Multiomic analyses uncover immunological signatures in acute and chronic coronary syndromes.

Acute and chronic coronary syndromes (ACS and CCS) are leading causes of mortality. Inflammation is considered a key pathogenic driver of these diseases, but the underlying immune states and their clinical implications remain poorly understood. Multiomic factor analysis (MOFA) allows unsupervised data exploration across multiple data types, identifying major axes of variation and associating these with underlying molecular processes. We hypothesized that applying MOFA to multiomic data obtained from blood might uncover hidden sources of variance and provide pathophysiological insights linked to clinical needs. Here we compile a longitudinal multiomic dataset of the systemic immune landscape in both ACS and CCS (n = 62 patients in total, n = 15 women and n = 47 men) and validate this in an external cohort (n = 55 patients in total, n = 11 women and n = 44 men). MOFA reveals multicellular immune signatures characterized by distinct monocyte, natural killer and T cell substates and immune-communication pathways that explain a large proportion of inter-patient variance. We also identify specific factors that reflect disease state or associate with treatment outcome in ACS as measured using left ventricular ejection fraction. Hence, this study provides proof-of-concept evidence for the ability of MOFA to uncover multicellular immune programs in cardiovascular disease, opening new directions for mechanistic, biomarker and therapeutic studies.

Single-Cell Dissection of the Immune Response After Acute Myocardial Infarction.

BACKGROUND: The immune system's role in ST-segment-elevated myocardial infarction (STEMI) remains poorly characterized but is an important driver of recurrent cardiovascular events. While anti-inflammatory drugs show promise in reducing recurrence risk, their broad immune system impairment may induce severe side effects. To overcome these challenges, a nuanced understanding of the immune response to STEMI is needed. METHODS: For this, we compared peripheral blood mononuclear single-cell RNA-sequencing (scRNA-seq) and plasma protein expression over time (hospital admission, 24 hours, and 6-8 weeks post-STEMI) in 38 patients and 38 controls (95 995 diseased and 33 878 control peripheral blood mononuclear cells). RESULTS: Compared with controls, classical monocytes were increased and CD56dim natural killer cells were decreased in patients with STEMI at admission and persisted until 24 hours post-STEMI. The largest gene expression changes were observed in monocytes, associating with changes in toll-like receptor, interferon, and interleukin signaling activity. Finally, a targeted cardiovascular biomarker panel revealed expression changes in 33/92 plasma proteins post-STEMI. Interestingly, interleukin-6R, MMP9 (matrix metalloproteinase-9), and LDLR (low-density lipoprotein receptor) were affected by coronary artery disease-associated genetic risk variation, disease status, and time post-STEMI, indicating the importance of considering these aspects when defining potential future therapies. CONCLUSIONS: Our analyses revealed the immunologic pathways disturbed by STEMI, specifying affected cell types and disease stages. Additionally, we provide insights into patients expected to benefit most from anti-inflammatory treatments by identifying the genetic variants and disease stage at which these variants affect the outcome of these (drug-targeted) pathways. These findings advance our knowledge of the immune response post-STEMI and provide guidance for future therapeutic studies.

Incidence and predictors of heart failure with reduced and preserved ejection fraction after ST-elevation myocardial infarction in the contemporary era of early percutaneous coronary intervention.

AIMS: The development and incidence of de-novo heart failure after ST-elevation myocardial infarction (STEMI) in the contemporary era of rapid reperfusion are largely unknown. We aimed to establish the incidence of post-STEMI heart failure, stratified by left ventricular ejection fraction (LVEF) and to find predictors for its occurrence. Furthermore, we investigated the course of left ventricular systolic and diastolic function after STEMI. METHODS AND RESULTS: A total of 1172 all-comer STEMI patients from the CardioLines Biobank were included. Patients were predominantly male (74.5%) and 64 ± 12 years of age. During a median follow-up of 3.7 years (2.0, 5.5) we found a total incidence of post-STEMI heart failure of 10.9%, of which 52.1% heart failure with reduced ejection fraction (HFrEF), 29.4% heart failure with mildly reduced ejection fraction and 18.5% heart failure with preserved ejection fraction (HFpEF). Independent predictors for the development of HFrEF were male sex (ß = 0.97, p = 0.009), lung crepitations (ß = 1.09, p = 0.001), potassium level (mmol/L, ß = 0.43, p = 0.012), neutrophil count (109/L, ß = 0.09, p = 0.001) and a reduced LVEF (ß = 1.91, p < 0.001) at baseline. Independent predictors for the development of HFpEF were female sex (ß = 0.99, p = 0.029), pre-existing kidney failure (ß = 1.95, p = 0.003) and greater left atrial volume index (ß = 0.04, p = 0.033) at baseline. Follow-up echocardiography (median follow-up 20 months) showed an improvement in LVEF (p < 0.001), whereas changes in diastolic function parameters showed both improvement and deterioration. CONCLUSION: In the current era of early STEMI reperfusion, still one in 10 patients develops heart failure, with approximately half of the patients with a reduced and half with a mildly reduced or normal LVEF. Predictors for the development of HFrEF were different from HFpEF.

