Risultati per: L'automisurazione della pressione arteriosa: I target pressori

Objectives
Target trial emulation is an approach that is increasingly used to improve transparency in observational studies and help mitigate biases. For studies declaring that they emulated a target trial, we aimed to evaluate the specification of the target trial, examine its consistency with the observational emulation and assess the risk of bias in the observational analysis.

Design
Methodological systematic review reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.

Data sources
The database MEDLINE (Medical Literature Analysis and Retrieval System Online) was interrogated for all studies published from 1 January 2021 to 3 July 2022. We performed an additional manual search of 20 general medical and specialised journals that spanned the same period.

Eligibility criteria
All studies that declared emulating a hypothetical or real randomised trial were eligible.

Data extraction and synthesis
Two independent reviewers performed the whole systematic review process (screening and selection of studies, data extraction and risk of bias assessment). The main outcomes were the definition of the key protocol components of the target trial and its emulation, consistency between the target trial and its emulation and risk of bias according to the ROBINS-I (Risk Of Bias In Non-randomised Studies – of Interventions) tool.

Results
Among the selected sample of 100 studies, 24 (24%) did not specify the target trial. Only 40 studies (40%) provided detailed information on all components of the target trial protocol. Eligibility criteria, intervention strategies and outcomes were consistent between the target trial and its emulation in 35 studies (46% of those specifying the target trial). Overall, 28 studies (28%) exhibited serious risk of bias and 41 (41%) had misalignments in the timing of eligibility assessment, treatment assignment and the start of follow-up (time-zero). As compared with studies that did not specify the target trial, those that did specify the trial less frequently seemed to have both time-zero issues (39% vs 52%) and serious risk of bias (26% vs 33%).

Conclusions
One-quarter of studies declaring that they emulated a target trial did not specify the trial. Target trials and their emulations were particularly inconsistent for studies emulating a real randomised trial. Risk of methodological issues seemed lower in observational analyses that specified versus did not specify the target trial.

Circulation, Volume 150, Issue Suppl_1, Page A4146556-A4146556, November 12, 2024. Introduction:Pulmonary hypertension (PH) is a fatal cardiovascular disease marked by extensive vascular remodeling. Pericytes, crucial for capillary function and typically associated with endothelial cells (ECs), are dysfunctional in PH and contribute significantly to vascular remodeling. Our research indicates that Aminopeptidase-N (APN) is overexpressed in the lungs of PH patients, contributing to pericyte proliferation, although the underlying mechanisms remain unclear. We recently discovered elevated stratifin (SFN) levels in the ECs of PH patients. SFN is known to interact with proteins like APN and activate downstream signaling pathways.Hypothesis:We hypothesize that elevated SFN binds to pericyte APN, triggering a pathological proliferative response.Methods:We utilized rats with the NFU1 (G208C) mutation, which develop spontaneous PH characterized by severe vascular remodeling and increased right ventricular systolic pressure (RVSP). To analyze cell phenotype shifts, we employed scRNA-seq and confocal imaging. Additionally, we used R18, a peptide that inhibits SFN activation of downstream targets, to explore if targeting SFN reverses PH.Results:We found elevated circulating SFN levels in PH patient plasma and observed high SFN expression and secretion in isolated ECs from PH patients. NFU1 rats mirrored these findings, showing significantly elevated SFN expression and secretion in ECs. Similarly, increased APN was found in both the lungs of PH patients and the isolated pericytes of NFU1 rats. scRNA-seq followed by Cell-Chat interaction analysis revealed that NFU1 pericytes had reduced interactions with ECs. Additionally, scRNA-seq indicated a shift to a “smooth muscle cell-like” phenotype in pericytes, characterized by increased calponin-3 and SMMHC expression. Confocal imaging confirmed significant disruption of pericyte-EC connections in NFU1 rats. Treatment with R18 in NFU1 rats significantly reversed vascular remodeling and RVSP. Echocardiography showed that R18 significantly improved the ratio of pulmonary acceleration to pulmonary ejection time. Furthermore, scRNA-seq demonstrated that R18 treatment improved pericyte-EC connections and regulated the pericyte phenotype shift in NFU1 rats.Conclusions:Endothelial stratifin induces a phenotype shift in pericytes, leading to vascular remodeling and PH. Targeting SFN signaling presents a novel strategy to combat PH.

