tbuckley/cabot-search huggingface dataset:
Abstract 14062: Nation-Wide Screening of Fabry Disease in Patients With Hypertrophic Cardiomyopathy in Czech Republic
Authors: David Zemanek, Jaroslav Januska, Tomas Honek, Karol Curila, Milos Kubanek, Stepanka Sindelarova, Milos Taborsky, Ales Linhart
Journal: Circulation (2021)

Introduction: Fabry disease (FD) is a rare X-linked genetic disorder caused by α-galactosidase A (AGALA) deficiency. While "classic" variant has multisystemic manifestation, the more recently described "later-onset" variant is characterized by predominant cardiac involvement that often mimics hypertrophic cardiomyopathy (HCM). Hypothesis: Routine screening in patients with hypertrophic cardiomyopathy may detect patients with Fabry disease who are not clinically characterized by a typical multi-organ disorder. Methods: Consecutive unrelated patients with HCM were screened for FD in 16 (out of 17) cardiac centers in the Czech Republic covering specialized cardiology care from June 2017 to December 2018. AGALA activity and globotriaosylsphingosine (lyso-Gb 3 ) levels were measured in all subjects using the dry blood spot method. FD was suspected in male patients with AGALA activity &lt;1.2μmol/h/L and in females with either low AGALA activity or lyso-Gb 3 &gt;3.5ng/mL. Positive screening results were confirmed by genetic testing. Results: We evaluated 589 patients (390 males, 66%) with HCM (mean maximal myocardial thickness 19.1±4.3 mm). The average age was 58.4±14.7 years. In total, 17 patients (11 males, 6 females) had a positive screening results and subsequently six of them (4 males and 2 females) had a genetically confirmed pathogenic variant (total prevalence of 1.02 %). Five of these patients were carrying the p.N215S mutation known to cause a typical later-onset cardiac FD. Conclusions: We confirmed the prevalence of FD repeatedly reported in previous screening programs (approximately 1 % irrespective of gender) in a non-selected HCM population in Central Europe. Our findings advocate a routine screening for FD in all adult patients with HCM phenotype including both genders. The dry blood spot method used led to identification of clearly pathogenic variants.
Abstract 11506: Optimal Detection of Ascending Aorta Aneurysms in Obese Patients
Authors: Sathwika Thodeti, Deni Drenic, Michael Yim, Ariel Godel, Sanjay Vallabhaneni, brandon mikolich, J Ronald Mikolich
Journal: Circulation (2021)

Introduction: Obesity is a known risk factor for the development of aneurysm of the ascending aorta (AscAoA). 2-D echo is the most commonly used cardiac imaging modality. 2-D Echo has a limited 90-degree field of view, and the ascending aorta may not be well visualized. Obesity causes further compromise of the field of view, as the 2-D transducer cannot be positioned in the rib space. Cardiac MRI (CMR) does not have this limitation. This study was designed to assess the detection of aneurysm of the ascending aorta in obese patients comparing 2-D echo and CMR. Hypothesis: Because of full field of view capability, CMR may be superior to 2-D Echo for the detection of aneurysm of ascending aorta in obese patients. Methods: An institutional cardiac imaging database was queried for all obese patients with a BMI greater than/equal to 30. The study cohort was composed of obese patients who had a 2-D and CMR within a 6-month period. The number of patients with AscAoA, defined as ascending aorta diameter &gt;3.5 cm measured perpendicular to flow, was computed for both 2-D and CMR modalities. Detection rates for AscAoA were statistically compared using McNemar test. Results: Of the 6930 patients in the cardiac imaging database, 4373 were obese, of which 275 had both 2-D and CMR within a 6-month period, constituting the study cohort. Only 32 of 275 patients had a 2-D Echo report with an entered value for the diameter of the ascending aorta (10.6%), an indicator of the technical difficulty encountered when measuring the ascending aorta with 2-D Echo. Conversely, 274 patients had a CMR report with an entered diameter value for the ascending aorta (99.64%). The formal CMR report identified 167 AscAoA among the 275 patients in the study cohort, for a detection rate of 58.9%. 2-D Echo only identified 12 patients with an AscAoA in the same patient cohort, for a detection rate of 4.36%. The detection rate of aneurysm of the ascending aorta was significantly different between the 2 modalities (p-value &lt;0.001). Conclusions: Despite 2-D and CMR offering similar diagnostic information regarding left ventricular function and valve function in obese patients, CMR reports a numeric value for the ascending aorta diameter 8 times more often than 2-D, and CMR detects AscAoA 13 times more often than 2-D in obese patients.
Abstract 10850: Investigating the Role of a Cardiac Enhancer in the Development of Heart Failure
Authors: Myo Htet, Marios Arvanitis, Brian Lin, Harshi Gangrade, Emmanouil Tampakakis
Journal: Circulation (2021)