The gut microbiome across the cardiovascular risk spectrum.

AIMS: Despite treatment advancements, cardiovascular disease remains a leading cause of death worldwide. Identifying new targets is crucial for enhancing preventive and therapeutic strategies. The gut microbiome has been associated with coronary artery disease (CAD), however our understanding of specific changes during CAD development remains limited. We aimed to investigate microbiome changes in participants without clinically manifest CAD with different cardiovascular risk levels and in patients with ST-elevation myocardial infarction (STEMI). METHODS: In this cross-sectional study, we characterized the gut microbiome using metagenomics of 411 faecal samples from individuals with low (n=130), intermediate (n=130) and high (n=125) cardiovascular risk based on the Framingham score, and STEMI patients (n=26). We analysed diversity, and differential abundance of species and functional pathways while accounting for confounders including medication and technical covariates. RESULTS: Collinsella stercoris, Flavonifractor plautii and Ruthenibacterium lactatiformans showed increased abundances with cardiovascular risk, while Streptococcus thermophilus was negatively associated. Differential abundance analysis revealed eight species and 49 predicted metabolic pathways that were differently abundant among the groups. In the gut microbiome of STEMI patients, there was a depletion of pathways linked to vitamin, lipid and amino-acid biosynthesis. CONCLUSION: We identified four microbial species showing a gradual trend in abundance from low-risk individuals to those with STEMI, and observed differential abundant species and pathways in STEMI patients compared to those without clinically manifest CAD. Further investigation is warranted to gain deeper understanding of their precise role in CAD progression and potential implications, with the ultimate goal of identifying novel therapeutic targets.

Despite previous studies demonstrating dysbiosis in STEMI patients, our understanding of the precise microbiome changes across the cardiovascular risk spectrum remains limited. This study addresses this knowledge gap by providing insights into the gut microbiome composition of individuals across varying cardiovascular risk levels and STEMI patients. By examining the gut microbiome of carefully selected participants from the general population with three different risk levels and a unique group of STEMI patients, we identified microbial species and pathways with differential abundance across the groups. Several of these species and pathways are associated with inflammation and lipid metabolism, which are key factors in CAD development. Collinsella stercoris, Flavonifractor plautii and Ruthenibacterium lactatiformans are increasingly abundant, while Streptococcus thermophilus is decreasingly abundant across the cardiovascular risk spectrum. The gut microbiome of STEMI patients showed eight differentially abundant species compared to groups at risk. Notably, four of these species, characterized by an elevated abundance in STEMI patients, have not been previously reported.

Fetuin-A and its genetic association with cardiometabolic disease.

