tbuckley/cabot-search huggingface dataset:
Abstract P396: Noncanonical Wnt5a Increases QT Interval And Susceptibility To Ventricular Arrhythmias
Authors: Jerry Wang, Aizhu Lu, Ying Xia, Hongwei Wang, Cagla Cimenci, Erik J Suuronen, Hadi Toeg, Marc Ruel, Darryl R Davis, Peter Liu, Rob S Beanlands, Wenbin Liang
Journal: Circulation Research (2021)

Background: Wnt signaling plays a critical role in both embryonic cardiogenesis and cardiac remodeling in adult heart disease. We have previously demonstrated that the canonical Wnt/β-catenin pathway inhibits cardiac sodium current, but it remains unclear whether the noncanonical Wnt pathway affects cardiac electrophysiology. Methods and Results: Western blot analysis of ventricular tissues from patients with heart failure (n=6) demonstrated a 2.3x fold increase (p&lt;0.01) in the protein level of Wnt5a, a noncanonical Wnt ligand, as compared to healthy ventricular tissues (n=5). To investigate if Wnt5a affects cardiac electrophysiology, adenovirus expressing Wnt5a and mCherry (Ad-Wnt5a) or control adenovirus expressing mCherry only (Ad-mCherry) was injected into the left ventricular free wall of adult rat hearts. At 4-5 days after virus injection, surface ECG revealed increased QT interval (p&lt;0.01) in Ad-Wn5a-injected rats (90.1±2.3 ms n=7, vs 72.3±2.0 ms in control Ad-mCherry rats n=7). In addition, ventricular tachycardia was induced by programmed electrical stimulation in 92% (11/12) Ad-Wnt5a hearts, but only in 22% (2/9) control Ad-mCherry hearts (p&lt;0.01). Patch-clamp recording of isolated single ventricular myocytes demonstrated that Ad-Wnt5a myocytes exhibited marked prolongation of action potential duration (APD 90 : 273±77ms, n=5) as compared to control cells (42±12 ms, n=7, p&lt;0.05). In addition, the prolonged action potentials in Ad-Wnt5a myocytes were associated with frequent early afterdepolarizations and delayed afterdepolarizations, two mechanisms for triggered ventricular arrhythmias. Conclusion: Wnt5a is increased in the myocardium of patients with heart failure. Viral expression of Wnt5a in rat ventricular tissue increases QT interval and ventricular arrhythmia susceptibility, which is associated with prolongation of action potentials in cardiomyocytes. This may be an important target for future therapies.
Abstract 12812: Creatine Chemical Exchange Transfer MRI Demonstrates Abnormal Calf Muscle Energetics in Peripheral Arterial Disease
Authors: Yaqub Betz, Toral Patel, Helen Sporkin, Roshin C Mathew, Chris Schumann, Craig Meyer, Christopher M Kramer
Journal: Circulation (2021)