Introduction: Alpha actinin-2 (ACTN2) is a major cytoskeletal protein that plays a critical role in maintaining the structural and functional integrity of the sarcomere. ACTN2 mutations, although rare, have been shown to be associated with various types of cardiomyopathy. Using genome-wide association and multi-omic approaches, we recently identified non-coding variants that showed a strong association with heart failure (HF). Two of the variants are within an evolutionary conserved transcriptional enhancer region that regulates the ACTN2 gene in human stem cell derived cardiomyocytes (hPSC-CMs). However, the role of cardiac enhancers in the development of HF remains unknown, therefore we used engineered heart tissues (EHT) from hPSC-CMs to investigate the effects of the ACTN2 enhancer. Methods: We used hPSC-CMs and performed morphologic and functional analyses by immunostaining, calcium transient measurements and quantitative assays such as western blotting, proteomics, qPCR and single cell transcriptomics. Next, we utilized CRISPR interference (CRISPRi) and chromatin immunoprecipitation (ChIP) to analyze the transcriptional regulation of the ACTN2 enhancer. Finally, we measured force generation using EHTs. Results: We first engineered hPSC-CMs carrying an ACTN2 enhancer deletion. This resulted in decreased ACTN2 gene and protein expression, and cardiomyocytes developed myofibrillar disarray, hypertrophy, lower beating rates and suppressed calcium transients. Moreover, EHTs demonstrated reduced mechanical force. Using CRISPRi and ChIP we found that the transcription factor MEF2c binds a short DNA sequence containing an enhancer variant to regulate ACTN2 expression. Single cell RNA-Seq analysis of hPSC-CMs treated with isoproterenol to model the hyperadrenergic state observed in HF, revealed the induction of pathways involved in protein quality control, actin fragmentation and apoptosis. We have also recently developed a mouse model to address the effect of the enhancer in vivo . Conclusions: Our study confirms that a conserved and clinically relevant enhancer region can effectively regulate ACTN2 , and variants within that region can have detrimental consequences on CMs which can contribute to HF.
Cold chain logistics: a possible mode of SARS-CoV-2 transmission?
Authors: Yuan-Yuan Li, Hong-Xiu Liu, Wei Xia, Gary W K Wong, Shun-Qing Xu
Journal: BMJ (2021)

<b>Objective:</b> To determine whether the improved outcome of a surgical procedure in high volume hospitals is specific to the volume of the same procedure. <b>Design and setting:</b> Analysis of secondary data in Ontario, Canada. <b>Participants:</b> Patients having an oesophagectomy, colorectal resection for cancer, pancreaticoduodenectomy, major lung resection for cancer, or repair of an unruptured abdominal aortic aneurysm between 1994 and 1999. <b>Main outcome measures:</b> Odds ratio for death within 30 days of surgery in relation to the hospital volume of the same surgical procedure and the hospital volume of the other four procedures. Estimates were adjusted for age, sex, and comorbidity and accounted for hospital level clustering. <b>Results:</b> With the exception of colorectal resection, 30 day mortality seemed to be inversely related not only to the hospital volume of the same procedure but also to the hospital volume of most of the other procedures. In some cases the effect of the volume of a different procedure was stronger than the effect of the volume of the same procedure. For example, the association of mortality from pancreaticoduodenectomy with hospital volume of lung resection (odds ratio for death in hospitals with a high volume of lung resection compared with low volume 0.36, 95% confidence interval 0.23 to 0.57) was much stronger than the association of mortality from pancreaticoduodenectomy with hospital volume of pancreaticoduodenectomy (0.76, 0.44 to 1.32). <b>Conclusion:</b> The inverse association between high volume of procedure and risk of operative death is not specific to the volume of the procedure being studied.
Abstract P439: Harnessing Multiscale Models Of A Dilated Cardiomyopathy Mutation For Precision Medicine
Authors: Lina Greenberg, W. Tom Stump, Andrea L Bredemeyer, Kory J Lavine, Michael J Greenberg
Journal: Circulation Research (2021)

