tbuckley/cabot-search huggingface dataset:
Abstract 4142906: Efficacy and Safety of Aficamten in Patients Guideline-Eligible for Septal Reduction Therapy in the FOREST-HCM Trial
Authors: Ahmad Masri, Lubna Choudhury, Pablo Garcia-Pavia, Theodore Abraham, Roberto Barriales-Villa, ozlem bilen, Perry Elliott, Albert Hagege, Sherif Nagueh, Srihari Naidu, Michael Nassif, Iacopo Olivotto, Artur Oreziak, Anjali Owens, Omar Wever-Pinzon, Albree Tower Rader, Stephen Heitner, Stuart Kupfer, Fady Malik, Chiara Melloni, Lixin Meng, Jenny Wei, Sara Saberi
Journal: Circulation (2024)

Background: Patients (pts) with obstructive hypertrophic cardiomyopathy (oHCM) with severe symptoms despite medical therapy are offered septal reduction therapy (SRT) when available. We report the efficacy and safety of aficamten in SRT-eligible pts in the Phase 2 open-label extension trial FOREST-HCM (NCT04848506). Methods: Pts completing an aficamten parent study were offered participation in FOREST-HCM. Aficamten was initiated in all participants at 5 mg and escalated (10, 15, and 20 mg) at investigators’ discretion with protocol guidance according to left ventricular ejection fraction (LVEF) and left ventricular outflow obstruction (LVOT) criteria. SRT eligibility was defined per guidelines as both New York Heart Association (NYHA) class III/IV and any peak LVOT-G ≥50 mmHg. Results: Of 180 oHCM pts (mean age 60.8±13.1 years, 54% male) enrolled in FOREST-HCM from May 28, 2021 to March 15, 2024 with ≥24 weeks of follow-up, 57 (31.6%) were SRT-eligible at baseline. By week 24, only 2 (3.5%) pts remained SRT eligible (32 [56.1%] met neither criteria, 20 [35.1%] had LVOT-G ≥50 mmHg but were NYHA class I/II, and 2 (3.5%) had NYHA III/IV but LVOT-G &lt;50 mmHg). NYHA improved ≥1 class in 52 (92.9%) SRT-eligible pts and in 80 (67.8%) pts of the remaining cohort. Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) improved more in SRT-eligible pts than remaining cohort (21.7±19.3 vs 13.5±13.9; p=0.003) {Figure}. Proportional reductions from baseline in NT-proBNP and high-sensitivity troponin were substantial in both groups. A modest reduction in LVEF occurred in both groups (-3.6% ±6.4 vs -3.4% ±6.2 in the SRT-eligible and remaining cohort respectively; between group p=0.34) {Figure}. Conclusions: A third of pts enrolled in FOREST-HCM were guideline SRT-eligible at baseline despite optimized standard of care therapy, with almost all pts no longer meeting SRT-eligibility criteria by 24 weeks with aficamten treatment. Aficamten may provide an effective alternative to SRT in some patients with oHCM.
Abstract 4142950: Somebody Help! PulsePoint Directed Layperson CPR Response in Healthcare Adjacent Facilities
Authors: Zachary Sedor-Schiffhauer, Nina Lane, Jonathan Xiong, Gnanesh Gutta, Leonard Weiss, Ankur Doshi, David Salcido
Journal: Circulation (2024)

Introduction: Cardiac arrest is an emergency that requires action via timely administration of CPR and AED use. PulsePoint is a phone application that alerts layperson users of nearby cardiac arrest events allowing them to provide aid before first responders arrive. Hospitals already have cardiac arrest protocols and are therefore excluded from PulsePoint. However, healthcare adjacent facilities (HAFS), locations that provide medical services without being inpatient treatment centers, may or may not have cardiac arrest protocols. It is unknown whether PulsePoint layperson dispatch to HAFS would be beneficial for CPR response or AED retrieval. Hypothesis: HAFS already have internal cardiac arrest response protocols. The same facilities can make AEDs available in nearby areas. Goal: Categorize HAFS related to cardiac arrest response or AED retrieval for PulsePoint alerts. Methods: We retrieved 940 records from the Allegheny County, PA PulsePoint deployment from 2022-2023, including only events occurring in public locations classified as HAFS. Health care adjacency was manually determined by a single reviewer, using a primary criterion of providing health care services but excluding inpatient facilities. The team contacted each site via telephone to administer a standardized survey querying the facility’s cardiac arrest response procedure, presence of an AED, and whether PulsePoint responders could enter their facility in response to an emergency. Results: Of the 108 HAFS identified, 46 (42.6%) completed the phone survey and 44/46 (95.7%) have a cardiac arrest response protocol. Additionally, 39/46 (84.8%) of facilities have an AED on-site and 100% of those facilities have staff present who are trained in AED use. A total of 5/46 (10.9%) facilities were aware of or had staff who were aware of PulsePoint. Permission for PulsePoint responders to enter their facility 9/46 (19.6%) was low, but AED use in the nearby community was higher at 25/46 (54.3%). Conclusion: The majority of HAFS have existing cardiac arrest protocols and AEDs available. Dispatch of PulsePoint volunteers to HAFS may be inefficient, however, willingness to provide AEDs suggests that HAFS could play a supportive role to bystander cardiac arrest response. Future steps would best focus on exploring means to overcome low survey participation to properly characterize response protocols, investigating individualized location designation within PulsePoint, and increasing knowledge of PulsePoint.
Abstract 4142982: Long-Term Myocardial Tissue Characterization in Women with Preeclampsia
Authors: Rukmini Roy, Haonan Wang, Sherry Huang, Iva Minga, Meaghan O'Hara, Maxine Tang, Shuo Wang, Jeremy Slivnick, Tamar Polonsky, Sarosh Rana, Roberto Lang, Sajid Shahul, Hena Patel
Journal: Circulation (2024)

