tbuckley/cabot-search huggingface dataset:
Abstract 16922: Accelerated Degeneration and Late Detachment of the Freestyle Aortic Root in Young Adults
Authors: Hatem Hosny, Ahmed Eldowaik, Amir Samaan, Peter P Selwanos, Soha Romeih, Mohamed Hassan, Mohamed El-Khatib, Muhammed Hebala, Ismail Bouhout, Ismail El-Hamamsy, Ahmed Afifi, Magdi Yacoub
Journal: Circulation (2018)

Introduction: The ideal valve substitute for the aortic valve in young adults is yet to be identified. The Freestyle stentless aortic root seems to be a viable candidate, but there is not enough data about how it behaves in young patients. Methods: This study reports the mid-term clinical outcome after total aortic root replacement with stentless porcine root (Medtronic Freestyle) for patients younger than 50 years, in a single center, during the period from 2009 to 2017. Results: 173 patients were enrolled to this study. The median age at operation was 32 years (6-50). 56% were males. 89 patients (51%) had rheumatic heart disease, while 25 patients (14%) had bicuspid aortic valve. 10 patients (6%) had aortic aneurysm. The median valve size was 25 (21-29). 43 patients (25%) had a concomitant procedure during operation, mostly mitral valve surgery. The median bypass time was 180 minutes (82-380). The median follow-up period was 41 months (2-101). In-hospital mortality was 1.2%, while late mortality was 4%. Valve degeneration included virtual disappearance of the walls of the sinuses (encountered in 2 patients after 9 months and 3 years) and late detachment of the valve ring (in 2 patients after 2 and 5 years), resulting in false aneurysms (Figure 1a). Alarmingly, 2 of the patients who developed false aneurysms were discovered by MSCT during routine follow-up, one of them had a normal MSCT 3 years earlier, 2 years after the operation (Figure 1b). 3 patients had re-operation for false aneurysm, with no early mortality. One patient presented in cardiogenic shock caused by severe stenosis due to calcification (Figure 1c) and died after re-operation. Structural valve deterioration (defined as mean aortic gradient &gt; 20 mmHg or aortic regurgitation &gt; 2/4) was 21 ± 8% at 5 years. Freedom from aortic reintervention is 98 ± 3% at 5 years. Conclusions: Although the Freestyle aortic root offers excellent hemodynamics, the risk of early degeneration and the development of false aneurysms were found to be major concerns. Freestyle implantation in young patients should be used with caution. We recommend annual screening of those patients with contrast-enhanced imaging for early detection of such complications.
Abstract 16752: Aortic Pulsatility, and Not Mean Arterial Pressure, is an Independent Determinant of Left Main Coronary Artery Disease
Authors: Azra Mahmud, Mohammad Balghith, Kamal Ayoub, Fayaz Khan, Samir AlChighouri, Fawaz Al Mutairi, Ali Al Ghamdi
Journal: Circulation (2018)

Introduction: Left main coronary artery(LMCA) disease is prognostically the most important lesion in the coronary tree. LMCA differs from the other coronaries in having high elastin content. As aortic blood pressure (BP) directly affects the heart and emerged as independent predictor of major cardiovascular events, there is heightened interest in exploring its relationship with coronary artery disease (CAD). Aortic pulsatility (AP) measurement eliminates the effect of cardiac output and vascular resistance and is shown to be an independent predictor of cardiovascular events in CAD. Hypothesis: As the left main is an elastic vessel, we hypothesized that pulsatile stress may be an independent determinant of disease in this artery. Methods: This was a prospective cohort study in patients undergoing coronary angiography for suspected CAD between the years 2011 and 2016(n=4633, 25% female) at King Abdul Aziz Cardiac Center, Riyadh, Saudi Arabia. We excluded patients with acute myocardial infarction, cardiogenic shock and significant valvular heart disease. Aortic systolic and diastolic BP were measured in the ascending aorta. MAP was obtained by direct integration of the BP curve. PP was calculated as the difference between systolic and diastolic BP. AP was calculated as PP divided by MAP. CAD was defined as &gt; 50% stenosis in LMCA and the 3 major coronaries (left anterior descending, circumflex and right coronary artery). The AP in patients with LMCA disease was compared to those with non-obstructive, 1, 2 and 3-vd as well with LMCA and 3-vd. Results: Six percent of the study population had LMCA disease (mean age 60±11 years, 25% female). LMCA disease was associated with higher PP (69±22 vs. 58±18, p&lt;0.0001) despite similar MAP (94±16 vs. 94.5±14, p=0.92) compared with non-LMCA disease. AP was significantly higher (0.72±0.30) in LMCA disease compared with; 3-vd( 0.63±0.32); 2-vd(0.61±0.28), 1-vd(0.58±0.31) and non-obstructive CAD (0.52±0.26) (p&lt;0.0001). In a stepwise regression model, AP was an independent predictor of LMCA disease( R 2 =0.68,P&lt;0.0001) when adjusted for potential confounders, including MAP, age and gender. Conclusions: We conclude that LMCA disease is independently associated with high aortic pulsatility compared with disease of other coronary vessels,including 3-vd. Considering aortic pulsatile stress to be an independent cardiovascular prognosticator, stiffness of the LMCA may play an important role in plaque formation, hitherto ignored. More research is warranted to test our proof-of-concept study, including outcome.
Abstract 16940: Frailty Predicts Mortality Among Patients Referred for Cardiac Catheterization
Authors: Robert J Widmer, Amrit Kanwar, Mohammed A Al-Hijji, Rajiv Gulati, Abdallah El Sabbagh, Ryan J Lennon, Amir Lerman, Mandeep Singh
Journal: Circulation (2018)