Familial dilated cardiomyopathy (DCM) is a leading cause of both adult and pediatric heart failure. Currently, there is no cure for DCM, and the 5-year transplant free survival rate is &lt;50%. There is therefore an outstanding need to develop new therapeutics. Prior studies have established a strong genetic basis for DCM and identified causative genetic mutations. These observations provide unique opportunities to apply precision medicine approaches that target and circumvent the effects of deleterious mutations. Here, we used a multiscale approach to study the consequences of a human mutation in troponin T that causes DCM, ΔK210. We found that at the molecular scale ΔK210 changes the positioning of tropomyosin along the thin filament, leading to molecular hypocontractility. Using genome edited human stem cell derived cardiomyocytes heterozygous for the mutation, we show reduced cellular contractility at the single cell and tissue levels. Importantly, we demonstrate that mutant tissues show a reduced Frank-Starling response, increased stiffness, and misaligned myocytes. Based on our molecular mechanism, we hypothesized that treatment of ΔK210 with Omecamtiv Mecarbil (OM), a thin filament activator in clinical trials for heart failure, would improve the function of mutant tissues. We found that treatment of ΔK210 molecular complexes and tissues with OM causes a dose-dependent increase in cardiac function, reversing the mutation-induced contractile defect. Taken together, our study demonstrates how mechanistic molecular studies can be harnessed to identify precision medicine therapeutics.
Abstract 11505: Left Ventricular Mass Index and Risk of Cognitive Decline in a General Elderly Population (Tanushimaru Cohort Study)
Authors: Nagisa Morikawa, Hisashi Adachi, Mika Enomoto, Ako Fukami, Akiko Sakaue, Maki Yamamoto, Hiromi Satou, Yoshihiro Fukumoto
Journal: Circulation (2021)

Introduction: Elevated cardiovascular disease risk factor burden is a recognized contributor to poorer cognitive function. Recent cohort study suggested that higher N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels predicted incident dementia. However, there is little study of the longitudinal association between left ventricular (LV) structure and future cognitive decline. Hypothesis: LV structure is associated with cognitive decline. Methods: We recruited 1943 participants (mean age: 65.8±11.3 years, male 39.9%) as a population-based sample of Tanushimaru, Japan in 2009 and followed 837 adults in 2018 after excluding those with heart disease history. The subjects received 2-dimensional echocardiography to quantify LV mass index (LVMI) in 2009. The 30-point Mini-Mental State Examination (MMSE) was used to assess cognitive function in 2009 and in 2018. We classified MMSE scores ≦23, 24-27, ≥28 as dementia, mild cognitive impairment (MCI) and normal cognition (NC). Multivariable logistic regression analyses were performed to examine the association between LVMI and cognitive decline. Results: Mean MMSE scores in 2009 and in 2018 among 837 participants were 28.1±2.0 and 28.4±2.3, respectively. Cognitive status progressed from NC to MCI/dementia in 19.3% (96/498) or from NC/MCI to dementia in 2.9% (24/826). Mean LVMI levels were 81.9±19.7g/m2 in men and 76.5±18.4g/m2 in women. Conversion from NC to MCI/dementia was not associated with LVMI, while larger LVMI was significantly associated with the progression from NC/MCI to dementia (p=0.002). Age, sex-adjusted odds ratio for progression to dementia was 1.50 (95% confidence interval, 1.16-1.97) as LVMI increased by 10 g/m2. The association was independent of body mass index, systolic blood pressure, and microalbuminuria. LVMI &amp;gt; 90.6 g/m 2 in men and &amp;gt; 99.9 g/m 2 in women accurately predicted progression to dementia (p &amp;lt; 0.0001). These cutoff points were smaller in men and larger in women than the current criteria for LV hypertrophy. Conclusions: Larger LVMI was not associated with early stage of cognitive decline, but can be a risk factor for progression to dementia. We recommend to carefully evaluate cognitive function among at-risk individuals with larger LVMI.
Abstract 12053: Clinical Outcomes of Stent-graft Versus Polymer-free, Paclitaxel-coated Stent Implantation for Patients With Peripheral Artery Diseases Presenting Femoropopliteal Artery Lesions
Authors: Takuya Tsujimura, Osamu Iida, Mitsutoshi Asai, Masaharu Masuda, Shin Okamoto, Takayuki Ishihara, Kiyonori Nanto, Takashi Kanda, Shota Okuno, Yasuhiro Matsuda, Yosuke Hata, Jaya Kanduri
Journal: Circulation (2019)