Fetuin-A acts as both an inhibitor of calcification and insulin signaling. Previous studies reported conflicting results on the association between fetuin-A and cardiometabolic diseases. We aim to provide further insights into the association between genetically predicted levels of fetuin-A and cardiometabolic diseases using a Mendelian randomization strategy. Genetic variants associated with fetuin-A and their effect sizes were obtained from previous genetic studies. A series of two-sample Mendelian randomization analyses in 412,444 unrelated individuals from the UK Biobank did not show evidence for an association of genetically predicted fetuin-A with any stroke, ischemic stroke, or myocardial infarction. We do find that increased levels of genetically predicted fetuin-A are associated with increased risk of type 2 diabetes (OR = 1.21, 95%CI 1.13-1.30, P = < 0.01). Furthermore, genetically predicted fetuin-A increases the risk of coronary artery disease in individuals with type 2 diabetes, but we did not find evidence for an association between genetically predicted fetuin-A and coronary artery disease in those without type 2 diabetes (P for interaction = 0.03). One SD increase in genetically predicted fetuin-A decreases risk of myocardial infarction in women, but we do not find evidence for an association between genetically predicted fetuin-A and myocardial infarction in men (P for interaction = < 0.01). Genetically predicted fetuin-A is associated with type 2 diabetes. Furthermore, type 2 diabetes status modifies the association of genetically predicted fetuin-A with coronary artery disease, indicating that fetuin-A increases risk in individuals with type 2 diabetes. Finally, higher genetically predicted fetuin-A reduces the risk of myocardial infarction in women, but we do not find evidence for an association between genetically predicted fetuin-A and myocardial infarction in men.

Single-cell profiling of low-stage endometrial cancers identifies low epithelial vimentin expression as a marker of recurrent disease.

BACKGROUND: Identification of aggressive low-stage endometrial cancers is challenging. So far, studies have failed to pinpoint robust features or biomarkers associated with risk of recurrence for these patients. METHODS: Imaging mass cytometry was used to examine single-cell expression of 23 proteins in 36 primary FIGO IB endometrial cancers, of which 17 recurred. Single-cell information was extracted for each tumor and unsupervised clustering was used to identify cellular phenotypes. Distinct phenotypes and cellular neighborhoods were compared in relation to recurrence. Cellular differences were validated in a separate gene expression dataset and the TCGA EC dataset. Vimentin protein expression was evaluated by IHC in pre-operative samples from 518 patients to validate its robustness as a prognostic marker. FINDINGS: The abundance of epithelial, immune or stromal cell types did not associate with recurrence. Clustering of patients based on tumor single cell marker expression revealed distinct patient clusters associated with outcome. A cell population neighboring CD8+ T cells, defined by vimentin, ER, and PR expressing epithelial cells, was more prevalent in non-recurrent tumors. Importantly, lower epithelial vimentin expression and lower gene expression of VIM associated with worse recurrence-free survival. Loss and low expression of vimentin was validated by IHC as a robust marker for recurrence in FIGO I stage disease and predicted poor prognosis also when including all patients and in endometrioid patients only. INTERPRETATION: This study reveals distinct characteristics in low-stage tumors and points to vimentin as a clinically relevant marker that may aid in identifying a here to unidentified subgroup of high-risk patients. FUNDING: A full list of funding that contributed to this study can be found in the Acknowledgements section.

Identification of genetic variants that impact gene co-expression relationships using large-scale single-cell data.

BACKGROUND: Expression quantitative trait loci (eQTL) studies show how genetic variants affect downstream gene expression. Single-cell data allows reconstruction of personalized co-expression networks and therefore the identification of SNPs altering co-expression patterns (co-expression QTLs, co-eQTLs) and the affected upstream regulatory processes using a limited number of individuals. RESULTS: We conduct a co-eQTL meta-analysis across four scRNA-seq peripheral blood mononuclear cell datasets using a novel filtering strategy followed by a permutation-based multiple testing approach. Before the analysis, we evaluate the co-expression patterns required for co-eQTL identification using different external resources. We identify a robust set of cell-type-specific co-eQTLs for 72 independent SNPs affecting 946 gene pairs. These co-eQTLs are replicated in a large bulk cohort and provide novel insights into how disease-associated variants alter regulatory networks. One co-eQTL SNP, rs1131017, that is associated with several autoimmune diseases, affects the co-expression of RPS26 with other ribosomal genes. Interestingly, specifically in T cells, the SNP additionally affects co-expression of RPS26 and a group of genes associated with T cell activation and autoimmune disease. Among these genes, we identify enrichment for targets of five T-cell-activation-related transcription factors whose binding sites harbor rs1131017. This reveals a previously overlooked process and pinpoints potential regulators that could explain the association of rs1131017 with autoimmune diseases. CONCLUSION: Our co-eQTL results highlight the importance of studying context-specific gene regulation to understand the biological implications of genetic variation. With the expected growth of sc-eQTL datasets, our strategy and technical guidelines will facilitate future co-eQTL identification, further elucidating unknown disease mechanisms.