Introduction: Creatine chemical exchange saturation transfer (CrCEST) is a novel MRI technique utilizing radiofrequency pulses to monitor creatine concentrations at high spatial resolution. The study utilized CrCEST kinetics to compare post-exercise creatine decay in peripheral arterial disease (PAD) patients to normal subjects and to validate against phosphocreatine (PCr) recovery by 31 phosphorus (P) MR spectroscopy (MRS). Methods: 23 subjects with PAD (claudication and ankle-brachial index&lt;0.9) and 28 healthy subjects were enrolled. All underwent 3T MRI (Siemens Prisma) using a knee coil around the calf. Pre- and post-exercise images were obtained around plantar flexion ergometry (Ergospect) until exhaustion. Regions of interests were drawn around major muscle groups. Creatine decay times were obtained by fitting an exponential curve to the CrCEST values. 31 P spectra were obtained 20 minutes later at peak exercise using a surface-coil localized, free induction decay acquisition with 25 signal averages at a repetition time of 550s with calculation of PCr recovery time constant. Results: 23 PAD subjects (mean ABI 0.66 ± 0.11, age 64 ± 8, 17% females) had prolonged median overall calf muscle creatine decay time of 286 seconds (s) (Interquartile Range (IQR) 134 to 370) versus 152 s (IQR 114 to 193) in controls (age 63 ± 9, 70% females), p = 0.009. The gastrocnemius muscle demonstrated a creatine decay time of 316 s in PAD (IQR 189 to 510) versus 181 s in controls (IQR 102 to 236), p = 0.003 and the posterior tibialis muscle, 186 s (IQR 119 to 653) versus 125 s (IQR 72 to 221), p = 0.013. 8 PAD patients and 6 controls underwent CrCEST and 31 P MRS which were compared over the entire calf. Bland-Altman analysis (Figure 1B) yielded a mean difference of 71s (SD 109). Conclusions: Imaging with CrCEST demonstrates prolonged creatine kinetics in PAD patients compared to normal subjects with high spatial resolution and good agreement with 31 P MRS, although PCr recovery appears faster.
Abstract 10092: Prophylactic Ventricular Tachycardia Ablation in Ischemic Cardiomyopathy: An Updated Meta-Analysis of Randomized Controlled Trials
Authors: Pattara Rattanawong, Justin N Shipman, Olubadewa Fatunde, Dan Sorajja
Journal: Circulation (2021)

Introduction: Catheter ablation of the arrhythmogenic substrate reduces the recurrence of ventricular tachycardia (VT) in patients with ischemic cardiomyopathy and implantable cardioverter-defibrillator (ICD). However, the all-cause mortality benefit in this population is unclear. Hypothesis: Prophylactic ablation of the arrhythmogenic substrate decreases all-cause mortality and prevents the recurrence of VT/ventricular fibrillation (VF) in patients with ischemic cardiomyopathy. Methods: We searched the MEDLINE and EMBASE databases from inception through May 2021. We included randomized controlled trials that compared all-cause mortality and ventricular arrhythmia recurrence in patients with ischemic cardiomyopathy who underwent ICD implantation with and without prophylactic ablation. The data from each study was combined using a fixed effects model to calculate the hazard ratio and 95% confidence interval (CI). Results: Four randomized controlled trials during 2007-2020 involving 505 patients (249 patients with and 256 patients without prophylactic VT ablation) were included in our meta-analysis. Compared with control, prophylactic VT ablation did not decrease the all-cause mortality (pooled hazard ratio = 0.94, 95% CI 0.54-1.63, p = 0.818, I2 = 5.8%). However, prophylactic VT ablation significantly decreased appropriate ICD therapy (pooled hazard ratio = 0.58, 95% CI 0.41-0.82, p = 0.002, I 2 = 26.1%) and VT/VF recurrence (pooled hazard ratio = 0.70, 95% CI 0.52-0.93, p = 0.015, I 2 = 0.0%). Conclusions: Prophylactic VT ablation in patients with ischemic cardiomyopathy did not decrease all-cause mortality; however, it did lead to decreased appropriate ICD therapy and VT/VF recurrence.
Abstract 10694: Relationship of Serum Triglycerides with Incident End Stage Renal Disease Across Urine Albumin-to-Creatinine Ratio Subgroups and Chronic Kidney Disease Stages
Authors: Yousif Arif, Melissa Soohoo, John Rizk, Leila Hashemi, Maria Marroquin, Jui-Ting Hsiung, Jessica Edward, Elani Streja
Journal: Circulation (2021)

