Sex Differences Research Articles

Sex, Age, and Species Differences of Perfluorooctanoic Acid Modeled by Flow- versus Permeability-limited Physiologically-Based Pharmacokinetic Models.

This study aimed to investigate sex, age, and species differences of perfluorooctanoic acid (PFOA) using physiologically-based pharmacokinetic (PBPK) models in rats and humans. PBPK models were generally developed as either flow- or permeability-limited models. The flow-limited model is cost-effective and allows for human PK prediction through simple allometric scaling, while the permeability-limited model can incorporate detailed information on the disposition process through in vitro-in vivo extrapolation (IVIVE). PFOA was administered via oral or intravenous administration with 5mg/kg in male and female rats of different ages and the data was used to develop the PBPK models. Our results showed that both models successfully captured sex differences in rats, while only the flow-limited model with male rats and the permeability-limited model with both male and female rats provided comparable predictions in the human clinical study. More than the flow-limited model, the permeability-limited model effectively explained sex differences in rats and species differences through IVIVE. Additionally, the ontogeny-based mechanistic description of PFOA disposition enabled the interpretation of age- and sex-dependent pharmacokinetics. Although the flow-limited PBPK model lacked mechanistic interpretability compared to the permeability-limited model, it demonstrated reliable human prediction through simple allometric scaling. In conclusion, the permeability PBPK model could interpret age, sex, and species differences and it could improve the accuracy of human prediction.

Sex and gender differences in hepatitis C virus risk, prevention, and cascade of care in people who inject drugs: systematic review and meta-analysis

People who inject drugs (PWID) are a priority population in HCV elimination programming. Overcoming sex and gender disparities in HCV risk, prevention, and the cascade of care is likely to be important to achieving this goal, but these have not yet been comprehensively reviewed. Systematic review and meta-analysis. We searched Pubmed, EMBASE and the Cochrane Database of Systematic Reviews 1 January 2012-22 January 2024 for studies of any design reporting sex or gender differences among PWID in at least one of: sharing of needles and/or syringes, incarceration history, injection while incarcerated, participation in opioid agonist treatment or needle and syringe programs, HCV testing, spontaneous HCV clearance, direct-acting antiviral (DAA) treatment initiation or completion, and sustained virological response (SVR). Assessment of study quality was based on selected aspects of study design. Additional data were requested from study authors. Data were extracted in duplicate and meta-analysed using random effects models. PROSPERO registration CRD42022342806. 9533 studies were identified and 92 studies were included. Compared to men, women were at greater risk for receptive needle and syringe sharing (past 6-12 months: risk ratio (RR) 1.12; 95% confidence interval (CI) 1.01-1.23; <6 months: RR 1.38; 95% CI 1.09-1.76), less likely to be incarcerated (lifetime RR 0.64; 95% CI 0.57-0.73) more likely to be tested for HCV infection (lifetime RR 1.07; 95% CI 1.01, 1.14), more likely to spontaneously clear infection (RR1.58; 95% CI 1.40-1.79), less likely to initiate DAA treatment (0.84; 95% CI 0.78-0.90), and more likely to attain SVR after completing DAA treatment (RR 1.02; 95% CI 1.01-1.04). There are important differences in HCV risk and cascade of care indicators among people who inject drugs that may impact the effectiveness of prevention and treatment programming. Developing and assessing the effectiveness of gender-specific and gender-responsive HCV interventions should be a priority in elimination programming. Réseau SIDA-MI du Québec.

Predictors of Urinary and Fecal Incontinence in Prefrail and Frail Older Adults: A Cross-Sectional Study of the FRAGSALUD Project.

