tbuckley/cabot-search huggingface dataset:
Abstract 4139817: Systolic Blood Pressure in Heart Failure with Mildly Reduced or Preserved Ejection Fraction: A Pooled Participant-Level Analysis of 4 Large-Scale Trials
Authors: Henri Lu, Toru Kondo, Brian Claggett, Muthiah Vaduganathan, Brendon Neuen, Iris Beldhuis, Pardeep Jhund, Finnian Mc Causland, Inder Anand, Marc Pfeffer, Bertram Pitt, Faiez Zannad, Michael Zile, John McMurray, Scott Solomon, Akshay Desai
Journal: Circulation (2024)

Background: Hypertension is common in patients with heart failure with preserved ejection fraction (HFpEF). Treatment of systolic blood pressure (SBP) to a target &lt;130 mmHg in this population is often recommended based on general ACC/AHA and ESC hypertension guidelines but limited data are available to substantiate this recommendation in patients with HF. We aimed to explore the impact of baseline SBP on cardiovascular (CV) outcomes in a pooled dataset of 4 large, well-characterized cohorts of patients with HF with mildly reduced EF (mrEF) or HFpEF. Methods: I-PRESERVE, TOPCAT, PARAGON-HF and DELIVER were global, multicenter, randomized clinical trials testing irbesartan, spironolactone, sacubitril/valsartan and dapagliflozin respectively, against either a placebo or an active control (valsartan, in PARAGON-HF), in patients with HF and a LVEF &gt;40% (in DELIVER) or ≥45% (in all other 3 trials). The continuous relationship between baseline SBP and the incidence rates (IR) of 1 st HF hospitalization (HFH) or CV death was analyzed with restricted cubic splines and adjusted for known risk factors of CV disease. Results: A total of 18,627 patients (mean age 71±9 years, 49% men, mean SBP 131±15 mmHg) were included. Over a median follow-up of 2.9 years, 3,852 patients experienced a first HFH or CV death (7.4 events per 100py). The relationship between the IR of 1 st HFH or CV death and SBP appeared to be nonlinear, J-shaped ( Figure 1 ), with a nadir of IR observed for SBP values between 120 and 130 mmHg, and an increase for SBP values above 130 mmHg. Above 130 mmHg, each 5 mmHg-increase in SBP was associated with a significantly higher risk of the primary outcome (adjusted HR: 1.07; 95% CI: 1.05-1.10). When stratifying the study population by sex, men had a higher risk for 1 st HFH or CV death across the spectrum of SBP. The J-shaped relationship remained consistent in both men and women (P interaction =0.43; Figure 2 ). Conclusions: Our analysis of a large pooled dataset from 4 clinical trials including over 18,600 patients with HFmrEF or pEF suggests a graded relationship between SBP and CV risk, with risk nadir at SBP between 120 to 130 mmHg, without evidence of difference according to sex.
Abstract 4139465: Integrin α5β1 represents a novel therapeutic target to improve vascular remodeling in pulmonary arterial hypertension
Authors: Sarah-Eve Lemay, Monica Montesinos, Yann Grobs, Tetsuro Yokokawa, Tsukasa Shimauchi, Charlotte Romanet, Melanie Sauvaget, Sandra Breuils Bonnet, Alice Bourgeois, Charlie Theberge, Sandra Martineau, Blaise Lippa, Bryan Goodwin, Albert Lin, Hua Wang, James Dowling, Min Lu, Qi Qiao, T. Andrew McTeague, Terence I. Moy, Francois Potus, Steeve Provencher, Olivier Boucherat, Sebastien Bonnet
Journal: Circulation (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&amp;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.
Abstract 4139271: Investigation of familial hypercholesterolemia prevalence and association with cardiovascular disease in an African ancestry cohort.
