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001). Using a genetic score of 5 screened single-nucleotide polymorphisms in

and

as the instrumental variable, genetically predicted elevation in PARP activity showed a causal association with obstructive CAD (odds ratio=1.35,

<0.001). In contrast, the genetic risk of CAD had no significant effect on PARP activity. Ex vivo and in vitro cultures of human monocytes showed that rs747657, as the lead single-nucleotide polymorphism strongly associated with PARP activity, caused the differential binding of transcription factor GATA2 (GATA-binding protein 2) to an intronic regulatory region in

, thus modulating

expression and PARP activity.

Greater PARP activity may have causal roles in the development of obstructive CAD among patients with diabetes mellitus.

Greater PARP activity may have causal roles in the development of obstructive CAD among patients with diabetes mellitus.

Characterize homozygous familial hypercholesterolemia (HoFH) individuals from Iberoamerica. Approach and Results In a cross-sectional retrospective evaluation 134 individuals with a HoFH phenotype, 71 adults (age 39.3±15.8 years, 38.0% males), and 63 children (age 8.8±4.0 years, 50.8% males) were studied. Genetic characterization was available in 129 (96%). The majority (91%) were true homozygotes (true HoFH, n=79, 43.0% children, 46.8% males) or compound heterozygotes (compound heterozygous familial hypercholesterolemia, n=39, 51.3% children, 46.2% males) with putative pathogenic variants in the

. True HoFH due to

variants had higher total (

=0.015) and LDL (low-density lipoprotein)-cholesterol (

=0.008) compared with compound heterozygous familial hypercholesterolemia. Children with true HoFH (n=34) tended to be diagnosed earlier (

=0.051) and had a greater frequency of xanthomas (

=0.016) than those with compound heterozygous familial hypercholesterolemia (n=20). Previous major cardiovascular evardiovascular complications were heterogeneous and associated with the type of molecular defect.

Deep vein thrombosis and pulmonary embolism referred as venous thromboembolism (VTE) are a common cause of morbidity and mortality. Plasma from healthy controls or individuals who have experienced a VTE were analyzed using metabolomics to characterize biomarkers and metabolic systems of patients with VTE. Approach and Results Polar metabolite and lipidomic profiles from plasma collected 3 months after an incident VTE were obtained using liquid chromatography mass spectrometry. Fasting-state plasma samples from 42 patients with VTE and 42 healthy controls were measured. Plasma metabolomic profiling identified 512 metabolites forming 62 biological clusters. Multivariate analysis revealed a panel of 21 metabolites altogether capable of predicting VTE status with an area under the curve of 0.92 (

=0.00174, selectivity=0.857, sensitivity=0.971). Multiblock systems analysis revealed 25 of the 62 functional biological groups as significantly affected in the VTE group (

<0.05 to control). CP43 Complementary correlation network analysis of the dysregulated functions highlighted a subset of the lipidome composed mainly of n-3 long-chain polyunsaturated fatty acids within the predominant triglycerides as a potential regulator of the post-VTE event biological response, possibly controlling oxidative and inflammatory defence systems, and metabolic disorder associated dysregulations. Of interest was microbiota metabolites including trimethylamine N-oxide that remained associated to post incident VTE patients, highlighting a possible involvement of gut microbiota on VTE risk and relapse.

These findings show promise for the elucidation of underlying mechanisms and the design of a diagnostic test to assess the likely efficacy of clinical care in patients with VTE.

These findings show promise for the elucidation of underlying mechanisms and the design of a diagnostic test to assess the likely efficacy of clinical care in patients with VTE.

Extracellular vesicles (EVs) have the potential to act as intercellular communicators. The aims were to characterize circulating EVs in patients with pulmonary arterial hypertension (PAH) and to explore whether these EVs contribute to endothelial activation and angiogenesis. Approach and Results Patients with PAH (n=70) and healthy controls (HC; n=20) were included in this cross-sectional study. EVs were characterized and human pulmonary endothelial cells (hPAECs) were incubated with purified EVs. Endothelial cell activity and proangiogenic markers were analyzed. Tube formation analysis was performed for hPAECs, and the involvement of PSGL-1 (P-selectin glycoprotein ligand 1) was evaluated. The numbers of CD62P

, CD144

, and CD235a EVs were higher in blood from PAH compared with HC. Thirteen proteins were differently expressed in PAH and HC EVs, where complement fragment C1q was the most significantly elevated protein (

=0.0009) in PAH EVs. Upon EVs-internalization in hPAECs, more PAH compared with HC EVce activation of hPAECs and in vitro angiogenesis. These effects were partly because of platelet-derived EVs evasion of lysosomes upon internalization within hPAEC and through possible involvement of P-selectin-PSGL-1 pathway.