Frailty is associated with urinary and fecal incontinence, which are common geriatric syndromes. This study aims to identify health factors associated with incontinence in prefrail or frail older adults living in the community. This multicenter cross-sectional study included 225 older adults (75.0 ± 6.4 years) with prefrailty or frailty based on the 5-component Fried phenotype. Physical function was assessed using the Short Physical Performance Battery (SPPB). Physical activity, inactivity, and sleep were estimated using a wrist-worn accelerometer. Urinary or fecal incontinence was registered using the Barthel scale (urine and bowel items). Multivariable logistic regression analyses, with age as a covariate, were conducted to identify associations of incontinence. In our participants, 27% presented urinary or fecal incontinence with no sex differences (p = .266). Our results showed that age, daily medication count, and number of falls in the previous year independently predicted incontinence in frail and prefrail older adults (p < .05). Some Fried's criteria, including self-reported exhaustion, gait speed, and handgrip strength, were associated with the presence of incontinence (p < .05), but not Fried's classification. The SPPB total score and its isolated variables were significantly associated with the urinary and fecal incontinence (p < .05). However, none of the accelerometer outcomes showed significant associations with incontinence status. According to this study, age, number of medications, and falls (but not sex) are linked to urinary and fecal incontinence in frail or prefrail older adults living in the community, recommending the assessment of physical function using the SPPB rather than estimating daily physical activity, inactivity, or sleep.

Parenting and other potential protective factors associated with polysubstance use among public school students in Lagos, Nigeria.

Substance use is a growing problem in Nigeria. The present study extended recent work documenting the importance of parenting as protective against substance use in Nigerian youth by testing a model linking parenting, additional protective factors and polysubstance use. Public school students (N = 1607; 56% female; M age = 14.88; SD = .44 years) living in the greater Lagos region participated in school-based data collection. Lifetime polysubstance use, defined as use of two or more substances including alcohol or illicit drugs, or misuse of over-the-counter medications, was reported by 5.2% of the sample. Structural equation modelling that accounted for adolescent age and sex on all constructs revealed good model fit. Positive parenting (support and solicitation) was significantly associated with higher perceived harmfulness of substance use, religiosity and positive relationships at school. Positive school relationships were associated with a decreased likelihood of polysubstance use. Multiple group analysis revealed no overall sex differences in the model paths. Strengthening parent-adolescent relationships may have a cascading effect on protective factors and subsequent substance use, and should be included in youth substance use prevention programmes.

Sex Differences in the Severity and Progression of Neuropsychiatric Symptoms Across Different Dementia Types.

Dementia presents not only differing neuropsychiatric symptoms (NPS) across Alzheimer disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB) but also subjective cognitive decline (SCD). This study examined sex-based variations in NPS severity and progression across these conditions. We performed a longitudinal cohort study including 1,068 participants. Hierarchical generalized linear mixed models were used to model NPS as a function of disease severity and biological sex at birth. Female participants with AD exhibited NPS more frequently than male participants. In FTD, female participants had more frequent delusions, hallucinations, and depression/dysphoria, while male participants had higher instances of agitation/aggression, apathy, disinhibition, and irritability/lability. In DLB, male participants showed higher instances of depression, and female participants more frequently experienced anxiety. In SCD, female participants showed higher nighttime behaviors. The trajectory of NPS significantly differed between sexes. These findings highlight sex-specific NPS impact in different neurodegenerative conditions.

A population-aware retrospective regression to detect genome-wide variants with sex difference in allele frequency

A population-aware retrospective regression to detect genome-wide variants with sex difference in allele frequency

The association of the dietary inflammatory potential with risk of overall and site-specific cancers: A community-based longitudinal study in the UK Biobank