Authors: Alexander Berry, Alexandra Winters, Melissa Kelly, Nuha Mohammed, Laney Jones, Samuel Gidding, Matthew Oetjens
Journal: Circulation (2024)

Familial hypercholesterolemia (FH) is an inherited condition consisting of lifelong elevated LDL cholesterol levels and increased risk of cardiovascular disease. Among Western populations, the prevalence of FH has been reported to be between 1:212 to 1:331. African ancestry individuals are underrepresented in submissions to genetic resources used to determine variant pathogenicity and there are no known reports on the prevalence of FH in those populations. To create an African ancestry cohort, we performed principal component analyses on genetic data from Geisinger’s MyCode (N = 175,500) and the NIH’s All of Us (N = 98,590) cohorts to identify individuals who cluster with 1000 Genomes African superpopulation (1KG AFR). We assessed sequence variants in FH genes from our African ancestry cohort for pathogenicity using American College of Medical Genetics criteria. Lipid levels and use of lipid lowering medications were compared among those with and without a variant. Among 29,931 individuals who clustered with the 1KG AFR group, we identified 31 unique pathogenic or likely pathogenic FH variants among 108 individuals, yielding a prevalence of 1:277. Most of the pathogenic variants identified (94%) were missense variants in the LDLR gene. Mean age for individuals with a pathogenic FH variant was 40.5 years in MyCode and 50.4 years in All of Us. Of those with a pathogenic FH variant and at least one LDL measurement, we found that 52.5% had an LDL &gt; 190mg/dl and 37.5% had an LDL &gt; 250 mg/dl, compared to 5.7% and 0.6% of African ancestry individuals without an FH variant, respectively. The effect size of an FH variant on maximum LDL levels adjusted for age, sex, and principal components of ancestry was 90.4 mg/dL (95% CI, 69.8-111.0; p=1.1x10-17) in MyCode and 126.5 mg/dL (95% CI, 110.5-142.6, p=4.0x10-53) in All of Us. In the combined cohort, 29.6% of individuals with a pathogenic FH variant had been prescribed an LDL-lowering medication, compared to 20.9% of individuals without a variant. Overall, the prevalence of FH in an African ancestry cohort was consistent with the prevalence of FH in studies of European ancestry cohorts. The effect size of an FH variant on LDL in this cohort was large. These data suggest that African ancestry individuals with pathogenic FH variants have a high likelihood of increased LDL and concomitant cardiovascular disease risk and that there is an opportunity for additional identification and treatment of FH in this population.
Abstract 4139383: Non-Inferiority Of Extracorporeal Photopheresis To Immunosuppression Therapy In Heart Transplantation Rejection
Authors: Mehrbod Vakhshoori, Amir Abdi pour
Journal: Circulation (2024)

Background: Immunosuppressive (IS) therapy is currently used as first-line treatment for heart transplant (HTx) rejection. However, they are not without complications, and less toxic therapies are needed. This study aims to compare extracorporeal photopheresis (ECP) as an adjuvant therapy with standard IS regimens in patients with HTx rejection. Methods: This cross-sectional single-center study included HTx patients who underwent ECP in conjunction with standard IS therapy. Patient were matched with regular IS group in a 1:13 ratio based on rejection score. Data on graft function (International Society of Heart and Lung Transplantation (ISHLT) rejection score and left ventricular ejection fraction (LVEF)) at different time points and survival status were collected from the medical records. Results: A total of 84 patients met the inclusion criteria (age at rejection diagnosis: 40.4±21.7 years, males: 58.4%). The median (range) of ECP duration in the ECP plus standard IS group was 228.5 (170-295) days. Patients in ECP adjuvant group had lower LVEF and similar rejection score distribution in comparison to the IS group (P= 0.047, and P= 0.707, respectively). However, matching in 1:1 ratio based additionally on age, sex, and race showed similar outcomes between groups (P&gt; 0.05) ( Table 1 &amp; Figure 1 ). Kaplan-Meier analysis revealed similar survival benefits between groups (log-rank P: 0.12) ( Figure 1E ). The multivariate-adjusted odds ratio of graft status, LVEF improvement, all-cause and cardiovascular diseases mortality were not found to be different in the ECP adjuvant group compared to the standard IS group (P= 0.412, P= 0.449, P= 0.418, and P= 0.627 respectively) ( Table 2 ). Conclusions: ECP adjuvant therapy is non-inferior to standard IS regimen. Considering patients who do not respond well to IS therapy are referred for ECP, this treatment potentially improves their outcomes and reduces the risk of complications associated with heavy immunosuppression. Further studies are required to validate these findings.