Introduction: Preeclampsia, a pregnancy-specific complication, is an established risk factor for long-term cardiovascular complications, including heart failure with preserved ejection fraction (HFpEF), however, the exact mechanism of this cardiovascular dysfunction remains unclear. This study aimed to characterize the cardiac structure and myocardial tissue using cardiac magnetic resonance imaging (CMR) in women with a long-term history of preeclampsia. We hypothesized that prior preeclampsia is associated with myocardial fibrosis or scarring. Methods: Women with singleton pregnancies delivered between 2004 and 2019 were identified and prospectively enrolled to undergo CMR (1.5T Signa Artist GE HealthCare) with cine imaging, tissue multiparametric quantitative mapping and late gadolinium enhancement (LGE) imaging. Results: Twenty-three subjects (41.0±6 years, 12.7±5 years post-partum) were included. Women with a history of preeclampsia (n=11) were compared to a healthy control group of women with prior normotensive, uncomplicated pregnancy (n=12). There was no significant difference in LV systolic function, LV mass, T1 and T2 mapping, or LGE between the preeclamptic group versus controls, although right ventricular (RV) systolic function was significantly higher (65±7.5% vs 58±7.7%; p=0.04) in individuals with preeclampsia ( Panel A ). Notably, global extracellular volume fraction (ECV) was significantly higher in women with preeclampsia versus normotensive pregnancies (47.2±21.2% vs 31.0±4.8% respectively; p=0.02) ( Panel B ). Conclusions: Global myocardial ECV appears to be increased with preeclampsia, many years after the index pregnancy, potentially reflecting diffuse interstitial fibrosis. Diffuse fibrosis may stiffen the myocardium and reduce myocardial compliance, resulting in loss of diastolic function. Further research is needed to determine whether these alterations in cardiac structure and increased myocardial fibrosis contribute to preeclampsia-associated HFpEF and cardiovascular outcomes.
Abstract 4142996: Controlled LDL levels can Attenuate the Lp(a) Cardiovascular Risk in Patients Who Underwent Percutaneous Coronary Intervention
Authors: Ahmed Mahmoud, Kamal Awad, JUAN FARINA, Mohammed Tiseer Abbas, Nima Baba, Hesham Abdalla, Amro Badr, Muhammed Elahi, Moaz Kamel, Milagros Pereyra, Isabel Scalia, Chadi Ayoub, Reza Arsanjani
Journal: Circulation (2024)