Introduction: Survivorship needs to be comprehensively evaluated amongst older adults. We examined follow-up mortality in patients referred to cardiac catheterization laboratory by prospectively examining frailty. Methods: Frailty in 923 patients ≥55 years was determined using Rockwood’s deficit index. The frailty deficit was based on symptoms, signs, disabilities, diseases, and laboratory measurements. The number of deficits was expressed as a proportion of the total measured deficits. Frailty index was grouped into &lt;0.10 (control), 0.10-&lt;0.20, 0.20-&lt;0.30, 0.30+ and age- and gender-adjusted follow-up mortality was determined using a Cox proportional hazards model. Results: There were 180 (20%) with frailty index &lt;0.10, 348 (38%) in 0.10-&lt;0.20, 215 (23%) in 0.20-&lt;0.30 and 177 (19%) with an index of 0.30 or higher. Patients with a frailty index of 0.30+ were significantly older than those with an index &lt;0.10 (75 ± 10 vs 67 ± 8 years; p&lt;0.001) and more likely to be women (50% vs 20%; p&lt;0.001). Patients with frailty index ≥0.20 and ≥0.30 had a significantly higher mortality risk (HR 3.95, 95% CI 1.51-10.3 and HR: 10.3, 95% CI 4.11-25.7, respectively) on follow-up which remained significant following adjustment for age and gender (HR 3.20, 95% CI 1.21-8.45 and HR: 7.99, 95% CI 3.13-20.4). Conclusions: Among older adults refereed to catheterization laboratory, frailty deficit index predicts follow-up mortality.
Abstract 16680: Bioengineered Peptibodies as Novel Therapeutic Potassium Channel Blockers
Authors: Bojjibabu Chidipi, Mengmeng Cheng, Michelle Reiser, Michael Teng, Sami F Noujaim
Journal: Circulation (2018)

Background: Currently available antiarrhythmics are small molecules with limited safety and efficacy. Therefore, there is an increasing need for novel, safe, and potent ion channel blockers that can be used as antiarrhythmics. We thus bioengineered a peptibody, as a blocker of the acetylcholine activated inward rectifier potassium current (I KACh ). I KACh has been postulated to play a role in chronic atrial fibrillation, making this potassium current a viable therapeutic target. The bioengineered peptibody was generated as a TertiapinQ- human IgG1 Fc fragment fusion protein. TertiapinQ is a 21 aminno acid blocker of I KACh isolated from the European honey bee venom. We hypothesized that the bioengineered peptibody is a more potent blocker of I KACh compared to TertiapinQ. Methods: We used conventional patch clamp, western blot, as well as whole animal electrophysiology to evaluate the effects of the peptibody on I KACh . Results: The peptibody was expressed in Expi293F cells, collected from the culture supernatant, and purified. Western blot showed the correct weight of the purified peptibody, at about 26 KDa. In patch clamp, the IC50s for block of I KACh with the peptibody was 20 pM, versus 10 nM for TertiapinQ. In mice injected i.p. with carbachol, which opens I KACh and slows down the heart rate, the peptibody delivered via jugular vein injection (50 μL of 1.3 μM) completely abrogated the bradycardic effects of carbachol, while TertiapinQ or the Fc fragment at the same concentration did not. Conclusion: We provide proof for the novel idea that anti-ion channels peptibodies can be powerful and highly potent ion channel blockers and have the potential to be developed into novel antiarrhythmic modalities.
Abstract 16797: Long-Term Incidence of Clinically Important Aortic Stenosis Among Community-Dwelling Older Adults: The Cardiovascular Health Study
Authors: David S Owens, Daniele Massera, Traci Bartz, Mary Lou Biggs, John S Gottdiener, Jorge R Kizer
Journal: Circulation (2018)