ObjectivesThe association of the dietary inflammatory potential with cancer risk remains uncertain. We examined the relationship of the dietary inflammatory potential with risk of overall and site-specific cancers and explored its sex and age differences. DesignA community-based longitudinal study. SettingParticipants from the UK Biobank completed baseline surveys during 2006–2010 and were followed for up to 15 years to detect incident cancer. Participants170,899 cancer-free participants with dietary data available (mean age: 55.73 ± 7.95, 54.10% female). MeasurementsAt baseline, dietary intake was assessed with a 24-h dietary record for up to 5 times. The inflammatory diet index (IDI) was calculated to assess the dietary inflammatory potential as a weighted sum of 31 food groups (including 14 anti-inflammatory and 17 pro-inflammatory) based on plasma high-sensitivity C-reactive protein (hsCRP) levels, and tertiled as low (indicating low-inflammatory diet), moderate, and high IDI (as reference). Overall and site-specific cancers were ascertained via linkage to routine hospital admission, cancer registry, and death certificate data. Data were analyzed using Cox regression and Laplace regression. ResultsDuring the follow-up (median 10.32 years, interquartile range: 9.95–11.14 years), 18,884 (11.05%) participants developed cancer. In multi-adjusted Cox regression, low IDI scores were associated with decreased risk of rectal cancer (hazard ratio [95% confidence interval, CI] 0.76 [0.61, 0.94]), thyroid cancer [0.45 (0.27, 0.74)], lung cancer [0.73 (0.61, 0.88)]. However, the association between IDI score and the risk of overall cancer was not significant. Laplace regression analysis showed that 10th percentile differences (95% CIs) of cancer onset time for participants with low IDI scores was prolonged by 1.29 (0.32, 2.27), 1.44 (0.58, 2.30), and 2.62 (0.98, 4.27) years for rectal cancer, thyroid cancer, and lung cancer, respectively, compared to those with high IDI scores. Stratified analysis revealed that low IDI scores were associated with a lower risk of rectal cancer (p interaction between IDI score and sex = 0.035) and lung cancer in males, but not in females, and with a reduced risk of thyroid cancer in females, but not in males. Moreover, low IDI scores were associated with a reduced risk of rectal cancer and lung cancer in the participants aged ≥60 years, but not in those <60 years, and with a reduced risk of thyroid cancer in those aged ≥60 years and <60 years. ConclusionsA low-inflammatory diet is associated with decreased risk and prolonged onset time of rectal cancer and lung cancer, especially among males and individuals aged ≥60 years, and thyroid cancer among females.

Three-dimensional Characterization of Sex Differences in Abdominal Aortic Aneurysm Progression via Vascular Deformation Mapping

Three-dimensional Characterization of Sex Differences in Abdominal Aortic Aneurysm Progression via Vascular Deformation Mapping

Mortality in patients with systemic lupus erythematosus: A meta-analysis of overall and cause-specific effects.

Our objective was to assess the overall and cause-specific standardized mortality ratios (SMRs) among patients diagnosed with systemic lupus erythematosus (SLE). An exhaustive systematic review was undertaken, encompassing studies that scrutinized SMRs, both overall and for specific causes, in patients diagnosed with SLE compared to the general populace. The databases of PUBMED, EMBASE, and Cochrane were meticulously searched to collate relevant literature. Following this comprehensive search, a meta-analysis was executed to methodically assess all-cause, sex-specific, ethnicity-specific, and cause-specific SMRs in individuals with SLE. The inclusion criteria were met by 29 studies encompassing 72,342 patients with SLE and documenting 7352 deaths. The meta-analysis disclosed a pronounced 2.87-fold elevation in the SMR for all-cause mortality in SLE patients relative to the general population (SMR, 2.866; 95% confidence interval [CI], 2.490-3.242; p < .001). Region-specific assessments showed variable all-cause SMRs, with Europe reporting 2.607 (95% CI, 1.939-3.275; p < .001), Asia revealing 3.043 (95% CI, 2.082-4.004; p < .001), and particularly high SMRs noted in North America and Oceania. Gender-focused analyses presented a pooled SMR of 3.261 (95% CI, 2.674-3.848; p < .001) for females, and 2.747 (95% CI, 2.190-3.304; p < .001) for males. Evaluations specific to cause of death illustrated notably elevated SMRs for renal disease (SMR, 4.486; 95% CI, 3.024-5.948; p < .001), infections (SMR, 4.946; 95% CI, 4.253-5.639; p < .001), cardiovascular diseases (CVD) (SMR, 2.931; 95% CI, 1.802-4.061; p < .001), cerebrovascular accidents (CVA) (SMR, 1.588; 95% CI, 0.647-2.528; p = .001), and cancer (SMR, 1.698; 95% CI, 0.871-2.525; p < .001). This meta-analysis underscores a significant 2.87-fold elevation in the SMR among patients with SLE compared to the general population, transcending differences in sex or geographical regions. Moreover, an appreciable increase in mortality due to specific causes, including renal disease, infection, CVD, CVA, malignancy, and neuropsychiatric SLE, accentuates the imperative for targeted interventions to mitigate these elevated risks in SLE patients.