An exploratory study of clinical characteristics and gait features of adolescents with hypermobility disorders.

BACKGROUND: In adolescents with non-pathological and pathological joint hypermobility, gait deviations have been associated with pain and fatigue. It remains unclear what distinguishes the non-pathological form of joint hypermobility (JH) from pathological forms (i.e. hypermobile Ehlers-Danlos syndrome (hEDS) or hypermobility spectrum disorders (HSD). Our objective was to identify discriminative clinical characteristics and biomechanical gait features between adolescents with hEDS/HSD, JH, and healthy controls (HC). METHODS: Thirty-two adolescents were classified into three subgroups (hEDS/HSD=12, JH=5, HC=15). Clinical characteristics (e.g. pain intensity and surface, fatigue, functional disability) were inventoried. The gait pattern was assessed using a three-dimensional, eight-camera VICON MX1.3 motion capture system, operating at a sample rate of 100 Hz (VICON, Oxford, UK). Spatiotemporal parameters, joint angles (sagittal plane), joint work, joint impulse, ground reaction force and gait variability expressed as percentage using Principal Component Analysis (PCA) were assessed and analysed using multivariate analysis. Multivariate analysis data is expressed in mean differences(MD), standard error(SE) and P-values. RESULTS: The hEDS/HSD-group had significantly higher fatigue score (+51.5 points, p = <0.001) and functional disability (+1.6, p < .001) than the HC-group. Pain intensity was significantly higher in the hEDS/HSD-group than the other subgroups (JH; +37 mm p = .004, HC; +38 mm, p = .001). The hEDS/HSD-group showed significantly more gait variability (JH; +7.2(2.0)% p = .003, HC; + 7.8(1.4)%, p = <0.001) and lower joint work (JH; -0.07(0.03)J/kg, p = .007, HC; - 0.06(0.03)J/kg, p = .013) than the other subgroups. The JH-group showed significantly increased ankle dorsiflexion during terminal stance (+5.0(1.5)degree, p = .001) compared to hEDS/HSD-group and knee flexion during loading response compared to HC-group (+5.7(1.8) degree, p = .011). SIGNIFICANCE: A distinctive difference in gait pattern between adolescents with non-pathological and pathological joint hypermobility is found in gait variability, rather than in the biomechanical features of gait. This suggests that a specific gait variability metric is more appropriate than biomechanical individual joint patterns for assessing gait in adolescents with hEDS/HSD.

Predictors of adverse diastolic remodeling in non-diabetic patients presenting with ST-elevation myocardial infarction.

BACKGROUND: Adverse systolic remodeling after ST-elevation myocardial infarction (STEMI) is associated with poor clinical outcomes. However, little is known about diastolic remodeling. The purpose of this study was to identify the factors leading to diastolic remodeling. METHODS: Echocardiography was performed during hospitalization and at 4 months follow-up in 267 non-diabetic STEMI patients from the GIPS-III trial. As parameters of diastolic remodeling we used (1.) the E/e' at 4 months adjusted for the E/e' at hospitalization and (2.) the change in E/e' between hospitalization and 4 months. Multivariable regression models correcting for age and sex were constructed to identify possible association of clinical and angiographic variables as well as biomarkers with diastolic remodeling. RESULTS: Older age, female gender, hypertension, multi vessel disease, higher glucose and higher peak CK were independent predictors of higher E/e' at 4 months in a multivariable model (R2:0.20). After adjustment for E/e' during hospitalization only female gender, multivessel disease and higher glucose remained predictors of E/e' at four months (R2:0.40). Lower myocardial blush grade, AST and NT-proBNP were independent predictors of a higher increase of E/e' between hospitalization and at 4 months in a multivariable model (R2:0.08). CONCLUSIONS: Our data supports the hypothesis that female gender, multivessel coronary artery disease, and microvascular damage are important predictors of adverse diastolic remodeling after STEMI. In addition, our data suggests that older age and hypertension prior to STEMI may have contributed to worse pre-existing diastolic function. TRIAL REGISTRATION: NIH, NCT01217307. Prospectively registered on October 8th 2010, https://clinicaltrials.gov/ct2/show/NCT01217307 .

