tbuckley/cabot-search huggingface dataset:
Abstract 16485: Treatment With PCSK9 Inhibitors Influence miRNAs Expression and Changes of Arterial Wall Properties
Authors: Andreja Rehberger Likozar, Sabina Ugovšek, Tina Levstek, Katarina Trebušak Podkrajšek, Miran SEBESTJEN
Journal: Circulation (2023)

Background and aim: MicroRNAs (miRNAs) are involved in the synthesis of proprotein convertase subtilisin-kexin type 9(PCSK9), which is one of regulators of low-density lipoprotein cholesterol (LDL-C) metabolism. There is no data on whether changes in the expression of miRNAs involved in PCSK9 metabolism, could be related to arterial wall properties changes. The aim was to verify whether PCSK9 inhibitors (PCSK9i) treatment and the changes in the expression of miRNAs are associated with arterial wall properties in post-myocardial infarction (MI) patients with insufficiently regulated LDL-C levels and increased Lp(a) levels. Methods: Seventy-six participants after MI were enrolled and randomized to a placebo group or PCSK9i group. The treatment group received subcutaneous alirocumab 150 mg or evolokumab 140 mg, every 2 weeks. Blood for biochemical and genetic analysis was taken and ultrasound measurements of flow-mediated dilation of brachial artery (FMD), carotid intima-media thickness (c-IMT) and pulse wave velocity (PWV) were performed. All measurements were measured initially and after 6 months of treatment. Results: FMD improved from 10.9±6.3 to 14.4±5.7% in the PCSK9i group and 10.8±6.8 to 11.2±4.6% in the placebo group (p&lt;0.001, p=0.584). PWV changed from 5.8±1.4 to 5.5±1.6 m/s (p=0.024) in the PCSK9i group and in the placebo group from 5.6±1.5 to 5.5±1.1 m/s (p=0.879), with better improvement in the treated group (p=0.007). c-IMT decreased in the PCSK9i group (from 0.65±0.10 to 0.63±0.10 mm; p=0.017), with no change in the placebo group (from 0.64±0.09 to 0.63±0.09 mm; p=0.482). The expression of miR-191-5p and miR-483-5p increased in the PCSK9i group (p=0.028, p=0.020; respectively). The expression of miR-191-5p significantly decreased in the placebo group (p&lt; 0.001). A decrease in c-IMT was associated with a decrease in the expression of miR-224-5p (r=0.303; p=0.019), miR-337-3p (r=0.329; p=0.010) and miR-483-5p (r=0.367; p=0.004). Conclusions: Our results suggest that changes in selected miRNAs were associated with changes in the morphological properties of the arterial vessel wall. We have shown that the increase in miR-483-5p expression can be a good indicator of the regression of morphological atherosclerotic changes.
Abstract 17975: Improvement in Exercise Capacity After Surgical Septal Myectomy in Obstructive Hypertrophic Cardiomyopathy Patients is Related to Peak Exercise Strain Rate and Mechanical Reserve
Authors: Hernan L Vera Sarmiento, Hongyun Liu, Angie Carreno Martinez, Iraklis Pozios, Bereketeab Haileselassie, Daiyin Lu, Ioannis Ventoulis, Lars Sorensen, Susan Phillip, M Roselle Abraham, Theodore Abraham
Journal: Circulation (2023)

Background: Significant improvements in functional capacity are noted after septal myectomy in symptomatic patients with obstructive hypertrophic cardiomyopathy (oHCM). However, the underlying mechanism behind these improvements is unclear. Methods: Conventional and strain echocardiography, at rest and post-exercise, was performed pre-and post-septal myectomy in 59 OHCM patients (42 men; mean age 50±12years). Exercise capacity was expressed as metabolic equivalents (METs) after treadmill exercise testing. Global longitudinal peak systolic strain (S) and stain rate (SR) were measured at rest and peak-exercise. Results: After myectomy, outflow gradient decreased significantly (resting gradient: 69±43 to 13±8mmHg; provoked gradient: 141±50 to 40±21mmHg; both p&lt;0.001) with no significant change in ejection fraction (66±5% to 65±4%, p=NS). METs improved significantly (9.5±3.2 to 10.6±2.9, p=0.001). There was no significant change in S and SR at rest (S: -15.17±2.89% to -15.27±2.75%; SR:-0.95±0.18S-1 to -0.92±0.15S-1, both p=NS) or post-exercise (S: -17.06±3.63% to -16.68±2.79%; SR: -1.45±0.30S-1 to -1.52±0.28S-1, both p=NS). Mechanical reserve (MRES, change in systolic SR with exercise) increased significantly (55±30% to 67±32%, p=0.02). METs correlated significantly with exercise SR and MRES determined pre-myectomy (exercise SR: r=-0.41, p=0.003; MRES: r=0.33, p=0.017) and post-myectomy (exercise SR: r=-0.53, p&lt;0.001; MRES: r=0.51, p&lt;0.001). Improvement in METs was significantly correlated with changes in MRES (r=0.36, p=0.019). Multivariable linear regression confirmed an independent correlation between exercise SR and MRES with METs. Conclusions: Resting and peak exercise myocardial contractility (longitudinal S and SR) do not change significantly after septal myectomy. Post-myectomy MRES improves significantly and exercise capacity post-myectomy correlates significantly with pre- and post-myectomy functional status.
Abstract 13981: Computed Tomography Angiography Measures of Carotid Artery Plaque Burden in Patients With Atherosclerotic Carotid Artery Disease Stratified by Status of Chronic Kidney Disease
Authors: Ankita Sinharoy, Olga A Gimnich, VIJAY NAMBI, Panagiotis Kougias, Addison A Taylor, Gerd Brunner
Journal: Circulation (2023)

Introduction: Atherosclerotic carotid artery disease (ACAD) is associated with an increased risk of cerebrovascular mortality and morbidity. We have analyzed associations of computed tomography angiography (CTA) measures of carotid artery (CA) plaque burden with chronic kidney disease (CKD). Hypothesis: CTA-based measures of CA plaque burden in patients with ACAD differ across stages of CKD. Methods: A total of 63 ACAD patients (13 without CKD, 50 with CKD), who completed CTA imaging and had demographic data were included in a retrospective analysis of patients from the Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC), Houston, Texas. CA plaque burden measures include the normalized wall index (NWI), wall area (WA), and lumen area (LA) at three distinct CA locations: CA bifurcation (BF), maximum total vessel cross-sectional area (MTVA) of the internal CA (ICA), and ICA peak stenosis (PS). CTA measures and patient demographics were compared across three CKD classes (no disease: n=13; CKD stages 1 and 2: n=31; and CKD stage 3 and above; n=19). Results: Baseline characteristics differed among CKD groups for the estimated glomerular filtration rate (p=&lt;0.0001) and the body mass index (p=0.046). Inter-observer variability, assessed by intraclass correlation (ICC) analysis, was excellent for CA lumen area and wall area (0.964 (confidence interval [CI]: 0.946, 0.976); 0.865 (CI: 0.804, 0.908): n=100 CTA slices, both). The mean NWI differed significantly among the CKD groups for two of the three CA locations (BF: p=0.018, MTVA: p=0.01; PS: p=0.057). Similarly, lumen area significantly differed between CKD categories (BF: p=0.045, MTVA: p=0.013; PS: p=0.017) but not the wall area. Conclusion: CTA-based measures of carotid plaque burden in ACAD patients are highly reproducible and differed across CKD groups. Imaging-based measures of CA plaque burden may be of interest in stratifying risk assessment of ACAD patients with concomitant CKD.