Background: Studies investigating serum triglycerides (TG) and renal outcomes including ESRD were mixed, and often these studies were unable to account for potential confounding for MetS components. It remains unclear how these relationships may present in patients with diabetic kidney disease and in consideration of albuminuria, or UACR. Methods: We studied 138,675 US diabetic veterans, with data on serum TG and UACR from 2004-2006 and follow-up until 2014. Using Cox models adjusted for clinical characteristics and laboratory markers (including UACR, body mass index, hemoglobin A1c and high-density lipoprotein), we evaluated the relationship of baseline TG with time to ESRD. All models were stratified by baseline CKD stage and baseline albuminuria stage ascertained at time of TG measurement. Results: The cohort was 65±11 years old, and included 28% with CKD 3A-5, and 4% with UACR &gt;300 mg/g. The median[IQR] of TG was 146[99,217] mg/dL. In non-albuminuric patients, we observed a linear relationship between TG and transition to ESRD among non-CKD patients, yet a U-shaped relationship for CKD 3A-3B (ref: TG 120-&lt;160 mg/dL). The relationship with TG ≥ 240 mg/dL diminished across CKD stages, where it was attenuated for CKD 4/5 patients (p-trend =0.05). In microalbuminuria patients, a trend towards an elevated risk of ESRD transition for TG ≥ 240 mg/dL was observed in CKD 3A and 4/5 only. Finally, patients with macroalbuminuria and elevated TG did not have a clear pattern in risk of ESRD across CKD stages (p-trend= 0.73). [Figure] Conclusion: In patients with diabetes and CKD, high TG levels predicted ESRD in CKD 3A non-albuminuria patients and in CKD 3A and 4/5 in patients with microalbuminuria. These associations were independent of glycemic control, MetS components, and medications including lipid-lowering drugs. These findings highlight the importance of investigating the impact of lipid modulating therapies specifically among patients with diabetic kidney disease.
Abstract MP209: Troponin I Phosphorylation Is Essential For Cardiac Reserve
Authors: Sarah L Sturgill, Lorien G Salyer, Vikram Shettigar, Elizabeth Brundage, Brandon J Biesiadecki, Mark T Ziolo
Journal: Circulation Research (2021)

In response to increase in metabolic demand (e.g., exercise), the heart must increase its pumping performance to meet this demand. To achieve this increase, the heart relies on its cardiac reserve, which is the ability to increase in its contractile and diastolic function. The mechanism responsible for cardiac reserve is poorly understood. The myofilament is the mechanism responsible for contraction and relaxation. Troponin I (the inhibitory subunit of troponin, TnI) is a key regulatory protein. Studies have shown TnI serine 23/24 (S23/S24) phosphorylation, the most abundant and important TnI phosphorylation, is a key mechanism for accelerating relaxation by decreasing Ca 2+ senstivity. The role of TnI in cardiac reserve is unknown. For this study, we thoroughly characterized the systolic and diastolic reserve in TnI S23/S24 phosphorylation-null transgenic mice (S23/S24 mutated to alanine, AA mice). Even with increased Ca 2+ sensitivity, the AA mice exhibited normal function at resting heart rate and no difference in cardiac structure compared to wildtype. To increase in vivo heart performance, the most important system is the Bowditch effect (i.e., an increase in contractile function with increasing heart rate). To examine the role TnI S23/S24 phosphorylation in systolic and diastolic reserve, we assessed hemodynamics via left ventricular catheterization on the Bowditch effect by increasing heart rate from 240 to 420 beats per minute. Our data exhibited a clear loss of diastolic and systolic reserve in the AA mice. Since we observed a clear inability to increase systolic and diastolic function in AA mice, we performed speckle tracking echocardiography to more quantitatively investigate AA mice function. We observed that AA mice demonstrated normal systolic function (radial strain rate) and impaired directional diastolic function (reverse radial strain rate) at resting heart rate. We conclude that TnI S23/S24 phosphorylation is essential for cardiac reserve by enhancing systolic and diastolic function. A blunted cardiac reserve leads to heart disease making TnI S23/S24 phosphorylation a potential therapeutic strategy.
Ski mountaineering: sports medical considerations for this new Olympic sport
Authors: Volker Rainer Schöffl, Thomas Bösl, Christoph Lutter
Journal: British Journal of Sports Medicine (2021)

On 20 July 2021 ski mountaineering (Skimo) was officially included into the 2026 Milan-Cortina Winter Olympics by the International Olympic Committee.1 This development underlines the consistent professionalisation of a sport that had been included in the Olympic programme in 1924 as well as having been a demonstration sport in the Olympic games from 1928 to 1948. It was then excluded due to several fatalities. It has since developed from an unorganised leisure sport to a professional sport, represented by the International Ski Mountaineering Federation (ISMF).2 In 2020, Skimo was included in the Youth Olympic Games in Lausanne. In the following we present the sports medical considerations of this new Olympic discipline.