Sex Difference in Characteristics and Predictors of In-Hospital Mortality Among Patients with COVID-19.

With the surge in the prevalence of coronavirus disease (COVID-19) in Beijing starting in October 2022, hospitalisations have increased markedly. The present study aimed to evaluate factors associated with in-hospital mortality in patients with COVID-19. Using data from hospitalised patients, sex differences in clinical characteristics, in-hospital management, and in-hospital mortality among patients diagnosed with COVID-19 were evaluated. Additionally, predictive factors associated with mortality in 1091 patients, who were admitted to the Beijing Anzhen Hospital (Beijing, China) for COVID-19 between October 2022 and January 2023, were also evaluated. Data from 1091 patients hospitalised with COVID-19 were included in the analysis. The in-hospital mortality rates were 14.9% and 10.4% for males and females, respectively. Multifactorial logistic analysis revealed that lymphocyte percentage (LYM%) (odds ratio [OR] 0.863 [95% confidence interval (CI) 0.805-0.925]; P&lt;0.001), uric acid (OR 1.004 [95% CI 1.002-1.006]; P=0.001), and high-sensitivity C-reactive protein (hs-CRP) (OR 1.094 [95% CI 1.012-1.183]; P=0.024) were independently associated with in-hospital mortality from COVID-19. Among female patients, multifactorial analysis revealed that LYM% (OR 0.856 [95% CI 0.796-0.920]; P&lt;0.001), older age (OR 1.061 [95% CI 1.020-1.103]; P=0.003), obesity (OR 2.590 [95% CI 1.131-5.931]; P=0.024), and high high-sensitivity troponin I level (OR 2.602 [95% CI 1.157-5.853]; P=0.021) were risk factors for in-hospital mortality. Receiver operating characteristic (ROC) curve analysis revealed that the efficacy of LYM% in predicting in-hospital death and its area under the ROC curve (AUC) for predicting in-hospital death in males was 0.800, with a sensitivity of 63.2% and specificity of 83.2%. The AUC for predicting hospital death in females was 0.815, with a sensitivity of 87.5% and specificity of 64.4%. LYM% was a consistent predictor of in-hospital mortality in both sexes. Older age and markers of systemic inflammation, myocardial injury, and metabolic dysregulation were also associated with higher mortality risk. These findings may help identify patients who require closer monitoring and tailored interventions to improve outcomes.

Investigating sexual and asexual modes of reproduction in Palmer Amaranth (Amaranthus palmeri)

Abstract Palmer amaranth (Amaranthus palmeri S. Watson), a dioecious wind-pollinated plant, is one of the most troublesome crop weeds in the United States and is spreading northwards. The prodigious production of seed contributes to establishment of populations and spread across the landscape. Sexual reproduction via outcrossing is likely the primary mode of seed production for this dioecious plant. However, A. palmeri may also be capable of autonomous asexual seed production (apomixis), which could be beneficial during colonization. We conducted two studies of female isolation from pollen to investigate the propensity for autonomous seed production in 19 populations across eastern North America. In the first we observed low frequency seed production on many isolated females. Using flow cytometry of seed samples (FCSS) we primarily found patterns of ploidy consistent with sexual reproduction; no significant differences in ploidy between seeds produced on isolated females (putative apomicts) and non-isolated females (putatively sexual) were detected. We also investigated patterns of DNA content and found no evidence for polyploidy in 153 samples, which is often observed in apomictic species. The second female isolation trial utilized sex-specific molecular markers to identify and remove males prior to flowering, and we observed zero seed production. Overall, we did not detect evidence in support of apomixis in these populations of A. palmeri, suggesting that apomixis is unlikely to have played a role in the northward advance of this species in eastern North America. We also investigated whether there is variation between females and males in size and secondary reproductive traits. We found evidence for sexual dimorphism in three of six traits investigated: females are taller at senescence, produce longer secondary branches, and more axillary flowers than males. Differences in cost of reproduction and strategies for pollen release vs. pollen capture are likely factors shaping the evolution of sexual dimorphism in this wind-pollinated dioecious plant.