Circulation, Volume 150, Issue Suppl_1, Page A4139465-A4139465, November 12, 2024. Introduction:Pulmonary arterial hypertension (PAH) is characterized by progressive obstruction and decreased compliance of pulmonary arteries (PA), leading to right ventricular failure and premature death. Sustained proliferation and resistance to apoptosis of PAs smooth muscle and endothelial cells (PASMCs, PAECs) and accumulation of extracellular matrix (ECM) elements are key features contributing to vascular remodeling. Integrins, members of the cell adhesion receptor superfamily, are known to promote cell proliferation and survival through ECM binding. Despite the recognition of the role of ECM elements in vascular remodeling in PAH, the contribution of integrins remains poorly studied. We hypothesized that integrin signaling could promote PAH-PASMCs and PAH-PAECs proliferation and resistance to apoptosis contributing to vascular remodeling.Methods&Results:Using Western blot (WB) and Meso Scale Discovery, we found that α5β1 was upregulated in distal PAs, PA smooth muscle cells (PASMC) and PA endothelial cells (PAEC) from PAH patients compared to controls. Small molecule, antibody (M200), or siRNA-mediated inhibition of α5β1 decreased PAH-PASMC and PAH-PAEC proliferation (WB, MCM2 and Ki67 labeling), resistance to apoptosis (WB, Survivin and Annexin V labeling) and migration (scratch test assay). RNA sequencing analysis revealed that inhibition of α5β1 regulates a FOXM1-dependant gene network through the activation of focal adhesion kinase, resulting in mitotic defects (Immunofluorescence: α-tubulin and pericentrin labeling).In vivo, in both monocrotaline and Sugen/hypoxia rats with established PAH, inhibition of α5β1 using a small molecule inhibitor or a neutralizing antibody alone or in combination with macitentan and tadalafil improved hemodynamics (RHC and echocardiography: mean pulmonary arterial pressure, cardiac output, pulmonary artery acceleration time) and vascular remodeling (Elastica Van Gieson staining).Ex vivo, inhibition of α5β1 decreased vascular remodeling in human precision-cut lung slices (PCLS) from PAH patients and attenuated growth factors-induced vascular remodeling in control PCLS.Conclusion:Integrin α5β1 plays a key role in vascular remodeling in PAH and represents a novel therapeutic target.

Circulation, Volume 150, Issue Suppl_1, Page A4126731-A4126731, November 12, 2024. Introduction:Cardiovascular health (CVH) in young adulthood (YA) is strongly associated with subclinical and clinical outcomes in later life. Longitudinal patterns of CVH exposure through YA (e.g., cumulative CVH exposure) may be particularly important. However, no studies have assessed cumulative CVH in YA and its association with target organ damage (TOD).Methods:CVH was defined using Life’s Essential 8 (LE8) score. CARDIA participants (ppts) with CVH assessed at ≥3 exams over 20 years of follow-up in YA (year [Y]0 to Y20 exams; mean ages 25 to 45 years) were included. Cumulative LE8 scores (cumLE8; higher = better CVH over time) were calculated as the sum of LE8 scores through YA carried forward between exams measured as point*years. Eight markers of TOD (listed in Results) were measured at subsequent exams (Y20 or Y25) including cardiac, renal, pulmonary, and neurologic markers. Associations of cumLE8 with markers of TOD were assessed using partial effects regression models adjusted for race, sex, and maximal education.Results:There were 3,485 ppts (43.4% men, 46.2% Black) with mean cumLE8 score of 1,448.6 (SD 211.4) point*years. Higher cumLE8 in YA was linearly associated with lower measures of cardiac (left ventricular mass index, carotid intima media thickness, prevalence of coronary artery calcium), renal (estimated glomerular filtration rate [eGFR] in men), and neurologic damage (proportion of white matter hyperintensity on brain MRI) (Figure). Higher cumLE8 was also linearly associated with better lung function (forced expiratory volume in 1 second, forced vital capacity). Urine albumin-creatinine ratio (in men and women) and eGFR (in women) were non-linearly associated with cumLE8.Conclusions:Our findings underscore the importance of high cumLE8 in YA and its association with reduced onset of TOD later in life. Primordial prevention strategies are needed to achieve and maintain high CVH through the critical period of YA.