Background: Secondary prevention after percutaneous coronary interventions (PCIs) is still challenging and lipoprotein(a) [Lp(a)] is believed to be a residual risk factor in this setting. However, the effect of Lp(a) in case of well-controlled low-density lipoprotein cholesterol (LDL-C) is still unclear. The interaction between Lp(a) and LDL-C has been studied in primary prevention but still needs to be investigated in secondary prevention. Hypothesis: Achieving adequate LDL-C control after PCI may reduce the cardiovascular (CV) risk associated with Lp(a). Methods: A retrospective study of consecutive patients who underwent PCI and reached their LDL-C target levels (&lt;70mg/dL) at three academic centers sites between 2006 and 2017. All included patients must have an Lp(a) measurement before the PCI intervention. Clinical outcomes on 10-year follow-up were collected by reviewing the electronic patients' records. The primary outcomes included all-cause mortality (ACM) and major adverse CV events (MACE) including non-fatal MI, ischemic stroke, coronary revascularization, and CV death. Kaplan-Meier curves were created to compare the survival probabilities among patients with high Lp(a) (≥50mg/dL) versus those with low Lp(a) (&lt;50mg/dL). Univariate and multivariate Cox regression analyses were performed to quantify the association of elevated Lp(a) with outcomes and control for potential confounders. Results: In total, 878 patients (median age = 68 years, 74% males) were included in the analysis. Of them, 242 (27.6%) had high Lp(a) ≥50mg/dL. Kaplan Meier analyses did not reveal any significant difference in survival probabilities across the Lp(a) groups for any of the outcomes (Figure 1). The results were consistent in univariate (MACE, HR: 1.08 [95%CIs 0.85-1.35]; ACM, HR: 0.97 [95% CI 0.76-1.23]) and multivariate analyses (MACE, HR: 1.14, [95% CIs 0.90-1.45]; ACM, HR: 1.08 [95% CI 0.84-1.39]). Conclusion: These findings suggest that, in patients who underwent PCI and achieved an LDL-C target of &lt;70 mg/dL, elevated Lp(a) levels were not associated with and increased risk of MACE or mortality. Controlling the LDL-C should still be the cornerstone in secondary prevention after PCI, however, larger prospective studies are still warranted to validate our results.
Abstract 4142987: Cardiac TRPM7 kinase plays a key role on diabetic heart failure with preserved ejection fraction
Authors: Man Liu, Hong Liu, Gyeoung-Jin Kang, Lynn Hartweck, Feng Feng, Kurt Prins, Samuel Dudley
Journal: Circulation (2024)

Introduction: Hypomagnesemia (HypoMg) and subsequent oxidative stress cause diabetic cardiac diastolic dysfunction (DD) and heart failure with preserved ejection fraction (HFpEF). A Mg 2+ transporter with both channel and kinase function, the transient receptor potential cation channel subfamily M 7 (TRPM7), is upregulated in HypoMg. Inhibition of TRPM7 kinase prevents HypoMg-mediated oxidative stress in the brain. Aims: We investigated the role of TRPM7 kinase in cardiomyocyte mitochondrial regulation and DD. Methods: Wild type (WT) C57BL/6J mice and transgenic mice with a global K1646R mutation in the TRPM7 kinase domain, TRPM7 K1646R (without kinase function) were fed with either a normal diet (control, 2000 mg/kg Mg 2+ ), high fat diet (HFD, 60% kcal from fat), or a low Mg 2+ diet (HypoMg, 15-30 mg/kg Mg 2+ ) starting from 10 weeks old. HFD lasted for 23-25 weeks. HypoMg diet lasted for 6 weeks. Mouse ventricles, cardiomyocytes, and mitochondria and human cardiac cell line, RL-14, were used for analysis. Results: Diabetic mice on HFD had HypoMg and elevated TRPM7 protein levels in heart. DM-associated DD was prevented by TRPM7 K1646R . In HypoMg mouse ventricles, TRPM7 mRNA and protein levels were also increased. HypoMg-induced DD (increased E/e’, decreased resting sarcomere length, and increased S-glutathionylated cardiac myosin binding protein C) and mitochondrial dysfunction (increased mitoROS, depolarized mitochondrial membrane potential, and decreased ATP, mitochondrial Mg 2+ and complex I/II activities) were prevented by TRPM7 K1646R . TRPM7 kinase regulated the overexpression of a Src kinase family member Fgr in mitochondria of HypoMg mouse ventricles, which co-localized with complex II, regulated complex II activity, and led to increased mitoROS. Conclusion: TRPM7 mediated mitochondrial dysfunction and cardiac DD in HypoMg. TRPM7 kinase enhanced Fgr expression in mitochondria, with subsequent complex II dysfunction and mitoROS overproduction. Inhibition of TRPM7 kinase function represents a potential novel therapeutic strategy to treat diabetic HFpEF.
Abstract 4142930: Title: Loss of estrogen receptor α causes early onset of right ventricular capillary rarefaction in female rats with experimental pulmonary hypertension
Authors: Jiajun Li, Vijaya Karoor, Andrea Frump, Avram Walts, Tim Lahm
Journal: Circulation (2024)