Abstract 4139432: The Mixing Enigma? Does Interchanging Leads and Generators Still Cause Concern in the MRI? Could this be the Final Device Hurdle for Routine MRI Patients?
Authors: Robert Biederman, RONALD WILLIAMS, Mark Boltralik, Richard Lombardi, Moneal Shah, Mark Doyle
Journal: Circulation (2024)

Background: Over the last two decades substantial efforts have been aimed at improving acceptability of pacemakers and ICD's in the MRI scanner. Many labs have evaluated the construction, safety, efficacy, reproducibility and more recently, clinical impact value in such legacy devices. In conjunction, there has been extensive effort by the major vendors to develop safe MRI compatible devices. We believe that there remain few reasons for hesitation in more universal useage of any PM/ICD in the MRI bore. Yet, mixing vendor leads and generators remain a major hurdle considerably limiting contemporary MRI usage in nearly all MRI laboratories. Accordingly, we Hypothesize: mixed leads and generators have no distinct safety signal from common devices; whether CIED or non-CIED. Methods: We undertook a retrospective DB analysis to determine safety signals in those patients possessing mixed vendor leads and devices. Comparisons of impedance, amplitude, threshold and battery voltage and patient safety etc. were performed. Results: Patients from 5/2004 to 5/2024, representing 2008 pts with CIED (78%) and non-CIED (22%) underwent an MRI in a dedicated CMR Lab. The majority of the mixed cohort were obtained from the non-CIED cohort (&gt;98%), having no need for generator replacement. Accordingly, 12% of these underwent MRI to include: 76% neurologic, 7% orthopedic and 17% cardiac indications. In safety signals comparisons between standard and mixed lead/generator implants, there were no differences in any implant parameters either pre-MRI or post-interrogation (p=NS). Similarly, there were no peri-MRI pt events reported in the 30d, 180d and 365 day post-MRI scan (p=NS). Importantly, especially for EP considerations, there were no added complications to interrogations. Moreover, utilizing a similar approach to manipulation of MRI parameters for maximum safety intrinsic to dependent/non-dependent PM status was employed regardless of lead/generator configuration yielding no complications. Conclusions: Developing a similar approach to MRI scanning in those patients with mixed vendor lead/generator configurations yielded no difference in a multitude of safety, interrogation, devices and efficacy parameters implementing a similar device interrogation/programming strategy as in traditional devices. This reassurance derived from a large MRI lab suggests, despite inherent incompatibility concerns between vendors while in the magnetic field, suggests no such fears are truly warranted.
Abstract 4140065: Feasibility of Self-Expanding Transcatheter Pulmonary Valves in Patients with Pyramidal RVOT: Favorable Mid-term Outcomes
Authors: Wenhao Zhu
Journal: Circulation (2024)

Background: Transcatheter pulmonary valve replacement (TPVR) has been acknowledged as a common and beneficial treatment for significant pulmonary regurgitation (PR), but data are still lacking about the mid-term effects of self-expanding valve implantation in patients with pyramidal right ventricular outflow tract (RVOT). Methods: This study was a multicenter retrospective analysis involving consecutive patients who underwent intentional TPVR between May 27, 2014, and September 14, 2023. Baseline characteristics and immediate/mid-term echocardiographic variables were gathered and compared among patients with pyramidal RVOT and those with other RVOT configurations. The primary endpoint of immediate device success rate and secondary endpoint within one year post-procedure were also evaluated in both groups. Results: A total of 68 patients were enrolled in the study. The primary endpoint showed a marginal difference between the two groups, with a significance level of P = 0.067 (86.7% in the pyramid-type group versus 100% in other types). At 1-year follow-up, the secondary endpoint demonstrated no intergroup differences in outcome (91.7% versus 86.0%; P = 0.605). Echocardiographic improvement and mid-term clinical outcomes were comparable in both groups (all P &gt; 0.05). However, prosthesis valves implanted in pyramidal RVOT were observed to be more prone to developing trivial regurgitation within the first month (6 out of 11, 54.5% versus 7 out of 45, 15.6%; P = 0.016). Conclusions: Despite slightly lower immediate device success rates, the outcomes of Venus P-Valve implantation in pyramidal RVOT were not only acceptable but favorable during mid-term echocardiographic and clinical follow-up. The utilization of self-expanding valves has significantly broadened the indications for TPVR, necessitating specific morphology assessments to better guide future procedures.