Circulation, Volume 150, Issue Suppl_1, Page A4143207-A4143207, November 12, 2024. Background:The HeartMate 3 Device (HM3) is an afterload-sensitive left ventricular assist device (LVAD). International guidelines suggest a target Doppler blood pressure (BP) range between 70-90 mmHg, though this recommendation is supported mostly by expert consensus. Optimal real-world data remains lacking regarding the ideal BP for these patients. Remote patient monitoring (RPM) can be utilized for outpatient Doppler blood pressure monitoring. We aimed to evaluate the association between time spent in goal BP range and mortality in HM3 LVAD recipients.Methods:1,427 HM3 LVAD recipients from 74 centers using the ActiCare Health RPM system, which allows patients to measure Doppler BP and upload results to their care team, were included in this analysis. Inclusion criteria included patients with at least two BP measurements. Outpatient Doppler BP values were collected, and a standard therapeutic range (70–90 mmHg) was established. The percentage of time in the therapeutic range (TTR) was calculated, categorizing patients as ≥75%, 50-75%, and ≤50%. Survival at 600 days on LVAD support and reporting frequencies were compared between groups.Results:We studied 738 HM3 LVAD recipients, implanted from 2015 to 2024, with a mean duration of 715 ± 19 days on LVAD support. 140 (19%) patients died. A total of 144,562 Doppler BP readings were analyzed, with a mean value of 82.8 ± 0.02 mmHg. There were 481 patients with TTR ≥75% (65%), 138 patients with TTR 50-75% (19%), and 119 patients with TTR ≤50% (16%). There was a significantly greater probability of survival for those with TTR ≥75% compared to ≤50% (94% vs. 85% at 400 days and 88% vs. 84% at 600 days, p = 0.05, Figure). The mean number of BP submissions per 100 days for the ≥75% group was 37.8 ± 0.87, compared to 25.8 ± 0.87 in the 50-75% group and 21.7 ± 1.25 in the ≤50% group (p < 0.001).Discussion:The data suggest that HM3 patients who spend more than 75% of the time with a Doppler BP between 70-90 mmHg have greater survival compared to those who are within range less than 50% of the time. RPM can be used for closer monitoring of Doppler BP in HM3 LVAD recipients. Patients with Doppler BP 70-90 mmHg may have improved survival.

Circulation, Volume 150, Issue Suppl_1, Page A4140333-A4140333, November 12, 2024. Background:Circulating proteins are attractive candidate drug targets for cardiometabolic diseases. Identifying promising circulating proteins that have a causal role in disease pathogenesis is challenging and expensive. Mendelian randomization (MR) has emerged as an important tool for testing potential causal effects while mitigating biases from confounding and reverse causation. MR findings require validation by colocalization analysis to guard against bias due to correlation between genetic variants (linkage disequilibrium, LD). However, existing colocalization methods often fail to validate MR findings because of highly complex LD structures in the genome, rendering a low yield of human genetics-based target discovery.Methods:In this study, we developed a new computational method, called SharePro, to effectively assess colocalization evidence for MR-identified circulating proteins as targets for cardiometabolic diseases. Based on large-scale genome-wide association studies, we performed MR analyses to assess the associations between 1,535 circulating proteins and key cardiometabolic traits, including diastolic blood pressure, systolic blood pressure, serum hemoglobin A1c, serum low-density lipoprotein cholesterol, and serum triglycerides. We then benchmarked SharePro against state-of-the-art colocalization methods, including coloc, coloc+SuSiE, and PWCoCo, and evaluated the power and robustness of these methods in supporting MR findings. We further examined whether colocalization evidence-supported associations implicated known drug targets for cardiometabolic diseases.Results:SharePro demonstrated the highest power and robustness in supporting 160 (79.6%) of the 201 Bonferroni-significant protein-trait associations identified by MR, while existing methods supported up to 46.8% of these associations. Protein-trait associations identified by MR and supported by SharePro were more likely to implicate known drug targets for cardiometabolic diseases (Figure 1). Furthermore, eight protein-trait associations were exclusively supported by SharePro, suggesting novel targets, such as HSF1 and HAVCR2.Conclusions:SharePro most effectively supports promising protein-trait associations identified through MR for cardiometabolic diseases. Combining multiple lines of evidence using different methods may substantially increase the yield of human genetics-based drug target discovery by nearly twofold.