Introduction: The polymer-free coating of paclitaxel Zilver PTXTM stent has successfully reduced restenosis and reintervention rates for patients presenting femoropopliteal (FP) artery lesions. On ...
Clonal Relapse Dynamics in Acute Myeloid Leukemia Following Allogeneic Hematopoietic Cell Transplantation
Authors: Clara Wienecke, Bennet Heida, Katrin Teich, Konstantin Büttner, Alessandro Liebich, Razif Gabdoulline, Letizia Venturini, Martin Wichmann, Wolfram Puppe, Michael Stadler, Arnold Ganser, Felicitas Thol, Michael Heuser
Journal: Blood (2021)
Haploidentical Stem Cell Transplantation Can be Fully Conducted on an Outpatient Basis
Authors: Iván Murrieta-Álvarez, Juan Carlos Olivares-Gazca, Yahveth Cantero-Fortiz, Andrés A. León-Peña, José Manuel Priesca-Marin, Guillermo J. Ruiz-Delgado, Guillermo J. Ruiz-Argüelles
Journal: Blood (2021)
ERK2 Substrate Binding Domains Perform Opposing Roles in Pathogenesis of a JAK2V617F-Driven Myeloproliferative Neoplasm
Authors: Billy Truong, Yong Zhang, Shawn Fahl, Kathy Q Cai, Esteban Martinez, Essel D. Al-Saleem, Yulan Gong, Dan Liebermann, Jonathan Soboloff, Roland Dunbrack, Ross L. Levine, Dietmar J Kappes, Stephen M. Sykes, Paul Shapiro, David Wiest
Journal: Blood (2021)
Abstract 14249: Response to Cardiac Resynchronization Therapy in Cancer Patients With Heart Failure
Authors: Scott R Schubert, Kaveh Karimzad
Journal: Circulation (2021)

Introduction: Heart failure is associated with poor clinical outcomes in cancer patients. Cardiac resynchronization therapy (CRT) provides a therapeutic avenue to improve left ventricular function and decrease symptoms. Historically, CRT has been underutilized in cancer patients. We assessed the hypothesis that cancer patients have a similar response to cardiac resynchronization therapy as the general heart failure population. Methods: This study included 37 patients with cancer who underwent CRT implantation between 2012 and 2020. The primary endpoints were response to CRT as measured by an improvement in left ventricular ejection fraction (LVEF) by &gt;=10% or decrease in left ventricular end systolic volume index (LVESVi) by &gt;=15% over 3 to 24 months. Secondary endpoints were change in LVEF, LVESVi, and New York Heart Association (NYHA) class. Results: Of 37 patients, primary and secondary endpoints were available for 34 patients (mean [SD] age, 68 [9] years; 24 men (71%); 26 nonischemic cardiomyopathy (76%), 8 ischemic (24%); mean QRSd 152 ms; 10 patients with NYHA II symptoms (29%), 24 NYHA III (71%)). 20 patients met the primary endpoint (65% [46%-80%]). This response rate is not significantly different than published response rates to CRT of 70% in the general heart failure population. The average improvement in LVEF was 12.9% ([9.4%-16.4%], p&lt;0.001). The average decrease in LVESVi was 25.4% ([17.2%-33.5%], p&lt;0.001). 23 of 34 patients had an improvement in NYHA classification (20 by one class, 3 by two), whereas 9 patients had no improvement and 2 patients had worsening symptoms (mean improvement 0.7 [0.46-0.96], p&lt;0.001). 2 of 37 patients had a complication (one late device infection, one right atrial lead dislodgment requiring reimplantation). 4 of 37 patients (10.8%) died within 12 months of primary oncologic cause. 4 of 34 (11.7%) CRT-D patients had received appropriate therapies on device interrogation at time of submission. Conclusions: CRT improves left ventricular function, reverses left ventricular remodeling, and improves exertional dyspnea in patients with cancer. Response rate is similar to that of a general heart failure population. Oncologic prognoses of over 12 months life expectancy at time of implant were reasonably accurate.
Ikaros Mediates Antigen Escape Following CD19 CAR T Cell Therapy in r/r B-ALL
Authors: Pablo Domizi, Jolanda Sarno, Astraea Jager, Reema Baskar, Warren D. Reynolds, Bita Sahaf, Sean Bendall, Charles G. Mullighan, Allison Barz Leahy, Regina M. Myers, Stephan A. Grupp, Elena Sotillo, David Barrett, Kara L. Davis
Journal: Blood (2021)
Abstract 11654: Myofibroblast Smad1 Activation Restrains Cardiac Fibrosis and Attenuates Post-Myocardial Infarction Adverse Remodeling
Authors: Anis Hanna, Nikolaos Frangogiannis
Journal: Circulation (2021)