Abstract 4139461: Proteomic and Phosphoproteomic Profiling in an Experimental Model of Electrical Storm
Authors: Yukiomi Tsuji, Masafumi Shimojo, Satoshi Yanagisawa, Yasuya Inden, Dobromir Dobrev, Stanley Nattel, Toyoaki Murohara
Journal: Circulation (2024)

Background: Electrical storm (ES), characterized by clustered ventricular tachycardia/fibrillation (VT/VF) episodes, is a major problem with substantial mortality in patients with implantable cardioverter-defibrillators (ICDs) and ischemic/non-ischemic cardiomyopathy, but available therapeutic approach is suboptimal, likely due to incomplete understanding of the pathophysiology. Objective: To identify the cardiac-specific features of protein/phosphoprotein changes in experimental ES. Methods: The model was created by inducing chronic complete atrioventricular-block in ICD-implanted rabbits, causing hypertrophy, QT prolongation, and frequent VT/VF-episodes. Relative protein/phosphoprotein abundances in hearts from 4 rabbits with ES (defined as ≥3 VF-episodes/24-hr period) experiencing 97±27 VF-episodes and 4 controls (CTL) were assessed by iTRAQ LC-MS/MS and key regulatory pathways were examined by Ingenuity-Pathway-Analysis. Results: Proteomic analysis identified 1938 proteins, 106 of which were differentially expressed between ES and CTL (False Discovery Rate (FDR)&lt;0.1). ES was profoundly associated with mitochondrial dysfunction, oxidative phosphorylation inactivation and ATP depletion along with decreased measurement of electron transport chain and ATP synthase proteins and inner membrane-localized transporters and enzymes. Reductions in mitochondrial matrix-enzymes inferred downregulation of fatty acid β-oxidation and TCA cycle. Phosphoproteome detected 641 phosphorylated proteins, 82 of which have changes in phosphorylation state in ES versus CTL (FDR&lt;0.1). Hyperphosphorylation of Z-disc proteins/associated proteins of sarcomeres, especially N-terminals of titin, and actin and protein kinase A subunits predicted striated muscle contraction and integrin signaling activation, which in part explain cardiac dilation with enhanced contractility due to sustained bradycardia in this model. Nuclear integrators for mitochondrial biogenesis and function, including cyclic AMP-response element binding, peroxisome proliferative activated receptor gamma, coactivator 1 alpha and nuclear respiratory factor 1, were activated, the prediction opposite to proteomic data. The activation status of other pathways linked to heart failure was undeterminable. Conclusion: ES is associated with evidence of mitochondrial dysfunction, known to contribute to ventricular dysfunction and arrhythmogenesis. Mitochondria-targeted agents merit further investigations as therapeutic targets in ES.