Sex differences in the impact of social relationships on individual vocal signatures in grey mouse lemurs (Microcebus murinus).

Vocalizations coordinate social interactions between conspecifics by conveying information concerning the individual or group identity of the sender. Social accommodation is a form of vocal learning where social affinity is signalled by converging or diverging vocalizations with those of conspecifics. To investigate whether social accommodation is linked to the social lifestyle of the sender, we investigated sex-specific differences in social accommodation in a dispersed living primate, the grey mouse lemur (Microcebus murinus), where females form stable sleeping groups whereas males live solitarily. We used 482 trill calls of 36 individuals from our captive breeding colony to compare acoustic dissimilarity between individuals with genetic relatedness, social contact time and body weight. Our results showed that female trills become more similar the more time females spend with each other, independent of genetic relationship, suggesting vocal convergence. In contrast, male trills were affected more by genetic than social factors. However, focusing only on socialized males, increasing time as cage partners caused greater divergence in males' trills. Thus, grey mouse lemurs show the capacity for social accommodation, with females converging their trills to signal social closeness to sleeping group partners, whereas males do not adapt or diverge their trills to signal individual distinctiveness. This article is part of the theme issue 'The power of sound: unravelling how acoustic communication shapes group dynamics'.

Examining Sex Differences in Relationships Between Subjective and Objective Measures of Upper Extremity Motor Impairment in a Sample of Stroke Survivors.

Rehabilitation professionals use subjective and objective outcome measures to assess stroke-related impact and impairment. Understanding if subjective and objective findings correlate among stroke survivors, especially if these associations differ between females and males, can inform care decisions. A retrospective cross-sectional design was used, with data selected from subacute to chronic stroke survivors on age, time since stroke, the hand domain from the Stroke Impact Scale version 3.0 (SIS-H), and the Fugl-Meyer Upper Extremity (FMUE) Assessment. Group differences were assessed for all outcomes based on sex and time poststroke. Separate correlations for females and males were performed between the subjective (SIS-H) and objective measures (FMUE) of upper limb function and impairment. Data from 148 participants (44 females) were included in this study. SIS-H was significantly correlated with FMUE in both females and males (Ps ≤0.001). No significant differences were found between the groups' mean SIS-H or FMUE scores based on sex or time poststroke. Subjective and objective measures of physical functioning were correlated in both females and males. Although we found no sex differences in our primary outcomes, the sample size of females was disproportionately lower than the males. This is consistent with an ongoing problem in the stroke recovery research field, where females are often underrepresented and understudied, and where females who experience higher levels of impairment are less likely to participate in research.

Editorial: Sex differences and cardiovascular therapeutics

Editorial: Sex differences and cardiovascular therapeutics

Sex-based Differences in Heart Failure Biomarkers.

Differences in HF biomarker levels by sex may be due to hormonal, genetic, and fat distribution differences. Knowledge of these differences is scarce, and it is not well established whether they may affect their usefulness in the management of HF. The different biomarker profiles in women and men have been confirmed in recent studies: in women, markers of cardiac stretch and fibrosis (NP and galectin-3) are higher, whereas in men, higher levels of markers of cardiac injury and inflammation (cTn and sST2) are found. The use of new biomarkers, together with growing evidence that a multimarker approach can provide better risk stratification, raises the question of building models that incorporate sex-specific diagnostic criteria. More and more research are being devoted to understanding sex-related differences in HF. The aim of this review is to review the dynamics of HF biomarkers according to sex and in different situations, to learn whether these sex differences may affect their use in the diagnosis and follow-up of HF patients.