Background: Subclinical aortic valve calcification is common among older adults, but the incidence and prevalence of clinically significant aortic stenosis (AS) in the general population is not well characterized. We leveraged the Cardiovascular Health Study (CHS), a population-based investigation of older adults with up to 25 years of follow up, to study AS at an epidemiologic level. Methods: We used a case capture methodology involving ICD-9 diagnosis and procedure codes and CHS echo data to ascertain probable or definite cases of AS at baseline and during longitudinal follow up. Using targeted procedure- and diagnosis-code screening, review of CHF hospitalizations and CHS echo data, along with systematic review of longitudinal hospital records, we identified CHS subjects who developed at least moderate AS, had AS-related hospitalizations, or had AS-related valve interventions. Results: There were 5888 participants in CHS (mean age 72.9, 42% male). Of these, 958 were identified for review based on screening methods. Among those with an echo at baseline (1989-1990 for the first cohort and 1994-1995 for the second cohort) and without AS at that time, there were 275 (4.7%) incident probable or definite cases of moderate or greater AS and 169 (2.9%) incident probable or definite cases of severe AS. The median time to moderate or greater AS was 11.3 (range 0.3-24.9) years following baseline echo. Among these subjects, 248 (90%) had an AS-related hospitalization, while only 98 (36%) underwent an aortic valve procedure in this largely pre-TAVR era. Sensitivity analyses were performed, showing that clinically significant AS among the non-reviewed subjects was uncommon (&lt;1%). Conclusions: To our knowledge, this is the first study to evaluate the long-term incidence of clinical AS in the general elderly U.S. population. Starting at age 65, moderate to severe AS affects about 1 in 20 individuals late in life, and is associated with high rate of morbidity leading to hospitalization.
Abstract 16796: Persistent Anemia Associates Long-Term Higher Mortality in Patients After Percutaneous Coronary Intervention
Authors: Takehiro Funamizu, Hiroshi Iwata, Shinichiro Doi, Hirohisa Endo, Hideki Wada, Tomotaka Dohi, Takatoshi Kasai, Shinya Okazaki, Katsumi Miyauchi, Hiroyuki Daida
Journal: Circulation (2018)

Introduction: Anemia is known to be associated with mortality in patients after percutaneous coronary intervention (PCI). However, the impact of temporal change in anemia on prognosis is not fully elucidated. Methods: We prospectively enrolled consecutive 4589 patients undergoing PCI from January 2000 to December 2016. Among them, patients, whose hemoglobin (Hb) level at PCI procedure (baseline) and follow-up coronary angiography (CAG, 6-12 months after PCI), were subjected to the study (n=1832). Patients were divided into 4 groups based on baseline and follow-up Hb level, such as anemia (-) to (-) (n=1122), anemia (-) to (+) (n=171), anemia (+) to (-) (n=159) and anemia (+) to (+) (n=380). Median follow-up period was 5.8±3.7 years. Results: Kaplan-Meier analysis showed that patients with persistent anemia, who had anemia at both baseline PCI and follow-up coronary angiogram (anemia (+) to (+)), had highest mortality rate, while survival rate in patients with recovered anemia (anemia (+) to (-)) was similar in patients without baseline anemia (anemia (-) to (-)) (p=0.01, anemia (+) to (+) vs. anemia (+) to (-)) (Figure). Adjusted Cox proportional hazard analysis showed that persistent anemia was an independent risk for all-cause mortality (Hazard-Ratio: 1.81, 95% confidential interval: 1.35-2.47, p=0.001). Conclusions: Persistent anemia, continuous anemia at PCI and 6-12 months later, is strongly associated with higher all-cause mortality.
Abstract 16895: Lrp1, an Endocytic Vesicle Trafficking Protein, is Associated With Congenital Heart Diseases - Through a "non-Autonomous" Action
Authors: Jiuann-Huey I Lin, Anupma Jha, Jaccob McCleary, Timothy Feinstein, Cecilia Lo
Journal: Circulation (2018)

