our analysis included 740 patients with complete data. At baseline, the health behavior profile of young patients with ACS was worse than that of the general population. Men had a lower fruit and vegetable intake, consumed alcohol more, and used recreational drugs more than women. Conversely, fewer men than women were smokers (34% vs 42%). At 1 year post-ACS, the proportion of those consuming ≥5 daily servings of fruits and vegetables increased modestly (+5% vs +1%, for men vs women) but remained lower than the general population. Among women, the prevalence of smoking remained about twice as high as the general population. Recreational drug use also remained higher than in the general population. CONCLUSIONS: Despite small improvements at 1 year post-ACS, the health behavior profile of young patients remained worse than that of the general population. Greater efforts to improve health behaviors post-ACS among young patients are needed, and a sex-based approach may be required to ensure successful behavioral changes.

A composite measure of gender and its association with risk factors in patients with premature acute coronary syndrome.

OBJECTIVE: To create a gender index by using principal component analyses (PCA) and logistic regression, and to determine the association between gender, sex, and cardiovascular risk factors among patients with premature acute coronary syndrome (ACS). METHODS: GENESIS-PRAXY is a cohort study including ACS patients aged 55 years or below, and with ACS recruited between 2009 and 2013 from 26 centres across Canada, the United States, and Switzerland. A sample of 1075 patients was used for this study. Psychosocial variables assumed to differ between sexes (i.e., gender related) were included in PCA. Variables identified on retained components were included in logistic regressions where coefficient estimates of variables associated with sex were used to calculate a gender score. Cardiovascular risk factors were assessed using self-report and chart review data. RESULTS: After the inclusion of 26 psychosocial variables in PCA, we identified 17 variables within retained components; 7 of which were associated with sex in logistic regression. The gender distribution revealed that half of women had a more androgyne or masculine gender score, and 16% of men exhibited a more feminine gender score. In univariable analyses, feminine gender scores and female sex were associated with hypertension, diabetes, family history of cardiovascular disease (only gender), and depressive/anxious symptoms. In multivariable models including both gender score and sex, feminine gender score but not female sex was associated with the presence of risk factors. CONCLUSIONS: Sex and gender are distinct constructs, and the derived gender index offers a current and pragmatic option to measure gender within ACS populations. Our results further suggest that traditional sex differences in cardiovascular disease risk factors may be partly explained by patient's gender-related characteristics.

Systematic Review and Individual Patient Data Meta-Analysis of Sex Differences in Depression and Prognosis in Persons With Myocardial Infarction: A MINDMAPS Study.

OBJECTIVE: Using combined individual patient data from prospective studies, we explored sex differences in depression and prognosis post-myocardial infarction (MI) and determined whether disease indices could account for found differences. METHODS: Individual patient data analysis of 10,175 MI patients who completed diagnostic interviews or depression questionnaires from 16 prospective studies from the MINDMAPS study was conducted. Multilevel logistic and Cox regression models were used to determine sex differences in prevalence of depression and sex-specific effects of depression on subsequent outcomes. RESULTS: Combined interview and questionnaire data from observational studies showed that 36% (635/1760) of women and 29% (1575/5526) of men reported elevated levels of depression (age-adjusted odds ratio = 0.68, 95% confidence interval [CI] = 0.60-0.77). The risk for all-cause mortality associated with depression was higher in men (hazard ratio = 1.38, 95% CI = 1.30-1.47) than in women (hazard ratio = 1.22, 95% CI = 1.14-1.31; sex by depression interaction: p < .001). Low left ventricular ejection fraction (LVEF) was associated with higher depression scores in men only (sex by LVEF interaction: B = 0.294, 95% CI = 0.090-0.498), which attenuated the sex difference in the association between depression and prognosis. CONCLUSIONS: The prevalence of depression post-MI was higher in women than in men, but the association between depression and cardiac prognosis was worse for men. LVEF was associated with depression in men only and accounted for the increased risk of all-cause mortality in depressed men versus women, suggesting that depression in men post-MI may, in part, reflect cardiovascular disease severity.

The interaction between anxiety and depressive symptoms on brachial artery reactivity in cardiac patients.

The association between anxiety, depression, and endothelial function (EF) was assessed in a sample of 295 cardiac outpatients (n=222 men; mean age=59). Patients were administered the Beck Depression Inventory-II and the State-Trait Anxiety Inventory, trait scale. EF was assessed through forearm hyperemic reactivity, a nuclear medicine variation of the flow-mediated dilatation technique, which calculates the rate of uptake ratio (RUR) between hyperaemic and non-hyperaemic arms. Neither effect of anxiety (F=1.40, p=.24) nor depression (F=2.66, p=.10) was found in a model predicting EF, however there was an interaction (F=4.11, p=.04). Higher anxiety and lower depressive symptoms were associated with superior RUR compared to lower anxiety and lower depressive symptoms. Anxiety had no influence on RUR in those patients with higher depressive symptoms, who generally displayed the lowest levels of RUR, i.e., poor function. It is speculative whether this potential protective role of anxiety may be guided by behavioral or physiological mechanisms.