Circulation, Volume 150, Issue Suppl_1, Page A4139675-A4139675, November 12, 2024. Background:The net benefit of aspirin cessation in older adults remains uncertain. This study aimed to use observational data to emulate a randomized trial of aspirin cessation versus continuation in older adults without cardiovascular disease (CVD).Methods:Post-hoc analysis using a target trial emulation framework (Table 1) applied to the immediate post-trial period (2017-2021) of a study of low-dose aspirin initiation in 19,114 adults aged 70 years and older (ASPREE; NCT01038583). Participants from Australia and US were included if they were free of CVD at the start of the post-trial intervention period (time zero, T0) and had been taking open-label or randomized aspirin immediately before T0 (Fig 1A). The two groups in the target trial were: aspirin cessation (participants who were taking randomized aspirin immediately before T0; assumed to have stopped at T0 as instructed) versus aspirin continuation (participants on open-label aspirin at T0 regardless of their randomized treatment; assumed to have continued at T0). The outcomes after T0 were incident CVD, major adverse cardiovascular events (MACE), all-cause mortality, and major bleeding during 3, 6, and 12 months (short-term), and 48 months (long-term) follow-up. Hazard ratios (HRs) comparing aspirin cessation to continuation were estimated from propensity-score (PS) adjusted Cox proportional-hazards regression models.Results:We included 6,103 CVD-free participants (cessation: 5,427, continuation: 676). Participant selection flow chart is presented inFig 1B. Over both short- and long-term follow-up, aspirin cessation versus continuation was not associated with elevated risk of CVD, MACE and all-cause mortality (HRs, at 3 and 48 months respectively were, 1.23 and 0.73 for CVD; 1.11 and 0.84 for MACE; 0.23 and 0.79 for all-cause mortality, p >0.05) but cessation had a reduced risk of incident major bleeding events (HRs at 3 and 48 months, 0.16 and 0.63, p

Circulation, Volume 150, Issue Suppl_1, Page A4147249-A4147249, November 12, 2024. Introduction:Magnesium (Mg) deficiency may increase the risk of heart failure (HF) in diabetic patients. Less is known about whether the use of Mg supplements is associated with a lower risk of HF in these patients.Research Questions:We emulated target trials to estimate the effects of Mg supplement use on preventing HF in diabetic patients.Methods:We analyzed data from the US Veterans Health Administration to identify eligible diabetic patients for a Mg supplement target trial from 01/01/2006 to 12/31/2020. Eligibility was checked at an outpatient visit with following criteria: 1) aged 40+ years, 2) free of outcomes, 3) had a HbA1C test in the past year, and 4) no prior Mg use. Mg supplement use was obtained by natural language processing of electronic health record. Mg supplement use was defined as use within 30 days of the eligible outpatient clinic visit. HF diagnosis was the primary outcome; Major adverse cardiac events (MACE), including death and HF hospitalization, was secondary outcome. Patients were followed up to 10 years until the outcome, censored due to no further Mg supplement use for Mg users or starting Mg supplement use for non-users, or receipt of a new Mg prescription.We used Inverse probability weighting to account for differences in baseline characteristics between Mg user and non-users. We conducted a Cox regression model on the weighted cohort to compare the effect of Mg Supplement use on outcomes.Results:A total of 94,239 patients were enrolled in the target trials (17,619 Mg users; mean age, 67.3 years; 4.9% females, 18.5% Blacks). The mean duration of Mg supplement use was 3.7±3.3 yrs. The incidence of HF was slightly lower in Mg users compared to non-users (16.9 vs. 17.9 events per 1000 person-years). Mg supplement use was associated with a lower risk of HF and MACE (Figure 1).Conclusion:Our study showed that long-term Mg supplementation was associated with a lower risk of HF and MACE in diabetic patients. The potential benefits of Mg supplement use should be further confirmed in a randomized-controlled trial.