Abstract 17260: Endothelium-Targeted Nanoparticle Delivery of FOXM1 Reactivates Aging-Impaired Endothelial Regeneration for Vascular Repair and Inflammatory Lung Injury Resolution: Precision Gene Therapy of Acute Respiratory Distress Syndrome
Authors: Xiaojia Huang, Xianming Zhang, Narsa Machireddy, Colin Evans, Youyang Zhao
Journal: Circulation (2023)

Introduction: Aging is a major risk factor of high incidence and increased mortality of acute respiratory distress syndrome (ARDS). However, the underlying molecular mechanisms remain elusive and there is no effective therapy for ARDS. Hypothesis: Impaired endothelial regeneration and vascular repair in aged lungs causes persistent lung injury leading to high incidence of ARDS and high mortality in elderly patients following sepsis challenge. Methods: Genetic lineage tracing was employed to determine the cell origin of endothelial regeneration. Aged Foxm1Tg mice was used for assessing the role of FoxM1 in activating endothelial regeneration. Endothelium-targeted nanoparticles were employed to deliver FOXM1 gene selectively to endothelial cells (ECs) in aged mice. Methylation analysis was employed to determine how aging impairs FoxM1 expression. Results: Genetic lineage tracing study showed that endothelial regeneration was mediated by lung endothelial proliferation in adult mice whereas this intrinsic regenerative program was impaired in aged mice. Expression of FoxM1, an important mediator of endothelial regeneration in young adult mice, was not induced in lungs of aged mice due to aging-induced hypermethylation of the Foxm1 promoter. Transgenic FOXM1 expression or in vivo endothelium-targeted nanoparticle delivery of FOXM1 gene reactivated endothelial regeneration, normalized vascular repair and promoted survival of aged mice following sepsis. Furthermore, nanoparticle delivery of FoxM1 gene selectively in lung ECs also reactivated endothelial regeneration in aged mice, supporting the novel concept of precision gene therapy. In COVID-19 lung autopsy samples, FOXM1 expression was not induced in vascular ECs of elderly patients in contrast to mid-age patients, validating the clinical relevance of our findings. Conclusions: We have demonstrate that persistent lung injury and high mortality in aged mice following sepsis challenge is ascribed to impaired endothelial regeneration and vascular repair. Therapeutic reactivation of FoxM1-dependent endothelial regeneration and vascular repair represents a potential effective therapy for elderly ARDS patients by endothelium-targeted nanoparticle delivery of FOXM1 gene.
Abstract 16954: Sex Differences in Cardiac and Vascular Function With Healthy Aging: Implications for Greater Risk of HFpEF in Women
Authors: Tiffany L Brazile, Denis J Wakeham, Diana De Oliveira Gomes, Christopher Hearon, James P Macnamara, Benjamin D Levine, Satyam Sarma
Journal: Circulation (2023)

Introduction: Mechanisms mediating the disproportionate risk for heart failure with preserved ejection fraction (HFpEF) in women are poorly understood. Impaired stroke volume (SV) reserve, increased afterload, arterial and left ventricular (LV) stiffness contribute to exercise intolerance in HFpEF. It is unknown whether subclinical changes in these measures predispose women to HFpEF; therefore, we compared resting and exercise cardiovascular structure and function across age in healthy men and women. Methods: We studied 192 sedentary normotensive, non-obese adults (53% female; age: 58 ± 13 [20-90] years) at rest, during sub- and maximal exercise. We measured systolic blood pressure (SBP; electrosphygmomanometry) and aortic stiffness (carotid-femoral pulse wave velocity; aPWV). Myocardial stiffness was assessed as the slope of individual pressure-volume (right heart catheterization-echocardiography) curves generated by graded LV loading and unloading. SV was calculated from cardiac output (Q˙c; C 2 H 2 rebreathe)/heart rate to assess afterload (Ea; SBP/SV) and SV reserve (% change from rest) during exercise. Data were compared via two-way ANOVA (age*sex). Results: There was no significant age*sex interaction for aPWV, SV reserve, resting or maximal SBP, or myocardial stiffness; however, there was a main effect for sex with higher myocardial stiffness in women (Figure). aPWV and SV reserve were not different between sexes (p=0.349, p=0.940). Maximal exercise SBP was lower in women, but a similar proportion of each sex had an exaggerated maximal exercise SBP (Men: &gt;210; Women: &gt;190 mmHg; 28% vs 35%, χ 2 =0.290). Peak exercise afterload was higher in women (Figure) due to lower SV. Conclusions: Increased risk for HFpEF in women may be driven in part by greater myocardial stiffness throughout the aging process. Sex related abnormalities in afterload were most prominent with exercise in women, which may predispose to LV hypertrophy and increased stiffness.