Backgrounds: Congenital heart diseases affect nearly 1% of neonates per year in the United States and are the leading cause of neonatal death. Despite a strong indication of genetic contribution to congenital heart diseases, the developmental processes and genetic components are poorly understood. From the large-scale forward genetic screen using inbred mice chemically mutagenized with ethyl-nitrosourea (ENU), a novel finding of endocytic trafficking gene mutations, including Lrp1, were recovered as causing congenital heart disease phenotypes. Endocytosis plays roles in modulating cell signaling by regulating the trafficking of the internalized endocytic vesicles to different endosomal compartments, some destined for fusion with lysosomes and degradation while others are recycled to the surface by recycling endosomes. Mutations in these genes causes a spectrum of congenital heart disease comprising of outflow tract abnormalities and alignment defects. Methods and Results: The LRP1 [line 1554(MGI 96828)] mutant mouse line recovered from a forward genetic screen results from a missense (C4232R) mutation in the region encoding the epidermal growth factor (EGF) repeat domain of LRP1. The mutants exhibit a spectrum of septation and outflow tract defects including endocardial cushion defects, double outlet of right ventricle with normal related great arteries as well as DORV with D-malposition of great arteries (Taussig-Bing anomalies). Mouse embryonic fibroblasts (MEF) from LRP1 m/m mutants demonstrated decreased cell-surface expression and increased retention in the endosomes. Migration assay of MEF demonstrated decreased migration of LRP1 m/m compared with control with normal Golgi orientation. The decreasing migration LRP1 m/m also observed in the endocardial cushion tissue from E9.5-10.5 embryos. Different cell lineages crucial to cardiac development with tissue-specific genetic manipulations were used to define the roles of the LRP1 pathway in these three fields of cells during outflow tract development and septation. Cardiac neural crest cell (Wnt1-Cre) knockout of LRP1 recapitulate LRP1 m/m cardiac phenotypes as well as Nkx2.5/Tie2-cre double knockout of LRP1. RNA expression profile suggests Notch pathway and integrin pathway are associated with LRP1 during cardiac development. Conclusions: We provide the first evidence of endocytic vesicle trafficking pathway associated with the development of congenital heart diseases with malalignment/septation and outflow tract defects
Abstract 16917: Shear Stress Regulates Blood-Brain Barrier Integrity Through the CD44 Receptor
Authors: Peter Galie
Journal: Circulation (2018)

Rationale: The “no-reflow” period that follows a stroke is characterized by reduced blood flow and an increase in blood-brain barrier (BBB) permeability, which exacerbates injury to the surrounding tissue. Objective: Here, we evaluate the hypothesis that reduced shear stress on the endothelium contributes to BBB breakdown through attenuation of a cd44-mediated signaling mechanism. Methods and Results: Our studies rely on a three-dimensional in vitro model of a cerebral arteriole that mimics specific aspects of the in vivo BBB, including an endothelium featuring tight junctions, a robust basement membrane, and interaction with astrocytic endfeet. The in vitro vessels are patterned inside a collagen/hyaluronan (HA) composite scaffold within a microfluidic device that allows for the application of controlled levels of shear stress to the endothelium. Perfusion with culture medium exerting a shear stress of at least 0.07 Pa for a period of four days establishes vessel permeability on par with in vivo vasculature, as determined by dextran exclusion experiments and transendothelial electrical resistance (TEER) using impedance spectroscopy. Ceasing the fluid flow resulted in a significant increase in the permeability of the in vitro vessels within two hours (Figure 1A). Removal of HA from the scaffold prevents the formation of tight junctions, suggesting that a cell surface receptor specific for HA could be responsible for the mechanotransduction of fluid shear stress. Knockout of the cd44 receptor using CRISPR-Cas9 negated flow-mediated barrier formation, as shown by reduced tight junction formation in Figure 1B. Quantification of vessel permeability demonstrated that cd44 knockout had a significant affect on barrier function (Figure 1C). Conclusions: Our in vitro model demonstrates the importance of shear stress for maintaining the BBB. Moreover, our findings indicate that the cd44 receptor is a crucial component of the mechanosensing complex that mediates the endothelial response to shear stress. Figure 1: A) Vessel permeability following cessation of fluid flow. B) 180-um diameter cd44 KO endothelial channel (green: actin, red: zonula-occludin 1, blue: nuclei). C) the effect of HA and cd44 knockout on vessel permeability.
Abstract 16705: Abnormal Atrial Substrate Underlies Atrial Fibrillation in Rats With Heart Failure With Preserved Ejection Fraction
Authors: Rui Zhang, Jae Hyung Cho, Joshua I. Goldhaber, Eduardo Marbán, Eugenio Cingolani
Journal: Circulation (2018)

