tbuckley/cabot-search huggingface dataset:
A de novo dominant-negative variant is associated with OTULIN-related autoinflammatory syndrome
Authors: Yukiko Takeda, Masahiro Ueki, Junpei Matsuhiro, Erik Walinda, Takayuki Tanaka, Masafumi Yamada, Hiroaki Fujita, Shunichiro Takezaki, Ichiro Kobayashi, Sakura Tamaki, Sanae Nagata, Noriko Miyake, Naomichi Matsumoto, Mitsujiro Osawa, Takahiro Yasumi, Toshio Heike, Fumiaki Ohtake, Megumu K. Saito, Junya Toguchida, Junko Takita, Tadashi Ariga, Kazuhiro Iwai
Journal: The Journal of Experimental Medicine (2024)

OTULIN-related autoinflammatory syndrome (ORAS), a severe autoinflammatory disease, is caused by biallelic pathogenic variants of OTULIN, a linear ubiquitin-specific deubiquitinating enzyme. Loss of OTULIN attenuates linear ubiquitination by inhibiting the linear ubiquitin chain assembly complex (LUBAC). Here, we report a patient who harbors two rare heterozygous variants of OTULIN (p.P152L and p.R306Q). We demonstrated accumulation of linear ubiquitin chains upon TNF stimulation and augmented TNF-induced cell death in mesenchymal stem cells differentiated from patient-derived iPS cells, which confirms that the patient has ORAS. However, although the de novo p.R306Q variant exhibits attenuated deubiquitination activity without reducing the amount of OTULIN, the deubiquitination activity of the p.P152L variant inherited from the mother was equivalent to that of the wild-type. Patient-derived MSCs in which the p.P152L variant was replaced with wild-type also exhibited augmented TNF-induced cell death and accumulation of linear chains. The finding that ORAS can be caused by a dominant-negative p.R306Q variant of OTULIN furthers our understanding of disease pathogenesis.
Abstract 14110: Inhibition of Lpl and CD36 Does Not Prevent Lipid Accumulation in the Hearts of Adipose Triglyceride Lipase (ATGL) Deficient Mice
Authors: Babajide Oluwadare, Ainara Gonzalez Cabodevilla, Ni-Huiping Son, Ira J Goldberg
Journal: Circulation (2021)

We tested whether murine ATGL deficiency-induced cardiotoxicity would be prevented by reducing uptake of circulating lipids through inhibition of lipoprotein lipase (LpL) or the fatty acid transporter CD36. Mice were created with floxed alleles for Atgl and Lpl and expression of MHC-Cre. Triglyceride content in the heart was 10x greater in the Atgl KO mice compared to control, and concurrent Lpl deletion did not change that. The Lpl Atgl DKO hearts had a comparable gross appearance and similar weights to the Atgl KO mice. The mice also had a similar survival rate with early death beginning at ~12 weeks. We then hypothesized that non-esterified fatty acids rather than triglyceride-derived fatty acids were the source of lipids in Atgl deficient hearts. To test this, we reduced CD36 expression using an antisense oligonucleotide (ASO) and also by creating heart specific combined Atgl and Cd36 knockout mice. The ASO knocked down CD36 expression in both CD31 (endothelial cells) and non-CD31 cells from the heart. It also reduced starvation lipid droplet formation and accumulated heart lipids after 3 weeks of a high fat diet. Surprisingly, neither the ASO nor genetic knockout rescued the Atgl deficient hearts from lipid accumulation or prevented early mortality. Placing mice on high fat (60%) or high sucrose (40%) diets also did not alter the development of heart dysfunction. We then hypothesized that the lipid accumulation with ATGL deficiency could occur independent of access to exogenous lipids. We tested this in vitro using H9c2(2-1) rat cardiomyocytes. After an overnight incubation in serum-free medium to deplete lipid droplets, inhibition of ATGL with Atglistatin led to cardiomyocyte accumulation of lipid droplets in the absence of a lipid source in the media. Concurrent inhibition of fatty acid synthase (FASN) with C75, cerulenin, or platensimycin prevented lipid droplet accumulation. Together, our data suggest that ATGL deficient lipid accumulation and toxicity can occur exclusive of lipid uptake.
Abstract 14284: "Weeding" Out Wellens' Syndrome
Authors: Moneeb Asghar, Joseph Adams, saadia memon, Amar Chadaga
Journal: Circulation (2021)

Introduction: Wellens’ syndrome, most often associated with proximal left anterior descending coronary artery stenosis, is considered highly specific for impending myocardial infarction (MI). Its diagnosis relies on symmetric biphasic or deeply inverted T waves in leads V1-V4, normal precordial R wave progression and normal to slightly elevated cardiac markers. Pseudo-Wellens’ syndrome presents similarly, but in the absence of coronary artery disease (CAD). We present a challenging case of a patient with history of excessive recreational cannabis use and incidental electrocardiogram (ECG) findings concerning for Wellens’ syndrome who ultimately was diagnosed with Pseudo-Wellens’ syndrome. With familiarity of cannabis associated Pseudo-Wellens’ syndrome, unnecessary invasive diagnostic and therapeutic procedures were avoided. Case: A 20 year old male without significant past medical history presented for evaluation of vomiting and abdominal pain of 2 days duration. In view of his daily cannabis use, he was diagnosed with cannabis hyperemesis syndrome. An ECG to measure QTc prior to administration of ondansetron demonstrated ST elevation in lead V2. A repeat ECG showed T-wave inversions in leads V2-4. Troponin levels were negative. The patient denied chest pain or shortness of breath. An echocardiogram showed normal cardiac wall motion and an estimated ejection fraction of 55-60%. The diagnosis of Pseudo-Wellens’ syndrome secondary to cannabis use was made and the patient was subsequently discharged home following extensive cannabis cessation counseling. Discussion: The definitive treatment of Wellens’ Syndrome relies on cardiac catheterization even in patients without cardiac history or risk factors for CAD. This immediate intervention is required to halt the evolution of MI and is crucial for a positive outcome. In contrast, Pseudo-Wellens’ syndrome occurs in the absence of CAD and has been reported in younger, healthy patients in association with illicit drug use. In the era of increased legalized marijuana use, it is imperative that health care providers are familiar with cannabis induced Pseudo-Wellens’ syndrome as to avoid the potential for inappropriate invasive diagnostic modalities in otherwise healthy individuals.
Abstract 14205: Myocarditis After COVID-19 Vaccination
Authors: Tatiana Echeverry, Matthew Norris, Vance Weber
Journal: Circulation (2021)