Abstract 15046: Atrial Sarcomeric Dysfunction in <i>Ttntv</i> Mice Indicates a Causal Relationship Between Rare Variation in <i>TTN</i> and Early Onset Atrial Fibrillation in Patients
Authors: Silje Madeleine Kalstoe, Morten Mattingsdal, Karoline B Rypdal, Michael Frisk, Pia Rengtved Lundegaard, Arnljot Tveit, Morten S Olesen, Ida G Lunde, Ingrid E Christophersen
Journal: Circulation (2023)

Background: Atrial fibrillation (AF) is a common cardiac arrhythmia with a substantial genetic component. Rare variation in TTN and other sarcomeric genes have been associated with AF, in particular in early-onset disease. Aim: To describe the burden of rare, functional variants in a Norwegian early-onset AF population and to perform functional characterization in a Ttn truncating variant ( Ttntv ) mouse model. Methods: We performed whole-genome sequencing in 90 individuals with onset of AF before age 50 years and calculated the burden of rare, functional variation for all genes. Variant frequencies and gene burden from gnomAD 3.1.2 NFE were used as controls. The burden was defined as the sum of allele counts for rare (MAF&lt;1%) and damaging variants (high and moderate impact) for each gene, and differences in burden was assessed using Fisher’s exact test. Functional characterization, including echocardiography, electron microscopy and mRNA expression analyses, was performed in atria from haploinsufficient Ttntv mice. Results: We identified an increased burden of rare, functional variation in 57 genes, including the sarcomeric genes TTN , MYH6 and OBSL1 , but also in the cell adhesion gene DCHS2 , in individuals with early-onset AF. Ttntv mice had normal cardiac function assessed by echocardiography, but electron microscopy revealed structural remodeling of the atria, with a patchy pattern of unorganized sarcomeres with focal fibrosis and lipid droplet accumulation. Molecular profiling of atria using RNA sequencing showed differential expression of genes related to cellular stress, sarcomeric structure and fibrosis, including increased levels of Anp , Malat1 and Kcna1 . Dchs2 displayed decreased expression in Ttntv atria. Conclusion: We identified an increased burden of rare, functional variation in genes associated with sarcomeric function in early-onset AF. Atrial myopathy with sarcomeric lesions, focal fibrosis, lipid droplet accumulation and altered gene expression of Anp , Malat1 and Kcna1 was found in atria of mice with Ttntv , suggesting a causal, pathophysiological relationship between TTN variants and AF. Interestingly, DCHS2 displayed both increased burden of rare variation in early-onset AF and decreased expression in Ttntv mouse atria.
Abstract 14708: Heart Failure While Homeless: Examining the Relationship Between HF Hospitalizations and Housing Insecurity
Authors: Martine S Webb, Boback Ziaeian
Journal: Circulation (2023)

Background: The association between housing insecurity and outcomes of hospitalizations for heart failure (HF) has not been previously well-established. Methods: We analyzed HF hospitalizations using the 2020 United States National Inpatient Sample database. Individuals were identified as having housing insecurity by related ICD-10 codes. Other demographic and comorbidity data were identified using corresponding ICD-10 codes. Characteristics of patients hospitalized for HF that were identified as having housing insecurity were compared to those hospitalized for HF who had no housing insecurity. We performed a multivariable risk adjustment for in-hospital mortality based on patient characteristics. Results: Out of 1,003,270 hospitalizations for HF, 16,150 were identified as having housing insecurity (1.6%). The average age of patients with housing insecurity hospitalized for HF was 56, as compared to 71 in the housed population. A higher proportion of patients in the housing-insecure group were Black (35% vs 20.1%) or Hispanic (11.1% vs 7.3%). Patients with housing insecurity were more likely to carry a diagnosis of alcohol use disorder (15.2% vs 3.3%) or substance use disorder (70.2% vs 17.8%), however they were less likely to use tobacco (18.3% vs 28.7%). Patients with housing insecurity were over 4.5 times more likely to have a primary Medicaid payer (52.4% vs 11.3%). Average length of stay did not differ between housing-insecure patients versus those without (5.37 vs 5.51 days). After adjusting for patient characteristics, housing insecurity was predictive of lower in-hospital mortality (OR 0.622, 95% CI 0.403 - 0.960). Conclusions: Significant differences occur between patients hospitalized for HF who also have housing insecurity. These differences are most pronounced for substance use and psychiatric disorders. However, housing insecurity was predictive of lower in-hospital mortality. Admissions for heart failure may provide important opportunities to screen for and address comorbid conditions for patients with housing insecurity, as well as for other vulnerable populations.