Skimo as a competition sport consists mainly of three types of races: (1) individual races with a minimum of three uphill and downhill sections,3 4 (2) vertical races (one uphill section) and (3) sprint races with short uphills and downhills.5 Additionally, there are relay races performed as individual and sprint races.

Skimo at the elite level demands good endurance as well as the ability to perform at high intensity.5 6 Competition race time is significantly correlated with peak rate of oxygen consumption (VO2peak), body mass index and the weight of the racing …
Abstract 13827: The Effect of Tanshinone IIA on Megakaryopoiesis in Immune Vasculitis
Authors: Mo Yang, Weiqing Su, Liuming Yang, Min Zhou, Hui Chen
Journal: Circulation (2021)

Introduction and Objective: Tanshinone IIA is an active component of Danshen (Radix Salviae Miltiorrhiza Bge), which has been used to treat hypercoagulation-related diseases for centuries. However, its role in megakaryopoiesis remains unclear. Therefore, the present study aimed to examine the effect of Tanshinone IIA on megakaryocytes and platelets in immune vasculitis, and to identify the underlying mechanism(s). Methods: Albino rabbits, aged 3-4 weeks, were used in the present study. Immune vasculitis was established by intravenous injection of BSA (2.5 ml/kg). Tanshinone IIA (5 mg/kg/d) was given through intravenous injection as well. Blood sample was collected from the ear vein and bone marrow was harvested from the femur. Megakaryocytes and CFU-MK were counted with Wright’s and acetylcholine esterase staining, respectively. The coagulation activity and IL-1β level were determined by ELISA. Megakaryocytic cell line CHRF was used to examine the effect of Tanshinone IIA (1-30 μg/mL) on apoptosis; the assay was performed with Annexin V/PI, Caspase 3 and JC-1 using flow cytometry. Results: In rabbits with immune vasculitis, the platelet count, platelet aggregation and prothrombin fragment were significantly increased when compared to their counterparts. Megakaryocytes and CFU-MK were also significantly increased in immune vasculitis. In addition, the level of IL-1β was significantly higher in rabbits with immune vasculitis, which was positively correlated with platelet count and platelet aggregation. Tanshinone IIA (5 mg/kg/d, 7d) significantly reduced the number of megakaryocytes, CFU-MK and platelets, and decreased the coagulation activity. It also significantly lowered the IL-1β level. In megakaryocytic cell line CHRF, Tanshinone IIA (1-30 μg/mL) induced dose-dependent apoptosis. Conclusion: The present study shows that not only platelets, but also megakaryocytes are involved in the pathogenesis of immune vasculitis. IL-1β contributes to the thrombocytosis by inducing megakaryopoiesis. Tanshinone IIA exerts anti-platelet, anti-inflammation and anti-megakaryocyte effects in immune vasculitis; the underlying mechanism may be related to its inhibitory effect on IL-1β and the proapoptotic effect on megakaryocytes.
Abstract 11913: Mortality Along the Rheumatic Heart Disease Cascade of Care in Uganda
Authors: Andrew Y Chang, Michele Barry, Eran Bendavid, David Watkins, Andrea Z Beaton, Peter Lwabi, Isaac Ssinabulya, Chris Longenecker, Emmy Okello
Journal: Circulation (2021)