Effects of specialist care lower limb orthoses on personal goal attainment and walking ability in adults with neuromuscular disorders.

BACKGROUND: Lower limb orthoses intend to improve walking in adults with neuromuscular disorders (NMD). Yet, reported group effects of lower limb orthoses on treatment outcomes have generally been small and heterogeneous. We propose that guideline-based orthotic care within a multidisciplinary expert setting may improve treatment outcomes. AIM: To examine the effectiveness of specialist care orthoses compared to usual care orthoses on personal goal attainment and walking ability. DESIGN: Cohort study. POPULATION: Adults with NMD who experienced walking problems due to calf and/or quadriceps muscle weakness and were provided with a specialist care lower limb orthosis between October 2011 and January 2021. METHODS: Three months after provision, the specialist care orthosis was compared to the usual care orthosis worn at baseline in terms of personal goal attainment (Goal Attainment Scaling (GAS)), comfortable walking speed (m/s), net energy cost (J/kg/m) (both assessed during a 6-minute walk test), perceived walking ability and satisfaction. RESULTS: Sixty-four adults with NMD were eligible for analysis. The specialist care orthoses comprised 19 dorsiflexion-restricting ankle-foot orthoses (AFOs), 22 stance-control knee-ankle-foot orthoses (KAFOs) and 23 locked KAFOs. Overall, 61% of subjects showed a clinically relevant improvement in GAS score. Perceived safety, stability, intensity, fear of falling and satisfaction while walking all improved (p≤0.002), and subjects were satisfied with their specialist care orthosis and the services provided. Although no effects on walking speed or net energy cost were found in combined orthosis groups, specialist care AFOs significantly reduced net energy cost (by 9.5%) compared to usual care orthoses (from mean (SD) 3.81 (0.97) to 3.45 (0.80) J/kg/m, p = 0.004). CONCLUSION: Guideline-based orthotic care within a multidisciplinary expertise setting could improve treatment outcomes in adults with NMD compared to usual orthotic care by improvements in goal attainment and walking ability. A randomized controlled trial is now warranted to confirm these results.

Mismatch repair markers in preoperative and operative endometrial cancer samples; expression concordance and prognostic value.

BACKGROUND: The endometrial cancer mismatch repair (MMR) deficient subgroup is defined by loss of MSH6, MSH2, PMS2 or MLH1. We compare MMR status in paired preoperative and operative samples and investigate the prognostic impact of differential MMR protein expression levels. METHODS: Tumour lesions from 1058 endometrial cancer patients were immunohistochemically stained for MSH6, MSH2, PMS2 and MLH1. MMR protein expression was evaluated as loss or intact to determine MMR status, or by staining index to evaluate the prognostic potential of differential expression. Gene expression data from a local (n = 235) and the TCGA (n = 524) endometrial cancer cohorts was used for validation. RESULTS: We identified a substantial agreement in MMR status between paired curettage and hysterectomy samples. Individual high expression of all four MMR markers associated with non-endometrioid subtype, and high MSH6 or MSH2 strongly associated with several aggressive disease characteristics including high tumour grade and FIGO stage, and for MSH6, with lymph node metastasis. In multivariate Cox analysis, MSH6 remained an independent prognostic marker, also within the endometrioid low-grade subgroup (P < 0.001). CONCLUSION: We demonstrate that in addition to determine MMR status, MMR protein expression levels, particularly MSH6, may add prognostic information in endometrial cancer.

Health-related quality of life in parents of adolescents one year into the COVID-19 pandemic: a two-year longitudinal study.