Abstract 4139260: Impact of Right Pulmonary Vein Anatomical Variations on Phrenic Nerve Trajectory in Pulmonary Vein Isolation
Authors: Oriol Rodriguez-Queralto, Michal Wasiak, Corentin Chaumont, Alireza Oraii, Helena Lopez-Martinez, Victor Ferrari, Ray Hu, Godefroy Chery, Jeffrey Stiffler, Francis Marchlinski
Journal: Circulation (2024)

Background: Anticipating phrenic nerve (PN) location relative to right pulmonary vein (PV) anatomy based on pre procedure imaging may limit the risk of PN damage. Aims: Analyze how the presence of a middle pulmonary vein (MPV) or its equivalent affects PN trajectory. Methods: The study included consecutive patients undergoing AF ablation from 2018 to 2022. PN location was mapped by high-output pacing. 3 zones were defined based on the most distal PN capture spot: Zone 1–no PN capture or capture only within right superior PV (RSPV) ostium, Zone 2-capture along the septal antrum of RSPV until mid-carina and Zone 3-capture extending the antral region of right inferior PV (RIPV) (Figure 1). Right PV anatomy based on MRI/CT was classified into typical anatomy (no MPV) versus MPV present or large proximal septal branch of RSPV near ostium (MPV equivalent). The presence of a MPV or equivalent and its association with PN trajectory and the need for antral/septal ablation line adjustments to avoid PN injury was analyzed. Results: Out of 103 patients included (median age 67y [IQR=12], 70% male; 73% paroxysmal AF). PN was mapped in zone 1 in 49% of patients, zone 2 in 21%, and zone 3 in 30%. PN capture in zone 3 was significantly higher in the presence of MPV (prevalence 59.1%, Prevalence ratio (PR)=16.6; CI95% 4-67.4) or MPV equivalent (64%, PR=17.9; CI95% 4.5-72.1) compared to no MPV group (3.6%). An ablation line modification more antral toward the septum was necessary in 28% of patients due to PN capture and was more common if MPV (50%, PR=7; CI95% 2.5-19.7) or MPV equivalent (56%, PR=7.8; CI95% 2.9-21.4) compared to no MPV (7%). Conclusions: A distal PN location into the RIPV's antral region is significantly more likely with a MPV or MPV equivalent. Adjusting the PV isolation line more septal is crucial if MPV is present. This finding is essential for planning transeptal puncture sites and catheter placement for effective and safe PV isolation during radiofrequency ablation.
Abstract 4139258: Aspirin vs Clopidogrel as a Monotherapy secondary prevention in Patients with Coronary Artery Disease: An updated Meta-Analysis
Authors: Omar Almaadawy, Mohamed Elnady, Ahmed Almahdy Mohamed, Abdelrahman Elshimy, Menna Sarhan, Abdul Rhman Hassan, Eman Moheyeldin, Alshaimaa Mohamed, Nada Ali, claudia georges, Youmna Elsalmouny, Karim Al-Azizi
Journal: Circulation (2024)

Introduction: Antiplatelet therapy plays a significant role in the management of patients with coronary artery disease (CAD) to prevent cardiovascular events. Current guidelines recommend 6-12 months of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) followed by either aspirin or clopidogrel monotherapy indefinitely. Previous meta-analyses have suggested a potential superiority of clopidogrel over aspirin. However, given the evolving landscape of cardiovascular medicine, there is a need for updated evidence to inform clinical practice. Hypothesis: This systematic review and meta-analysis, to our knowledge the most up-to-date, aims to compare the effectiveness and safety of aspirin versus clopidogrel as monotherapy in patients with coronary artery disease (CAD). Methods: We searched PubMed, Embase, and Cochrane Library databases for relevant randomized controlled trials (RCTs) and Non (RCTs) Studies published up to April 2024. The primary outcomes were Major Adverse Cardiovascular and Cerebrovascular Events, myocardial infarction, stroke, and Death, while secondary outcomes included major bleeding events, target vessel revascularization, repeated revascularization, and stent thrombosis. heterogeneity analysis, and pooled analysis conducted by RevMan 5.3 software. Results: A total of eleven (11) studies involving 26324 patients, of whom 11435 (43.4%) received clopidogrel met the inclusion criteria. Mean follow-up was 12-36 months. Duration of DAPT before antiplatelet monotherapy was 1-18 months. The meta-analysis revealed a significant reduction with Clopidogrel monotherapy in all the following compared to Aspirin monotherapy; myocardial infarction [ 0.77 -95%CI -(0.64 - 0.93)], stroke [ 0.59 -95%CI- (0.48 - 0.74)], major bleeding events [ 0.66 -95%CI- (0.53 - 0.84)], and repeated revascularization [ 0.88 - 95% CI ( 0.77 - 0.99 )]. There was no significant difference in the risk of major adverse cardiovascular and cerebrovascular events, death and cardiac death. Conclusion: Clopidogrel monotherapy may be associated with a lower risk of major bleeding, MI, stroke and repeated revascularization compared to aspirin monotherapy in patients with CAD. This supports the use of clopidogrel over aspirin in patients with CAD who require secondary prevention with long-term antiplatelet monotherapy.