Background: Right ventricular failure (RVF) determines survival in patients with pulmonary hypertension (PH). Insufficient angiogenesis and impaired RV endothelial cell (RVEC) function are key contributors of RVF development. Female patients with PH have better RV function compared to males. 17β-estradiol (E2), the most abundant female sex hormone, exerts RV-protective effects, including stimulation of angiogenesis. However, the mechanisms underlying E2’s pro-angiogenic function are unknown. Hypothesis: Estrogen receptor (ER)α promotes RVEC angiogenic function in vitro and RV angiogenesis in vivo. Objective: To identify the role of ERα in RVEC angiogenic function and RV angiogenesis. Methods: ERα loss-of-function mutant (ERα Mut ) rats were generated using CRISPR-Cas9. RVF was induced in rats with monocrotaline (MCT; 60 mg/kg) or pulmonary artery banding (PAB; 11 weeks). RV systolic pressure (RVSP) was measured, and Fulton index and cardiomyocyte area were used as measures of RV hypertrophy. RV capillary density was assessed by Isolectin B4 staining. RVECs were isolated from male and female WT and ERα Mut rats. Cell migration was assessed using transwell migration assay. Angiogenic gene expression in RVECs was measured using Qiagen RT2 Profiler PCR array. p&lt;0.05 by ANOVA or in Pearson’s correlation analyses was considered significant. Results: RV capillary loss was observed in male and female WT rats and female ERα Mut PAB rats, compared to sham (p&lt;0.05). Capillary density correlated negatively with RVSP and Fulton index (p&lt;0.001, r 2 =0.1386 and 0.4029, respectively). Time course experiments in MCT-rats demonstrated RV hypertrophy and capillary rarefaction in female ERα Mut rats (but not in WT) 10 days after MCT injection (p&lt;0.05). Microarray indicated reduced expression of pro-angiogenic angiogenin and leptin and increased expression of anti-angiogenic TIMP-1 in female ERα Mut vs WT RVECs. Pathway analysis reaveled a decrease in mediators of cell migration and blood vessel development in ERα Mut vs WT RVECs. Transwell migration assay revealed reduced migration in male and female ERα Mut vs WTs RVECs at 24h (p&lt;0.05). Conclusions: ERα regulates angiogenic processes in vivo and in RVECs in a sexually dimorphic manner. Functioning ERα protects females against capillary rarefaction during early stages of RV remodeling. Targeting ERα could pave the way for sex-specific treatment strategies aimed at bolstering RV adaptation in PH.
Abstract 4142847: <i>Dnmt3a</i> modifies the anti-inflammatory effect of the IL-6 classical pathway in macrophages to change the atherosclerosis burden.
Authors: Tetsushi Nakao, Thiago Rentz, Marie McConkey, Jason Williams, Mengyu Chen, Amelie Vromman, Mariana Janini Gomes, Samuel Moscavitch, Santiago Tobar, Grasiele Sausen, Eugenia Shvartz, Eduardo Folco, Benjamin Ebert, Peter Libby
Journal: Circulation (2024)

Background: Clonal hematopoiesis of indeterminate potential (CHIP) can contribute to cardiovascular risk. The Interleukin-6 receptor (IL6R) polymorphism (D358A) modifies the risk of coronary artery diseases among CHIP carriers in human cohorts. However, the effects of the IL6R D358A on IL-6 pathways are discordant with the canonical expectation, that the classical IL-6 signaling pathway is anti-inflammatory while the trans-signaling pathway is pro-inflammatory. Hypothesis: DNMT3A, the most frequent driver gene for CHIP, changes the inflammatory consequence of IL-6 classical signaling from anti-inflammatory to pro-inflammatory to worsen atherosclerosis. Method: We investigated if an anti-IL6R antibody modifies atherosclerosis associated with myeloid Dnmt3a deficiency in vivo . Ldlr -/- mice were transplanted with 10% bone marrow cells from Dnmt3a -/- mice/90% of wild-type (WT) cells compared with 100% WT transfer. After engraftment, mice consumed a high-fat diet, and received an anti-IL6R antibody for 10 weeks to assess aortic root atherosclerosis vs. control antibody treatment. We also investigated the differences between IL-6 classical- vs trans-signaling pathways and whether Dnmt3a deficiency in bone marrow-derived macrophages (BMDM) modifies the IL-6 pathways. RNA-seq was performed in BMDM stimulated with IL-6, which activates the classical IL-6 pathway, or IL-6/IL6R conjugate, which activates trans-signaling. We further compared IL-6 vs control stimulation between Dnmt3a -/- and WT BMDM using RNA-seq, and the major finding was replicated by quantitative PCR. In addition, IL-1β was quantified in the conditioned medium. Result: Anti-IL6R antibody treatment reduced atherosclerosis in the mice with myeloid Dnmt3a deficiency. IL4R expression rose significantly in BMDM stimulated by IL-6 compared to IL-6/IL6R conjugate. IL4R induction by IL-6, but not the IL-6/IL6R conjugate, fell significantly in Dnmt3a -/- BMDM compared to WT. IL-1β secretion declined with IL-6 stimulation and was higher in IL6R deficient BMDM, but IL-6 stimulation and deletion of IL6R did not affect IL-1β secretion in Dnmt3a -/- BMDMs. Conclusion: These data suggest that DNMT3A tonically limits the IL-6 classical pathway to limit atherogenesis in an IL-4 signaling-dependent manner. These findings promote understanding of the CHIP-atherosclerosis association and inform the development of management strategies for CVD risk in CHIP carriers.
Abstract 4143037: Prognostic Value of On-Treatment Left Ventricular Global Longitudinal Strain in Elderly Patients with Acute Heart Failure and Preserved Ejection Fraction
Authors: Chih-Hsueh Tseng, Wei Ming Huang, Shih-Hsien Sung
Journal: Circulation (2024)