AIM: For many adults, their role as a parent is a vital part of their life that may influence their health-related quality of life (HRQOL) and vary with the age of their child. The aim of the present study was to describe and compare sociodemographic and psychological factors, pain and HRQOL in parents of adolescents assessed at baseline and 2 years later,-during the COVID-19 pandemic. METHODS: A longitudinal study of 309 parents from the general Norwegian population was conducted. The parents were chosen based on their adolescent's school belonging and responded to a web-based questionnaire. We used data collected at baseline (T1), when the adolescents were aged 14-15 years (2018/2019), and two years later (T2), in 2021, when the COVID-19 pandemic was ongoing. The response rate was 55%. HRQOL was assessed using RAND-36. Data were analysed using McNemar tests, paired samples t-tests and multiple linear regression analyses. RESULTS: Of the participants, 82% were mothers and 18% fathers. From T1 to T2, the average pain score increased, 1.6 (95% CI [-1,4; 1.8]) vs 1.8 (95% CI [1,6; 2.0]), the pain interference emotion score increased, 1.6 (95% CI [1.3; 1.9]) vs 1.8 (95% CI [1.5; 2.1]), and a larger proportion reported pain duration > 3 months (44% vs 50%, p = 0.014). The parents were more lonely, 12.8 (95% CI [12.3; 13.3]) vs 13.7 (95% CI [13.2; 14.2]), and reported lower RAND-36 mental component summary (MCS) scores, 52.2 (95% CI [51.3; 53.2]) vs 50.9 (95% CI [49.8; 52.0]). There were no significant associations between gender, sociodemographic factors, psychological factors, pain at T1 and changes in RAND-36 physical component summary (PCS). A positive change in MCS from T1 to T2 was predicted by working part time, B = 5.22 (95% CI [1.05; 9.38]) (ref no paid work) and older age, B = 0.24, (95%CI [-001; 0.42]), and there was a negative change with stress, B = -17.39, (95%CI [-27.42; -7.51]). CONCLUSION: The parents experienced more pain and were lonelier, and more reported reduced mental HRQOL. However, the changes appear to be of limited clinical significance.

In what ways do emerging adults with substance use problems experience their communities as influencing their personal recovery processes?

Applying the multiple psychological sense of community concept (MPSOC), this study explored how emerging adults with substance use problems experience the influences of various senses of community and communities on their personal recovery processes. Semi-structured interviews with 21 emerging adults from different urban contexts in Norway were analysed using a collaborative, seven-step, deductive, and reflexive thematic approach. MPSOC is shown to be a key concept for achieving a broad, in-depth understanding of emerging adults' senses of community and personal experiences of community influences on recovery processes from substance use. Positive and negative senses of community in geographical, relational, substance use-related and ideal communities influence the potentials and challenges in emerging adults' recovery processes. Supportive and motivating community relationships, meaningful activities with peers, and distance from recovery-impeding communities were identified as important recovery components. To promote recovery and prevent substance use in emerging adults, community approaches and tools applied in substance use treatment have to take into account and utilise multidimensional and age group-specific aspects of belonging.

Relation of Iron Status to Prognosis After Acute Coronary Syndrome.

Iron deficiency has been extensively researched and is associated with adverse outcomes in heart failure. However, to our knowledge, the temporal evolution of iron status has not been previously investigated in patients with acute coronary syndrome (ACS). Therefore, we aimed to explore the temporal pattern of repeatedly measured iron, ferritin, transferrin, and transferrin saturation (TSAT) in relation to prognosis post-ACS. BIOMArCS (BIOMarker study to identify the Acute risk of a Coronary Syndrome) is a prospective, multicenter, observational cohort study conducted in The Netherlands between 2008 and 2015. A total of 844 patients with post-ACS were enrolled and underwent high-frequency (median 17) blood sampling during 1 year follow-up. Biomarkers of iron status were measured batchwise in a central laboratory. We analyzed 3 patient subsets, including the case-cohort (n = 187). The primary endpoint (PE) was a composite of cardiovascular mortality and repeat nonfatal ACS, including unstable angina pectoris requiring revascularization. The association between iron status and the PE was analyzed using multivariable joint models. Mean age was 63 years; 78% were men, and >50% had iron deficiency at first sample in the case-cohort. After adjustment for a broad range of clinical variables, 1 SD decrease in log-iron was associated with a 2.2-fold greater risk of the PE (hazard ratio 2.19, 95% confidence interval 1.34 to 3.54, p = 0.002). Similarly, 1 SD decrease in log-TSAT was associated with a 78% increased risk of the PE (hazard ratio 1.78, 95% confidence interval 1.17 to 2.65, p = 0.006). Ferritin and transferrin were not associated with the PE. Repeated measurements of iron and TSAT predict risk of adverse outcomes in patients with post-ACS during 1 year follow-up. Trial Registration: The Netherlands Trial Register. Unique identifiers: NTR1698 and NTR1106. Registered at https://www.trialregister.nl/trial/1614 and https://www.trialregister.nl/trial/1073.