Abstract 18432: Lipoprotein(a) is Associated With Long-Term Plaque Progression, Pericoronary Inflammation and High-Risk Plaque on Serial Coronary CT Angiography
Authors: Nick Nurmohamed, Emilie Gaillard, Shant Malkasian, Michiel J Bom, Robin de Groot, Shirin Ibrahim, Ruurt Jukema, Yannick Kaiser, James K Min, James Earls, R. Nils Planken, Andrew Choi, Erik S Stroes, Paul Knaapen
Journal: Circulation (2023)

Background This study investigated the effect of lipoprotein(a) (Lp[a]) on long-term plaque progression, high-risk plaque (HRP) and pericoronary adipose tissue attenuation (PCATa) in patients suspected of coronary artery disease. Methods: Per-protocol, patients from a coronary CT angiography (CCTA) cohort (Diemen et al., 2021) were invited for repeat CCTA imaging, regardless of symptoms. A total of 299 patients underwent follow-up CCTA imaging with a median scan interval of 10.2 [IQR 8.7-11.2] years. Patients who underwent coronary artery bypass grafting and vessels revascularized by percutaneous coronary intervention were excluded. Scans were analyzed using atherosclerosis-imaging quantitative CCTA (AI-QCT; Cleerly Inc.). The associations between high (Tertile 3; &gt;67 nmol/l) and low Lp(a) (Tertile 1 and 2; ≤67 nmol/l), baseline and follow-up plaque burden and characteristics were evaluated using multivariable regression adjusted for clinical risk factors, statin use and scanner settings. Results: In total, 274 patients were included, mean age was 57±7 years, 42% were women. Patients with high Lp(a) levels had higher volumes of percent atheroma volume (PAV) at baseline and follow-up and higher rate of plaque progression (Figure 1A). The difference in PAV caused by high Lp(a) versus low Lp(a) patients was similar to the effect of a 12-year age difference. At baseline, patients in the highest tertile of Lp(a) levels had a higher prevalence of both HRP (OR 2.24; p=0.009) and above-median right coronary artery PCATa (OR 1.76; p=0.049). Finally, patients with high Lp(a) levels had a twofold higher incidence of major adverse cardiovascular events (MACE; Figure 1B; p=0.044). Conclusion: Patients with high Lp(a) levels had increased coronary plaque burden, increased prevalence of high-risk plaque and pericoronary inflammation as well as increased plaque progression leading to an increased incidence of MACE throughout 10-year follow-up.