Circulation, Volume 150, Issue Suppl_1, Page ASu105-ASu105, November 12, 2024. Introduction:Hemorrhage remains a leading cause of preventable death in warfare and acute trauma. Given blood shortages, ongoing research is looking into successful artificial oxygen carriers. We engineered a non-globin heme-based molecule, the Bacterial Regulator of Carbon Monoxide Metabolism (RcoM), has oxygen carrier properties suitable for resuscitation in hemorrhagic shock.Hypothesis:We hypothesize that resuscitation with RcoM would improve mean arterial pressure (MAP) in hemorrhagic shock.Methods:A murine model of traumatic hemorrhagic shock was used to investigate the hemodynamic effects of RcoM. Mice were anesthetized with 1.5% isoflurane and received a laparotomy to induce soft-tissue trauma. The left femoral artery and vein were cannulated. The arterial cannula was used for blood pressure monitoring, and the venous cannula was used for bleeding and intravenous infusion. Upon stabilization, hemorrhage was induced by a 30-minute controlled pressure bleeding (25 to 40 mmHg) through the venous cannula then shock was maintained for another 30 minutes. This was followed by resuscitation infusion for 30 minutes by either lactated Ringer (LR) solution, human hemoglobin (HHb), or RcoM with a volume equal to the shed blood volume. The concentration was 2 mM for HHb and Rcom. Baseline MAP, post-resuscitation MAP, and MAP change were compared across the three groups using a one-way ANOVA.Results:There was no difference in the ratio of shed blood volume to the total blood volume (26.8 ± 3.4% for LR (n=7), 26.0 ±2.6% for HHb (n=3) and 27.6 ± 1.3% for Rcom (n=5), p = 0.7295). There was no difference for the baseline MAP between LR (83.5 ± 5.7 mmHg), HHb (87.4 ± 3.0 mmHg) and Rcom (82.3 ± 1.9 mmHg, p = 0.2931). The post-resuscitation MAP was significantly higher for RcoM (67.0 ± 6.3 mmHg) and HHb (60.4 ± 16.0 mmHg) compared to LR (25.9 ± 21.4 mmHg, p = 0.0029). There was no difference between Rcom and HHb in the post-resuscitation MAP (p = 0.8573). The MAP increase during resuscitation was significantly higher for Rcom (25.6± 5.8 mmHg) compared to LR (-8.5 ± 21.6 mmHg, p = 0.0197), but the difference between the HHb (19.0 ± 23.2 mmHg) and LR (p = 0.1155) was not statistically significant.Conclusion:This study demonstrates that resuscitation with RcoM supports the blood pressure in a murine traumatic hemorrhagic shock model, suggesting its potential application as a non-globin artificial oxygen carrier for hemorrhagic shock.

Circulation, Volume 150, Issue Suppl_1, Page A4143098-A4143098, November 12, 2024. Background:Translating therapeutic target biology from in vitro culture systems and animal models to humans remains a significant challenge in drug discovery. Recently, human precision-cut lung slices (hPCLS) have emerged as an innovative ex vivo model to better understand the pathophysiology of pulmonary disease. Given the difficulty in acquiring lung tissue from patients with pulmonary arterial hypertension (PAH), we aimed to develop a hPCLS culture system from healthy donors that replicates the PAH phenotype.Methods:Cryopreserved hPCLS from several healthy donors were obtained from AnaBios. Viability of the hPCLS was assessed using the lactate dehydrogenase (LDH) assay on cultured media. The hPCLS were cultured for seven days with growth factor (GF) cocktails containing various combinations of EGF, FGF, endothelin-1 (ET-1), PDGF-β, activin A, and TGF-β for 7 days to induce PAH-like phenotypes. The stimulated hPCLS were analyzed using RNA sequencing (RNA-seq). Histological analysis assessed pulmonary arterial (PA) medial wall thickness. RNA-seq data from human lungs with and without PAH served as a reference. Gene expression patterns were compared across key disease-associated pathways and processes. The effects of α5β1 integrin inhibition were investigated using the antibody M200 in the PAH-like hPCLS system.Results:LDH activity remained low across all treatment groups over the seven-day period, indicating no tissue toxicity. Histological analysis with H&E and EVG staining showed increased medial wall thickness and elastin deposition in pulmonary arteries stimulated by GFs. RNA-seq analyses revealed gene expression changes in response to several GFs that were consistent with the reference PAH dataset. Key gene sets related to extracellular matrix formation, integrin signaling, proliferation, senescence, and growth factor signaling showed similarities between several GFs and human PAH. Moreover, treatment with the α5β1 antibody, M200, in GF-stimulated hPCLS demonstrated modulation of PAH-like phenotypes.Conclusions:We successfully established a novel ex vivo model using hPCLS from healthy donors that mimics PAH characteristics when stimulated by GFs (ET-1, FGF, PDGF-β, and EGF). This model also demonstrated that α5β1 inhibition reduced PAH-like phenotypes. This hPCLS model, in conjunction with tissue from PAH patients, could be a valuable tool for evaluating new therapies, enhancing the translation from preclinical studies to human applications.