Large HDL particles negatively associate with leukocyte counts independent of cholesterol efflux capacity: A cross sectional study in the population-based LifeLines DEEP cohort.

BACKGROUND AND AIMS: Leukocytosis, the expansion of white blood cells, is associated with increased cardiovascular risk. Studies in animal models have shown that high-density lipoprotein cholesterol (HDL-c) suppresses leukocytosis by mediating cholesterol efflux from hematopoietic stem and progenitor cells. HDL-c showed a moderate negative association with leukocyte numbers in the UK Biobank and Multi-Ethnic Study of Atherosclerosis. Cholesterol efflux capacity of HDL (HDL-CEC) or HDL particle (HDL-P) number has been proposed as improved inverse predictor of CVD compared to plasma HDL-c. In the LifeLines DEEP (LLD) cohort (n = 962), a sub-cohort representing the prospective population-based LL cohort from the North of The Netherlands, we tested the hypothesis that HDL-CEC and HDL-P were associated with lower leukocyte counts. METHODS: We carried out multivariable regression and causal mediation analyses (CMA) to test associations between HDL-c, HDL-CEC, or HDL-P and leukocyte counts. We measured HDL-CEC in THP-1 macrophages and HDL-P and composition using nuclear magnetic resonance. RESULTS: HDL-c associated negatively with leukocyte counts, as did extra-large and large HDL-P, while HDL-CEC showed no association. Each one-standard deviation (SD) increase in extra-large HDL-P was associated with 3.0% and 4.8% lower leukocytes and neutrophils, respectively (q < 0.001). In contrast, plasma concentration of small HDL-P associated positively with leukocyte and neutrophil counts, as did small HDL-P triglycerides (TG) and total plasma TG. CMA showed that the association between S-HDL-P and leukocytes was mediated by S-HDL-TG. CONCLUSIONS: The association between HDL-P and leukocyte counts in the general population is dependent on HDL-P size and composition, but not HDL-CEC.

Translational insights from single-cell technologies across the cardiovascular disease continuum.

Cardiovascular disease is the leading cause of death worldwide. The societal health burden it represents can be reduced by taking preventive measures and developing more effective therapies. Reaching these goals, however, requires a better understanding of the pathophysiological processes leading to and occurring in the diseased heart. In the last 5 years, several biological advances applying single-cell technologies have enabled researchers to study cardiovascular diseases with unprecedented resolution. This has produced many new insights into how specific cell types change their gene expression level, activation status and potential cellular interactions with the development of cardiovascular disease, but a comprehensive overview of the clinical implications of these findings is lacking. In this review, we summarize and discuss these recent advances and the promise of single-cell technologies from a translational perspective across the cardiovascular disease continuum, covering both animal and human studies, and explore the future directions of the field.

What really matters: a patient-centered instrument to evaluate health-related quality of life in cardiovascular disease.

AIMS: Patient-reported outcome measures (PROMs) to assess health-related quality of life (HRQoL) are increasingly used to guide decision-making in cardiovascular care. However, many of the existing PROMs are developed with limited patient involvement and overlook personal health preferences. We aim to develop a cardiovascular disease (CVD)-specific patient-centred preference-based PROM to assess and monitor HRQoL in CVD patients. METHODS AND RESULTS: A mixed-methods study consisting of several phases was conducted to identify important health items: (i) a scoping literature review, (ii) first- and second-round expert group meetings, (iii) interviews with CVD patients, and (iv) an online survey asking CVD patients to indicate from a large set those health items that are considered the most important. The literature review, expert group meetings, and patient interviews resulted in a list of 55 items potentially important to CVD patients. In total, 666 CVD patients responded to the survey. The following nine items were considered the most important by CVD patients: mobility, activities, self-reliance, fatigue, shortness of breath, chest pain, palpitations, anxiety/worrying, and sexual limitations. An electronic preference-based PROM consisting of these nine items was developed within a cloud-based environment for clinical implementation. CONCLUSION: Nine items considered the most important for health by CVD patients were identified and included in a new preference-based patient-centred PROM. This new CVD-specific PROM can be easily implemented using the electronic application and has the potential to improve quality of care for CVD patients.