Introduction: Rheumatic heart disease (RHD) predominantly affects people living in low- and middle-income countries but receives little attention in relation to many infectious diseases. The Cascade of Care model, a tool developed for the public health response to HIV, has improved the care of HIV patients worldwide and has recently been adapted for RHD. The utility of these metrics would be improved if epidemiological evidence existed to confirm that clinical outcomes are linked to progression through the steps of the RHD cascade. Objective: We described the all-cause mortality of people living with RHD who were (1) retained in care, (2) appropriately prescribed prophylactic benzathine benzylpenicillin G (BPG), and (3) optimally adherent to BPG. Methods: We performed a retrospective cohort study using participant data between June 2009 and May 2018 in the Uganda National RHD Registry. Assigning subjects diagnosed with clinical RHD but not retained in clinical care to the reference group, hazard ratios for all-cause mortality risk were calculated for those who were retained in care (received at least annual follow-up), prescribed BPG, and optimally adherent to BPG (received ≥80% of indicated doses), using three multivariable Cox-proportional hazards models adjusted for age, sex, and heart failure history (chosen a priori as variables reported to most impact mortality). Survival was visualized with Kaplan-Meier curves. Results: Of 1568 subjects diagnosed with clinical RHD, only 357 (23%) were retained in care, 337 (21%) were prescribed penicillin, and 311 (20%) were optimally adherent over the study period. There were 46 deaths in the retained group (289 in those not retained) and 35 deaths among optimally adherent subjects (300 in those not optimally adherent). There was a trend towards a mortality benefit among individuals retained in care (HR 0.76, 95% CI 0.55-1.05), with a statistically significant difference in mortality risk among those retained in care and optimally adherent to penicillin compared to those not retained in care (HR 0.67, 95% CI 0.47-0.96). Conclusion: Our study is the first to assess mortality along the RHD Cascade of Care, providing preliminary evidence to support utilizing these metrics to improve RHD outcomes in Sub-Saharan Africa.
Abstract 11168: Right Atrial Adaptation in Pulmonary Hypertension: In-Depth Pressure-Volume Analysis
Authors: Jeroen N Wessels, Jari de Rover, Jessie Van Wezenbeek, J. Tim Marcus, lilian J meiboom, Harm J Bogaard, anton vonk noordegraaf, Gustav J Strijkers, Berend E Westerhof, Frances S De Man
Journal: Circulation (2021)

Introduction: Pulmonary hypertension (PH) is associated with increased right atrial (RA) pressure and volume. We hypothesized that RA stroke work and RA stiffness are higher in PH patients in comparison to healthy controls. Methods: RA PV loops were created through a novel method. RA volume was measured throughout the cardiac cycle on a magnetic resonance transverse stack of slices (typically 8-10). RA pressure was averaged over at least 10 cardiac cycles and approximately two respiratory cycles. Alignment of RA volume and pressure was done based on the v-wave (peak during ventricular contraction, see figure). RA stroke work was calculated as the area under the PV loop from the p-wave (start of atrial contraction) to the minimal RA volume. RA active emptying as the difference between p-wave and minimal volume. An exponential curve was fitted through the reservoir portion of the PV loop from the x-descent to the v-wave. The slope of this curve at the v-wave (RA end-reservoir elastance) was determined as a measure of RA stiffness. Results: RA PV loops were created for healthy controls (n=9) and PH patients (n=27). The averaged PV loops in the figure show RA dilatation in PH patients as well as elevated pressure, especially during atrial contraction. The difference between RA maximal pressure and p-wave pressure was higher in PH patients in comparison with controls (4.01 [3.12-6.75] vs 2.83 [2.54-3.06] mmHg; p=0.001). RA stroke work (493±253 vs 171±50 mmHg*ml; p=0.001) and active emptying (41±13 vs 23±5 ml; p&lt;0.001) were also higher in PH, while RA end-reservoir elastance was not (0.26 [0.23-0.37] vs 0.33 [0.24-0.64] mmHg/ml; p=0.22). Conclusions: PH patients have increased RA stroke work and active emptying, as assessed with a novel method to derive RA PV loops. They do not show signs of RA stiffening. Future associations with right ventricular diastolic stiffness will show whether RA stroke work is able to match the increase in RA afterload.
Antimicrobial Polypeptides Capable of Membrane Translocation for Treatment of MRSA Wound Infection In Vivo
Authors: Shengcai Yang, Yanming Wang, Jason Tan, Jye Yng Teo, Ko Hui Tan, Yi Yan Yang
Journal: Advanced Healthcare Materials (2021)