Immunohistochemical Investigation into Protein Expression Patterns of FOXO4, IRF8 and LEF1 in Canine Osteosarcoma

Osteosarcoma (OSA) is the most common type of primary bone malignancy in people and dogs. Our previous molecular comparisons of canine OSA against healthy bone resulted in the identification of differentially expressed protein-expressing genes (forkhead box protein O4 (FOXO4), interferon regulatory factor 8 (IRF8), and lymphoid enhancer binding factor 1 (LEF1)). Immunohistochemistry (IHC) and H-scoring provided semi-quantitative assessment of nuclear and cytoplasmic staining alongside qualitative data to contextualise staining (n = 26 patients). FOXO4 was expressed predominantly in the cytoplasm with significantly lower nuclear H-scores. IRF8 H-scores ranged from 0 to 3 throughout the cohort in the nucleus and cytoplasm. LEF1 was expressed in all patients with significantly lower cytoplasmic staining compared to nuclear. No sex or anatomical location differences were observed. While reduced levels of FOXO4 might indicate malignancy, the weak or absent protein expression limits its primary use as diagnostic tumour marker. IRF8 and LEF1 have more potential for prognostic and diagnostic uses and facilitate further understanding of their roles within their respective molecular pathways, including Wnt/beta-catenin/LEF1 signalling and differential regulation of tumour suppressor genes. Deeper understanding of the mechanisms involved in OSA are essential contributions towards the development of novel diagnostic, prognostic, and treatment options in human and veterinary medicine contexts.

Phylogenetic and phylogeographic insights into Sri Lankan killifishes (Teleostei: Aplocheilidae).

Three nominal species of the killifish genus Aplocheilus are reported from the lowlands of Sri Lanka. Two of these, Aplocheilus dayi and Aplocheilus werneri, are considered endemic to the island, whereas Aplocheilus parvus is reported from both Sri Lanka and Peninsular India. Here, based on a collection from 28 locations in Sri Lanka, also including a dataset of Asian Aplocheilus downloaded from GenBank, we present a phylogeny constructed from the mitochondrial cytochrome b (cytb), mitochondrial cytochrome c oxidase subunit 1 (cox1), and nuclear recombination activating protein 1 (rag1), and investigate the interrelationships of the species of Aplocheilus in Sri Lanka. The endemic Sri Lankan aplocheilid clade comprising A. dayi and A. werneri is recovered as the sister group to the clade comprising A. parvus from Sri Lanka and Aplocheilus blockii from Peninsular India. The reciprocal monophyly of A. dayi and A. werneri is not supported in our molecular phylogeny. A. dayi and A. werneri display strong sexual dimorphism, but species-level differences are subtle, explained mostly by pigmentation patterns. Their phenotypes exhibit a parapatric distribution and may represent locally adapted forms of a single species. Alternatively, the present study does not rule out the possibility that A. dayi and A. werneri may represent an incipient species pair or that they have undergone introgression or hybridization in their contact zones. We provide evidence that the Nilwala-Gin region of southwestern Sri Lanka may have acted as a drought refugium for these fishes.

An Evolutionary Psychological Approach Toward BDSM Interest and Behavior.

Bondage/discipline, Dominance/submission, and Sadism/Masochism (BDSM) have gained increased attention and discussion in recent years. This prevalence is accompanied by a shift in perceptions of BDSM, including the declassification of sadomasochism as a paraphilic disorder. Evolutionary psychology offers a unique perspective of why some individuals are interested in BDSM and why some prefer certain elements of BDSM over others (e.g., dominance versus submission). In this paper, we examine BDSM from an evolutionary standpoint, examining biopsychosocial factors that underlie the BDSM interests and practice. We articulate this perspective via an exploration of: proximate processes, such as the role of childhood experiences, sexual conditioning, and physiological factors; as well as ultimate explanations for power play and pain play dimensions of BDSM, highlighting the potential adaptive advantages of each. While BDSM may not be adaptive in itself, we examine the literature of sex differences in BDSM role preferences and argue that these preferences may stem from the extreme forms of behaviors which enhance reproductive success. In the realm of pain play, we explore the intersection of pain and pleasure from both physiological and psychological perspectives, highlighting the crucial role of psychological and play partner factors in modulating the experience of pain. Finally, we encourage future research in social sciences to utilize evolutionary frameworks to further explore the subject and help alleviate the mystification surrounding BDSM. This multifaceted exploration of BDSM provides valuable insights for clinicians, kink-identified individuals, and scholars seeking to understand the evolutionary perspectives of human sexual behavior and preferences.