Circulation, Volume 150, Issue Suppl_1, Page A4141929-A4141929, November 12, 2024. Background:Peripheral arterial disease (PAD), when comorbid with type 2 diabetes (T2D), is associated with increased risk of adverse limb events, and therapeutic options for these patients are limited. The STARDUST trial recently demonstrated that Liraglutide significantly improves lower limb perfusion in PAD patients with concomitant T2D in an open label randomized setting, potentially expanding the use of Glucagon-like Peptide-1 Receptor (GLP1R) agonists to this population. Using data from the Million Veteran Program (MVP), we aimed to estimate the effects of GLP1R and gastric inhibitory peptide (GIP) agonists on PAD using genetic proxies.Methods:We obtained previously published GWAS summary statistics for T2D from the DIAMANTE consortium, and performed an association analysis for PAD in MVP at the GLP1R and GIP loci. For our primary analysis in MVP, association testing was performed with clinical PAD using logistic mixed models controlling for age, sex and population structure. We performed a colocalization analysis of PAD and T2D association signals at these loci using hyprcoloc, and then tested the association with PAD stratified by T2D status. Genome-wide significance (5x10e-8) was used to determine statistical significance for our primary analysis.Results:We identified 51330 participants with and 256807 participants without PAD in MVP. Among the European population, we observed evidence of association for PAD at the GIP locus (lead variant rs35895680, OR = 1.048, P = 1.723e-10 for the C risk allele), but not at the GLP1R locus (lead variant rs113678890, OR = 1.6434, P = 1.150e-3). The lead PAD variant at the GIP locus was observed to be the lead T2D variant in the recent DIAMANTE consortium GWAS analysis, and we observed evidence of colocalization between T2D and PAD at the GIP locus, (Posterior Probability of the same causal variant = 0.99). Logistic regression for rs35895680 in the MVP PAD data revealed significant associations in both diabetics (OR=1.04, P = 9.02e-5) and non-diabetics (OR 1.04, P = 1.35e-3), without evidence of heterogeneity (P = 0.60281).Conclusions:These findings highlight GIP as a promising target for PAD intervention, potentially benefiting a broader patient population beyond those with concomittent diabetes. Consequently, future trials incorporating therapies inhibiting both GLP1R and GIP, such as tirzepatide, could offer superior therapeutic benefits for PAD compared to GLP1R agonists alone.

Circulation, Volume 150, Issue Suppl_1, Page ASu1201-ASu1201, November 12, 2024. Background:Various parameters of cerebrospinal fluid (CSF) flow measured through magnetic resonance imaging (MRI) flowmetry are utilized to assess the progression of certain diseases. Our study evaluated changes in CSF flow using MRI flowmetry in survivors of out-of-hospital cardiac arrest (OHCA) who underwent target temperature management (TTM).Methods:This prospective observational cohort study was conducted from May 2023 to April 2024 at a single center. We performed Wilcoxon signed-rank tests to compare maximum velocity (Vmax), stroke volume (SV), maximum flow (flowmax), and stroke distance measured immediately after return of spontaneous circulation (ROSC) with those measured at 72 h after ROSC.Results:Of the 20 patients enrolled, 7(35.0%), 1(5.0%), 2(10.0%), 5(25.0%) and 5(25.0%) patients had CPC scores of 1, 2, 3, 4, and 5, respectively. Vmax, SV, flowmax, stroke distance measured immediately after ROSC were 3.41 (2.03~4.96), 14.00 (4.00~23.38), 0.09 (0.06~0.22), -0.07 (-0.17~0.05), respectively. Vmax, SV, flowmax, stroke distance measured at 72h after ROSC were 5.26 (2.76~9.28), 24.00 (10.38~42.25), 0.14 (0.08~0.31), -0.07 (-0.18~0.03), respectively. Although Vmax, SV, and flowmaxmeasured at 72 h after ROSC were statistically significantly higher compared to those measured immediately after ROSC (p = 0.002, 0.02, 0.002), there was no significant difference between the stroke distances measured immediately after ROSC and at 72 h after ROSC (p = 0.43). Additionally, the caudocranial direction of CSF flow was observed in 13 (65.0%) patients immediately after ROSC, and in 14 (70.0%) patients 72h after ROSC.Conclusion:This study demonstrated that alterations in cerebrospinal fluid flow were observed in OHCA patients. However, Further studies are needed to determine whether there are differences in alteration in CSF flow based on neurological prognosis.