Abstract Multidrug resistant infections are plaguing the healthcare sector over the past few decades with limited treatment options. To overcome this problem, the authors synthesize a series of novel guanidinium‐functionalized polypeptides. Specifically, poly( l ‐lysine) (PLL) with different lengths is first synthesized by ring‐opening polymerization of N ε ‐benzyloxycarbonyl‐ l ‐lysine‐ N ‐carboxyanhydride (Lys(Z)‐NCA) followed by functionalization with a guanidinium‐functional group to obtain guanidinium‐functionalized PLL (PLL‐Gua). To study the effect of hydrophobicity on antimicrobial activity, relatively more hydrophobic leucine‐NCA monomer or hydrophobic vitamin E moiety is introduced to PLL‐Gua. These polypeptides are characterized for antimicrobial activity against a panel of microbes including multidrug‐resistant bacteria, and hemolytic activity. Among all the polypeptides, PLL 22 ‐Gua is most effective against bacteria and yeast. Particularly, excellent bactericidal activity is observed against Staphylococcus aureus and MRSA. PLL 22 ‐Gua kills bacteria mainly by membrane translocation. In addition, PLL 22 ‐Gua kills MRSA with low resistance frequency (&lt;3.3 × 10 −8 ). In an MRSA‐caused wound infection mouse model, two‐day treatment (twice daily) with 10, 20, or 40 mg per kg of PLL 22 ‐Gua shows up to 99.5% bacterial removal. Moreover, no acute dermal toxicity is observed even at a dose of 200 mg per kg. These promising results show the excellent potential of PLL 22 ‐Gua as an antimicrobial agent against multidrug‐resistant infection in vivo.
Abstract 13630: Impella Alone vs Intra-Aortic Balloon Pump Plus Impella in Cardiogenic Shock Patients Undergoing Percutaneous Coronary Intervention: Two Are Better Than One?
Authors: Md Bhuiyan, Tia Bimal, Greg Haggerty, Puneet Gandotra, Samy Selim, Lawrence Ong, Luis Gruberg
Journal: Circulation (2021)

Background: Cardiogenic shock (CS) is still one of the leading causes of cardiovascular mortality despite advances in therapeutic options. Aggressive management with percutaneous coronary intervention (PCI) and the use of mechanical circulatory support (MCS) devices has been associated with improved survival. The most frequently used MCS devices are the intra-aortic balloon pump (IABP) and the axial flow pump (Impella). Aim: To assess in-hospital bleeding complications and outcomes in CS patients treated with either Impella alone vs. IABP combined with Impella while undergoing PCI. Methods: Between 12/2010 and 03/2018 a total of 62 CS patients underwent PCI with Impella (n = 33) or IABP and Impella combined (n =29) at 6 hospitals in our system. Bleeding complications were classified according to the Bleeding Academic Research Consortium (BARC). BARC Type 4 (coronary bypass grafting-related) and Type 5 (fatal) bleeding events were excluded. Chi square was used for categorical values and t-test for continuous variables. P&lt;0.05 was considered significant. Results: Clinical characteristics, bleeding complications and in-hospital outcomes are shown in the Table. There was a trend towards a higher percentage of STEMI patients treated with both devices. There was a significant higher rate of BARC 2 bleeding events in patients treated with both devices (6% v 28%, p=0.02) and a higher rate of BARC 3 bleeding events in patients treated with Impella alone (70% v 38%, p=0.01). Both groups had high rates of acute kidney failure and acute neurological events. Conclusions: In a limited series of CS patients undergoing PCI: 1) the use of Impella alone was associated with a significantly higher rate of BARC 3 major bleeding events; 2) patients treated simultaneously with both devices had a significantly higher rate of BARC 2 bleeding events; and 3) in-hospital acute neurological events and mortality rates were very high but similar in both groups.