Cardiac fibroblasts play a pivotal role in repair and remodeling of myocardial infarction (MI) by transforming to myofibroblasts, and acquiring inflammatory, proangiogenic, or matrix-synthetic phenotypes. Members of the Transforming Growth Factor (TGF)β superfamily (including TGFβs and BMPs) are activated following MI and play an important role in regulating fibroblast phenotype, and cardiac fibrosis. Canonical TGFβ superfamily signaling is mediated through the receptor-activated Smads: TGF-βs activate Smad2/3, whereas BMPs predominantly stimulate the Smad1/5 cascade. Smad3 signaling plays an important role in activation of infarct myofibroblasts; however, the role of the Smad1 pathway has not been studied. We hypothesized that fibroblast-specific actions of Smad1 regulate repair and remodeling in the infarcted myocardium. In mouse infarcts, Smad1 was activated in infiltrating myofibroblasts 7 days after coronary occlusion, not only by BMPs but also by TGF-β isoforms. In order to examine the effects of Smad1 in infarct fibroblasts, we generated mice with myofibroblast-specific Smad1 loss (MFS1KO). Echocardiography at 7 and 28 days following MI revealed that MFS1KO mice had accentuated systolic dysfunction, and increased left ventricular dilation (p&lt;0.01, N=13-49) . Worse adverse remodeling in infarcted MFS1KO hearts was associated with scar expansion, and accentuated fibrosis. Smad1 knockdown in control or TGF-β1-stimulated cardiac fibroblasts increased mRNA levels of structural and matricellular genes (including Col1a1, Col3a1, Postn, Thbs1&amp;3 ) while reducing matrix metalloproteinase levels. Analysis of unbiased RNA-seq data revealed that Smad1 loss activates pathways involved in matrix regulation, and collagen biosynthesis, and that the anti-fibrotic actions of Smad1 are carried out through inhibition of pro-fibrotic cascades as the TGF-β/Smad3 axis, p53, and IL4/STAT6 signaling. In conclusion, Smad1 activation in infarct myofibroblasts restrains the fibrotic response and protects the infarcted heart from adverse remodeling through inhibiting key pro-fibrotic signaling pathways. These findings suggest that Smad1 activation may be a promising strategy to restrain cardiac fibrosis in infarcted and failing hearts.
Abstract 11847: Acute Myocarditis Following COVID-19 mRNA Vaccination
Authors: Anthony Simone, John Herald, Aiyu Chen, Neil Gulati, Albert Yuh-Jer Shen, Bruno Lewin, Ming Lee
Journal: Circulation (2021)

Introduction: Acute myocarditis after coronavirus disease 2019 (COVID-19) mRNA vaccination is not well described. Recent public reports have signaled that this is an entity that requires ongoing surveillance. The goal of this study is to investigate myocarditis incidence following COVID-19 mRNA vaccination, and to report the clinical course and outcomes. Methods: This is a retrospective population-based cohort study performed at Kaiser Permanente Southern California (KPSC), an integrated health care system in California. Patients who received at least one dose of BNT162b2 (Pfizer) or mRNA-1273 (Moderna) mRNA vaccine were included. Clinically significant cases of acute myocarditis within 10 days of COVID-19 mRNA vaccination were identified between 12/14/2020 and 5/31/2021. Key demographic, clinical, laboratory, diagnostic data, and clinical course were obtained from medical record review. Results: Of 1,776,608 KPSC members who received at least one dose of COVID-19 mRNA vaccines, 12 developed acute myocarditis within 10 days following vaccination, for an estimated incidence of 6.6 cases per 1 million patients. All patients were relatively healthy White or Hispanic men between the ages of 18 and 40 years. Patients reported chest pain two to eight days after vaccine administration (Moderna N=5; Pfizer N=7). Eleven patients developed myocarditis after the second dose, and one after the first dose. Troponin I elevations ranged from 1.53-32.30 ng/mL. All cases were self-limited, with troponin peaking within 24-48 hours of admission and symptom resolution prior to discharge. None of the patients had evidence of decompensated heart failure. Length of stay was 1-4 days, with all patients discharged home and no recurrence, readmission, or major adverse cardiac events. Conclusions: Acute myocarditis after COVID-19 mRNA vaccination is a rare and self-limited event that warrants further description and investigation.