Background: Left ventricular global longitudinal strain (GLS) has been associated with mortality and heart failure hospitalization (HFH) among subjects with chronic heart failure, but not in patients with acute decompensated heart failure (ADHF). The study therefore investigated the prognostic role of GLS in the elder patients with ADHF and preserved left ventricular ejection fraction (LVEF). Methods: Patients, aged≥ 65 years hospitalized for ADHF with LVEF ≥ 50% were enrolled in this study. Echocardiography was performed at discharge and after 6-month heart failure treatment. Post-discharge adverse events of cardiovascular death (CVD) and HFH were obtained. Subjects with adverse events during the 6-month treatment were excluded from this analysis. Results: Among a total of 514 participants (82.6 ± 13.9 years, 50.6% men), 97 patients encountered CVD or HFH during a mean follow-up duration of 26.8 ± 11.6 months. The eventful subjects had a higher prevalence of diabetes, higher estimated pulmonary pressure, lower hemoglobin levels and was less on treatment with renin-angiotensin system inhibitors. The on-treatment GLS but not pre-discharge GLS was independently associated with adverse events after accounting for age, gender, diabetes, hemoglobin, renal failure, medications and echocardiographic indices [hazard ratio (HR) and 95% confidence intervals (CIs): 1.05, 1.01-1.09]. Additionally, the change in GLS from discharge to 6-month was also associated with adverse clinical outcomes (HR and 95% CIs: 1.05, 1.01-1.09). Conclusions: The on-treatment GLS and the change in GLS, but not pre-discharge GLS were independently related to cardiovascular events in the elder patients with HF and preserved LVEF (HFpEF). This study highlights the importance timing to assess GLS among patients with decompensated HFpEF.
Abstract 4142981: Incidence and Predictors of Symptom-Arrhythmia Association During Holter Monitoring
Authors: Avinash Saraiya, Douglas Corsi, Saaniya Farhan, Cameo Hazlewood, Grace Qiu, Behzad Pavri
Journal: Circulation (2024)

Introduction: Reported symptomatic activations by patients who are prescribed Holter monitors often do not correlate with true arrhythmia, and recorded ectopy is often asymptomatic. The prevalence of symptom-arrhythmia association (SAA) and relation with age, sex, and underlying co-morbidities are not well described. Goals: Identify the overall likelihood of symptoms being associated with true arrhythmia. Identify patient characteristics associated with SAA. Methods: In this retrospective chart review, extended Holter recordings (analyzable data &gt;72 hrs) from 100 consecutive patients (Apr-Jul 2023) were selected. Patients activated the monitor when they experienced an arrhythmia-related symptom. Holters with excessive artifact and &lt;2 symptomatic activations were excluded. Accuracy was defined as the percent of activations associated with arrhythmia (APB, VPB, SVT, VT, 2nd/3rd degree AV block, or sinus exit block). We defined “SAA” as accuracy greater than zero. Patient characteristics were characterized as mean or percent (Table I). The relationship between important predictor variables and the presence of SAA was further explored using logistic regression (adjusting for sex, race, analysis duration, comorbidities and ectopy percent, Table II). Analyses were run in RStudio R 4.2.1. Results: For 100 patients (mean age: 55±18, 27% male, 66% Caucasian), the average accuracy was 22%. Of the 100 patients, 42 had SAA. On univariate analyses, patients with SAA were more likely to be older, have a lower LVEF, and be on cardioactive medications. None of these associations were significant after multivariable adjustment for variables shown in Table II. There was no difference in the percentage of females, percent Caucasians, presence of MVP, or the number of symptomatic activations in those with SAA versus without. Conclusion: The average probability of a symptomatic event during Holter recording being associated with a true rhythm disturbance was 22% and only 42% of patients demonstrated any SAA. There was no association between SAA and sex, number of symptomatic activations, or the presence of MVP.