Abstract 18492: Cross-Sectional Analysis of Demographic and Clinical Characteristics of Patients Using Icosapent Ethyl, With a Focus on Patients With Diabetes
Authors: Om P Ganda, Peter P Toth, Handrean Soran, John R Nelson, Nathan D Wong, David Abrahamson, Hakima Hannachi, Josh Hartman, Sephy Philip
Journal: Circulation (2023)

Background: Icosapent ethyl was approved in Dec 2019 to reduce CV event risk in statin-treated adults with elevated TG (≥150 mg/dL) and established CVD or diabetes with other risk factors of CVD. Hypothesis: Patients who take icosapent ethyl have demographic/clinical characteristics consistent with its indication. Aims: This study describes demographic/clinical characteristics of US patients taking icosapent ethyl, focusing on those with diabetes. Methods: A database of &gt;89 million US electronic medical records identified patients taking icosapent ethyl (ie, ≥2 prescriptions on 2 separate days). Patient demographic/clinical baseline data were retrieved. Results: As of Jan 19, 2023, 40,408 patients taking icosapent ethyl were identified, with a mean (SD) age of 60.3 (12.9) y, BMI of 31.9 (6.07) kg/m 2 , HbA1c of 7.24% (1.88), and glucose level of 143 (67.8) mg/dL. Most were men (60.5%), White (75.2%), and taking statins (71.8%). Mean (SD; median) TG in the 3 mo before icosapent ethyl initiation was 422 (506; 300) mg/dL; 8.1% of patients had TG ≥500 mg/dL. In line with the indication of icosapent ethyl, 65.3% had prior atherosclerotic CVD or diabetes and ≥1 risk factor. Among 16,564 patients with diabetes ( Figure ), 13.0% had a history of myocardial infarction, 12.5% had stroke, and 10.4% had revascularization. Overall, 14.2% had chronic kidney disease and 5.5% had type 2 diabetes mellitus with diabetic kidney disease. Common risk factors for CVD were hypertension (68.4%), obesity (40.9%), and history of cigarette smoking (21.6%). Common antidiabetic medications were metformin (37.4%), insulin (27.9%), and sulfonylurea (15.1%). Conclusions: Patients using icosapent ethyl often had diabetes and/or CVD, took statins, and had elevated TG, meeting indications for its use. However, the high median TG before therapy suggests that many physicians reserve icosapent ethyl for more severe TG; thus many patients with more moderate levels (&gt;150 mg/dL) could potentially benefit.
Abstract 18146: Deactivation Status of Defibrillation at the End of Life in Patients With Implantable Cardioverter Defibrillators
Authors: shoko narumi, Yusuke Kondo, Masahiro Nakano, Takatsugu Kajiyama, Ryo Ito, Toshinori Chiba, SATOKO RYUZAKI, Yutaka Yoshino, Yuya Komai, Yukiko Takanashi, Yoshio Kobayashi
Journal: Circulation (2023)

Background: Implantable cardioverter-defibrillators (ICDs) are effective in preventing sudden cardiac death due to fatal arrhythmias. However, defibrillation is also known to cause physical and emotional distress to the patients. When patients with an ICD are approaching the end of life, the guidelines on palliative care in cardiovascular diseases recommend that the benefits and burdens of ICDs are fully explained to the patients and that a policy regarding the deactivation of defibrillation function is discussed. However, there are few reports on the therapy status of ICD patients in the end-stage of life.Aim: To investigate the deactivation status of defibrillation in patients with an ICD. Methods: We retrospectively analyzed ICD database at our hospital and studied 143 ICD patients who died from 2006 to June 2023. The frequency of ICD therapy delivered before death and information about the discussion of deactivation and do not attempt resuscitation (DNAR) decisions were reviewed using medical charts. Results: Of 143 patients, 45 (31%) patients in the end-stage of life were assigned to DNAR and 24 (17%) patients was explained deactivation of ICD therapies at the time of DNAR order. Fifteen (10%) patients, including 11 patients in the end-stage heart failure, underwent deactivation and 2 patients received ICD therapies after DNAR order. Nine (6.2%) patients did not undergo deactivation. Of those, 4 patients received ICD shock therapies. Twenty-one patients (15%) were not given the explanation for the deactivation after DNAR order. Of those, 4 patients received ICD shock therapies. Conclusion: Our study shows that only 10% of Japanese ICD patients in the end-stage of life underwent deactivation of ICD therapies. Discussions regarding ICD deactivation in palliative care are necessary to reduce the risk of painful shocks and distress during the end of life.