Apo (apolipoprotein) CIII mediates the metabolism of triglyceride (TG)-rich lipoproteins. High levels of plasma apoCIII are positively correlated with the plasma TG levels and increase the cardiovascular risk. However, whether apoCIII is directly involved in the development of atherosclerosis has not been fully elucidated. Approach and Results To examine the possible roles of apoCIII in lipoprotein metabolism and atherosclerosis, we generated apoCIII KO (knockout) rabbits using ZFN (zinc finger nuclease) technique. On a normal standard diet, apoCIII KO rabbits exhibited significantly lower plasma levels of TG than those of WT (wild type) rabbits while total cholesterol and HDL (high-density lipoprotein) cholesterol levels were unchanged. Analysis of lipoproteins isolated by sequential ultracentrifugation revealed that reduced plasma TG levels in KO rabbits were accompanied by prominent reduction of VLDLs (very-low-density lipoproteins) and IDLs (intermediate-density lipoproteins). In addition, KO rabbits sho for atherosclerosis.

Gender disparities in authorship of heart failure (HF) guideline citations and clinical trials have not been examined.

We identified authors of publications referenced in Class I Recommendations in United States (n=173) and European (n=100) HF guidelines and of publications of all HF trials with >400 participants (n=118) published between 2001 and 2016. Authors' genders were determined, and changes in authorship patterns over time were evaluated with linear regression and nonparametric testing.

The median proportion of women authors per publication was 20% (interquartile range [IQR], 8%-33%) in United States guidelines, 14% (IQR, 2%-20%) in European guidelines, and 11% (IQR, 4%-20%) in HF trials. The proportion of women authors increased modestly over time in United States and European guidelines' references (β=0.005 and 0.003, respectively, from 1986 to 2016;

<0.001) but not in HF trials (12.5% [IQR, 0%-20%] in 2001-2004 to 8.9% [IQR, 0%-20%] in 2013-2016;

>0.50). Overall proportions of women as first or last authors in HF trials (16%) did not change significantly over time (

=0.60). North American HF trials had the highest likelihood of having a woman as first or senior author (24%). HF trials with a woman first or senior author were associated with a higher proportion of enrolled female participants (39% versus 26%,

=0.01).

In HF practice guidelines and trials, few women are authors of pivotal publications. Higher number of women authors is associated with higher enrollment of women in HF trials. Barriers to authorship and representation of women in HF guidelines and HF trial leadership need to be addressed.

In HF practice guidelines and trials, few women are authors of pivotal publications. Higher number of women authors is associated with higher enrollment of women in HF trials. Barriers to authorship and representation of women in HF guidelines and HF trial leadership need to be addressed.

The kidneys play an important role in heart failure (HF), but it is unclear if renal biomarkers improve HF risk prediction beyond established risk factors. We aimed to assess whether adding biomarkers of kidney disease to conventional risk factors improved 10-year risk prediction for incident HF in a contemporary community sample.

We included 450 212 participants in the UK Biobank aged 39 to 70 years without HF who had been assessed in 2006 to 2010 with the urine albumin-to-creatinine ratio and estimated glomerular filtration rate (eGFR) based on serum creatinine and cystatin C. There were 1701 incident cases of HF during up to 10.3 years of follow-up (mean 8.2±0.7 years). We used the Atherosclerosis Risk in Communities study heart failure risk score excluding natriuretic peptides as the base model to which we added eGFR and urine albumin-to-creatinine ratio. Harrell's C-statistic of ARIC-HF was 0.845 (95% CI, 0.831-0.859).

Each combination of added kidney measures (creat-eGFR, cysC-eGFR, and urine alburole of impaired kidney function in HF development in asymptomatic persons.

This study evaluates the impact of the 2018 allocation policy change on outcomes of orthotopic heart transplantation (OHT) in patients bridged with intra-aortic balloon pumps (IABPs).

Adult (≥18 years) patients undergoing OHT between 2013 and 2019 who were bridged with an IABP were stratified based on temporal relation to the policy change. Univariate analysis was used to compare baseline characteristics and postoperative outcomes. Multivariate Cox regression analysis was used to estimate risk-adjusted predictors of post-transplant mortality.

A total of 1342 (8.6%) OHT patients were bridged with an IABP during the study period. Rates of bridging with IABP to OHT increased significantly after the policy change (7.0% versus 24.9%,

<0.001). The mean recipient age was 54.1±12.1 years with 981 (73.1%) patients being male. Baseline characteristics were similar between the 2 groups whereas post-policy change patients spent fewer days on the waitlist (15 versus 35 days,

<0.001), had longer ischemic times (3.5 versus 3.0 hours,

<0.001), and received organs from a greater distance (301 versus 105 miles,

<0.001). By multivariable analysis, days on the waitlist (for every 30 days; odds ratio, 1.01 [95% CI, 1.00-1.02],

=0.031) and diabetes mellitus (odds ratio, 1.87 [95% CI, 1.16-3.02],

=0.011) emerged as significant predictors of post-transplant mortality. After the policy change, waitlisted patients requiring IABP support were more likely to survive to transplant (76.4 versus 89.8%,

<0.001).

IABP utilization has increased over 3-fold since the 2018 policy change with improved waitlist outcomes and comparable post-OHT survival. Thus, bridging patients to OHT with IABPs appears to be an effective strategy in the current era.

IABP utilization has increased over 3-fold since the 2018 policy change with improved waitlist outcomes and comparable post-OHT survival. Thus, bridging patients to OHT with IABPs appears to be an effective strategy in the current era.