Introduction: Atrial fibrillation (AF) is common in patients with heart failure with preserved ejection fraction (HFpEF), and heralds a poor prognosis, but the underlying mechanisms are not well studied. Hypothesis: We tested the hypothesis that prolonged atrial effective refractory period (AERP) and slow conduction predispose to AF in HFpEF rats. Methods: Dahl salt-sensitive rats were fed a high-salt diet from 7 weeks of age to induce HFpEF (n=32). Normal-salt fed rats were used as controls (n=26). Echocardiograms at 14-15 weeks of age were used to verify diastolic dysfunction and to assess left atrial size. Electrical phenotype was probed by electrocardiography (P wave duration, PR interval) and in vivo provocative electrophysiological testing (using a 1.5 French catheter) in echo-verified HFpEF and control rats. Optical mapping was performed to measure action potential duration (APD) and conduction velocity (CV) in ex vivo HFpEF and control hearts. Results: High-salt fed rats showed decreased E/E’ ratio with preserved ejection fraction (60-70%), hence were diagnosed with HFpEF. Left atrial size was increased in rats with HFpEF compared to controls (29.1±0.8 vs. 19.5±1.1 mm 2 , p&lt;0.001). P waves were prolonged in HFpEF rats compared to controls (17.8±0.5 vs. 13.5±0.6 ms, p&lt;0.001), as was the PR interval (57.8±1.1 vs. 48.8±1.3 ms, p&lt;0.001). AF induction after burst pacing was much easier in HFpEF rats (27/32 HFpEF rats compared to 5/26 controls, 84.4 vs. 19.2%, p&lt;0.001). Atrial effective refractory period (AERP) was prolonged in HFpEF rats compared to controls (37.8±1.7 vs. 30.6±1.8 ms, p&lt;0.01). During optical mapping, APD was prolonged in left atrium of HFpEF rats compared to controls (APD90 42.3±3.6 vs. 30.9±2.2 ms, p&lt;0.05), atrial CV was slower in HFpEF rats compared to controls (0.31±0.03 vs. 0.46±0.02 mm/ms, p&lt;0.01). Conclusions: Rats with HFpEF were at increased risk of inducible AF after burst pacing. Decreased atrial conduction velocity and prolonged AERP contribute to the pathogenesis of AF in HFpEF.
Abstract 16865: Debunking the Concept That the “Metabolically Obese Normal Weight” Phenotype is Independent of Fat: It is All About Central Obesity
Authors: Jose R Medina-Inojosa, John Batsis, Farzane Saeidifard, Andrea Maugeri, Martin Homolka, Thomas Allison, Amanda Bonikowske, Manlio Vinciguerra, Francisco Lopez-Jimenez
Journal: Circulation (2018)

Background: The Metabolically Obese Normal Weight (MONW) phenotype has been described as a unique subgroup of individuals with metabolic dysregulation similar to obese individuals, but not considered obese per se . In theory, these individuals have an adiposity-independent substrate predisposing them to metabolic dysregulation. We tested whether central obesity explains the metabolic abnormalities in persons with MONW in a prospective population-based cohort in the Czech Republic. Methods: We used data from Kardiovize Brno 2030 study, a prospective community-based cohort in Central Europe. We defined obesity using World Health Organization categories for body mass index (BMI) and central obesity by waist circumference (WC≥ 94 cm in men and ≥ 80 cm in women). Metabolically obese (MO) was defined using AHA criteria by having three or more of the following: Hypertriglyceridemia (≥ 1.7 mmol/l); HDL cholesterol level &lt;1.0 mmol/l in men or &lt;1.3 mmol/l in women; elevated blood pressure (systolic ≥ 130 mmHg and/or diastolic ≥ 85 mmHg) or antihypertensive drug treatment or history of hypertension; elevated fasting plasma glucose ≥ 5.6 mmol/l; or drug treatment and central obesity. Results: Of the 2,056 participants (46% men; mean age= 47.2 years, SD=11.2) included in the current analysis, 975 (47.4%) had normal weight and 696 (33.8%) were overweight. Prevalence of MO in the overall sample was 20.6% (n=424), 3.7% (n=36) among those with normal BMI and 9.9% (n=204) among overweight individuals. From the 36 subjects with MONW, 33 (91.6%) had central obesity by WC, while 201/204 (98.5%) with metabolically obese overweight, had central obesity by WC. Remarkably, in a subgroup of people with no metabolic obesity factors nobody had central obesity, see Figure . Conclusions: Metabolic dysregulation in people labeled as MONW can be explained by excessive visceral adiposity and not by an inherent predisposition, independent of adiposity.These findings underscore the importance of identifying central obesity in clinical practice even if BMI is below the obese criteria.