SEX DIFFERENCES IN THE CORONARY SYSTEM OF THE HUMAN HEART

The aim of this study is to investigate sex differences in the coronary system of the heart, considering all relevant consequence, and to compile and analyze the gathered data. Materials and Methods. The authors independently conducted a literature search and selection process using the PubMed database for the review, followed by the generalization of the obtained data. Results. Women exhibit a higher propensity than men for certain cardiovascular diseases, including persistent angina, non-obstructive coronary heart disease, coronary microvascular dysfunction, spontaneous coronary artery dissection, stress cardiomyopathy, and heart failure with preserved ejection fraction (HFpEF). In comparison to men, women typically present with elevated rates of underlying comorbidities, encompassing not only advanced age but also hypertension, diabetes mellitus, obesity, chronic renal failure, peripheral vascular disease, HFpEF, and inflammatory conditions like rheumatoid arthritis. Many of these conditions are linked to diffuse atherosclerosis and microvascular ischemia, with notable parallels between non-obstructive coronary heart disease and coronary microvascular dysfunction. Special attention is paid to patients sharing an increased risk of coronary heart disease events, which is consistent between women and men, except for those with severe coronary flow reserve (CFR) impairment, where women demonstrate an even higher risk. In particular, in cases where CFR impairment is not attributable to obstructive coronary heart disease (precluding revascularization to mitigate cardiovascular risk), there may be justification for a novel therapeutic approach for systemic coronary heart disease management. Cases of severe coronary microvascular dysfunction, often concurrent with non-obstructive coronary heart disease, may indicate a shared mechanism influencing coronary heart disease risk in both genders. This mechanism might involve inflammation, endothelial dysfunction, and heightened cardiomyocyte oxygen demand, culminating in microvascular ischemia, myocardial injury, and compromised cardiac function. Conclusions. Enhanced comprehension of the interplay between coronary vasomotor dysfunction and the concomitance of coronary heart disease with other conditions, such as insulin resistance and heart failure, could foster the advancement of novel systemic treatments aimed at leveraging “complete revascularization” more effectively.

Utilizing genetics and proteomics to assess the role of antihypertensive drugs in human longevity and the underlying pathways: a Mendelian randomization study.

Antihypertensive drugs are known to lower cardiovascular mortality, but the role of different types of antihypertensive drugs in lifespan has not been clarified. Moreover, the underlying mechanisms remain unclear. To minimize confounding, we used Mendelian randomization to assess the role of different antihypertensive drug classes in longevity and examined the pathways via proteins. Genetic variants associated with systolic blood pressure (SBP) corresponding to drug target genes were used as genetic instruments. The genetic associations with lifespan were obtained from a large genome-wide association study including 1 million European participants from UK Biobank and LifeGen. For significant antihypertensive drug classes, we performed sex-specific analysis, drug-target analysis and colocalization. To examine the mediation pathways, we assessed the associations of 2291 plasma proteins with lifespan, and examined the associations of drug classes with the proteins affecting lifespan. After correcting for multiple testing, genetically proxied beta-blockers (BBs), calcium channel blockers (CCBs) and vasodilators were related to longer life years (BBs: 2.03, 95% CI 0.78 to 3.28 per 5-mmHg reduction in SBP, CCBs: 3.40, 95% CI 1.47 to 5.33, and vasodilators: 2.92, 95% CI 1.08 to 4.77). The beneficial effects of BBs and CCBs were more obvious in men. ADRB1, CACNA2D2, CACNB3, CPT1A, CPT2, and EDNRA genes were related to extended lifespan with CPT2 further supported by colocalization evidence. 86 proteins were related to lifespan, of which 4 proteins were affected by CCBs. CDH1 may mediate the association between CCBs and lifespan. BBs, CCBs and vasodilators may prolong lifespan, with potential sex differences for BBs and CCBs. The role of CCBs in lifespan is partly mediated by CDH1. Prioritizing the potential protein targets can provide new insights into healthy aging.