Circulation, Volume 150, Issue Suppl_1, Page A4144351-A4144351, November 12, 2024. Novel means to account for BP fluctuations are being scrutinized to assess longitudinal control, including BP time in target range (TTR) assessment. TTR quantifies the percentage of time a patient’s BP is in the desired range. The present analysis sought to determine the relationship between BP TTR and long-term outcomes among participants in the NIH “All of Us” cohort.Systolic and diastolic BP TTR are differentially associated with long-term outcomes among low-risk primary prevention participants compared to high-risk primary, as well as secondary prevention participants.“All of Us” is an 800,000 participant cohort that is followed longitudinally and collects demographics, adverse events, medications, procedures, and laboratory and clinical measurements. A participant’s systolic BP was noted to be in target range if it was between 110-130 mm Hg and diastolic BP was in target range if it was between 70-80 mmHg. TTR was calculated via traditional and Rosendaal linear interpolation (RLI) methods. Participants were grouped into high and low-risk primary and secondary prevention groups and sorted into four groups based on the percentage of TTR:

Circulation, Volume 150, Issue Suppl_1, Page A4138335-A4138335, November 12, 2024. Introduction:Large observational and Mendelian randomization (MR) studies have demonstrated a strong association between elevated triglycerides (TG) and risk of aortic stenosis (AS). However, at present there remains no evidence for the use of lipid-lowering therapies to prevent or treat AS. To address this gap, we used a drug target MR approach to investigate whether emerging TG lowering therapies may reduce the risk of AS.Methods:We collected summary statistics for TG levels and AS from genome-wide association studies including 1,253,277 and 653,867 European participants, respectively. We first performed conventional MR techniques to investigate a causal relationship between TG levels and AS risk. Next, we identified genetic proxies for the TG-lowering therapies fenofibrate, volanesorsen and evinacumab as single nucleotide polymorphisms (SNPs) within 200kb of the target genes (PPARA, APOC3andANGPTL3, respectively) which were also significantly associated with TG at p

Circulation, Volume 150, Issue Suppl_1, Page A4141244-A4141244, November 12, 2024. Background and Aims:RNA interference therapy targeting the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene lower low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB) levels and is approved worldwide. As opposed to monoclonal antibodies neutralizing PCSK9 in the circulation, their effect on atherosclerotic cardiovascular disease (ASCVD) outcomes is unknown. We used drug-target Mendelian randomization (MR) to assess the potential impact of RNA interference therapies targetingPCSK9on cardiometabolic traits and outcomes.Methods:We performed RNA-sequencing of 246 liver samples and genome-wide genotyping was performed to identify single-nucleotide polymorphisms (SNPs) associated with liver expression ofPCSK9. Genome-wide association study (GWAS) summary statistics of plasma protein levels of PCSK9 from the deCODE study (n=35,559) were used to instrument inhibition of circulating PCSK9 levels. A three-sample MR approach was undertaken using SNPs that influence liverPCSK9gene expression levels (mimicking PCSK9 RNA interference) or plasma PCSK9 protein levels (mimicking PCSK9 neutralizing antibodies) as study exposures. Genetic instruments were standardized for their effect on apoB levels. Main outcomes measures included GWAS summary statistics on coronary artery disease (CAD), ischemic stroke (IS) and type 2 diabetes (T2D).Results:Each SD decrease in apoB was linked with a 55% and 56% reduction in CAD risk, respectively for genetically predicted reductions in plasma PCSK9 levels (OR [odds ratio]=0.45 [95% CI], 0.36-0.56, p=1.7e-13) and liverPCSK9gene expression levels (OR=0.44 [95% CI], 0.22-0.88, p=0.02). Genetically predicted reductions in plasma PCSK9 levels and liverPCSK9gene expression levels were associated with slightly lower IS risk (OR=0.82 [95% CI], 0.68-0.98, p=0.03 and OR=0.73 [95% CI], 0.51-1.04, p=0.08, respectively). Genetically predicted reductions in plasma PCSK9 levels and liverPCSK9gene expression levels were not associated with T2D risk (OR=1.08 [95% CI], 0.92-1.28, p=0.34 and OR=1.26 [95% CI], 0.93-1.71, p=0.14, respectively). The effect of PCSK9 inhibition on CAD was entirely mediated by reductions in apoB levels.Conclusions:Genetically predicted reductions in plasma PCSK9 levels and liverPCSK9gene expression levels were associated with lower ASCVD risk, suggesting that LDL-C/apoB reductions may provide cardiovascular benefits, regardless of how PCSK9 function is inhibited.