As of 6/2021, over 165 million Americans have received at least one dose of the COVID-19 vaccine. Two of the major COVID-19 vaccines administered in the United States utilize mRNA technology. With the novel vaccine being administered to millions, rarer adverse effects are more likely to be identified. The following case highlights a young male patient with myocarditis in the days after mRNA COVID-19 vaccination. Case presentation: Patient is a 31-year-old male with no past medical history who presented with burning chest pain for two days after receiving his second [MN1] mRNA COVID-19 vaccine. The pain was associated with orthopnea and paroxysmal nocturnal dyspnea. Initial EKG showed no acute ischemic changes. [MN2] Blood work revealed elevated troponin of 1.7 and negative CRP and ESR. [MN3] Transthoracic echocardiogram revealed an ejection fraction of 55% with no wall motion abnormalities. The following day patient had CMR that showed an area of myocardial hyper-enhancement in the apical anterior segment suggesting the diagnosis of myocarditis. Patient was discharged with Metoprolol and was instructed to refrain from strenuous exercise. Patient was seen outpatient, and endorses to still experience intermittent burning substernal chest pain. Discussion: In the past few months, myocarditis and myopericarditis have been increasingly reported in CDC and case series following mRNA vaccination. A case review in Pediatrics outlines seven cases in healthy 14- to 19-year-olds who developed symptoms within four days of receiving their second dose. A large Israeli study reported 275 cases of myocarditis over the span of five months. These cases seem to be mild in character and tend to resolve within a week of onset. The connection between the mRNA vaccines and these cases has yet to be confirmed and remains under investigation by the CDC. We present this case in support of the growing literature, as recognition of the relationship between myocarditis and mRNA COVID-19 vaccines will allow these patients presenting with chest pain to receive higher value care while hopefully sparing them from receiving unnecessary invasive cardiac procedures.
Abstract 14138: Effect of Nicotine Exposure to Induced Pluripotent Stem Cell Derived Endothelial Cell Therapy in a Murine Model of Peripheral Artery Disease
Authors: Alex Ho Pang Chan, Caroline Hu, Ngan F Huang
Journal: Circulation (2021)

Introduction: Clinical solutions for peripheral artery disease (PAD) remain elusive due to the many challenges of surgical intervention. Stem cell therapy offer a promising option, but barriers exist to their clinical translatability. Among these include lifestyle choices like tobacco use that may influence the efficacy of stem cell therapy. The objective of this study aims to examine the potential effects of nicotine on human induced pluripotent stem cell derived endothelial cells (iPSC-ECs) therapy in the context of PAD. Hypothesis: Chronic nicotine exposure negatively affects the therapeutic potential of implanted iPSC-ECs in a murine model of PAD. Methods: Mice were implanted with an osmotic pump for controlled exposed to nicotine or saline (control) for 28 days. Plasma cotinine was measured to confirm nicotine exposure. After 28 days of nicotine or saline exposure, the mice underwent induction of hindlimb ischemia and before receiving an injection of 10 6 iPSC-ECs. A second dose of cells were injected to the ischemic limb on day 7 post-surgery. All mice were monitored for blood perfusion recovery using laser Doppler spectroscopy imaging. Survival of the transplanted cells in vivo were tracked by bioluminescence imaging. The mice receiving iPSC-ECs were also imaged for cell survival using bioluminescence imaging. At day 14 post-surgery, mice were euthanized, and the gastrocnemius muscle and thigh muscle were harvested for histological analysis. Results: The average cotinine concentration in sera was ~200 ng/mL, which is within physiological range for a tobacco user. Blood perfusion recovery at day 14 showed trends of nicotine treated groups have hindered perfusion recovery, compared to those treated with saline. Importantly, nicotine exposure trended with poorer perfusion recovery after cell therapy. Bioluminescent imaging showed iPSC-ECs persisted in vivo for all groups without significant difference. Conclusion: Nicotine exposure was associated with poorer blood perfusion recovery after iPSC-EC therapy, compared to control saline exposure, suggesting that nicotine may have adverse effects on iPSC-EC therapy for treatment of PAD.
Abstract 14325: Socioeconomic Conditions Correlate to Reduction in Mortality Rates Attributable to Smoking in Brazil
Authors: Antonio Depaivafagundes Ju, Debora Carvalho Malta, Luisa Brant, Renato Teixeira, Carisi A Polanczyk, Glaucia Maria Moraes de Oliveira, Antonio L Ribeiro
Journal: Circulation (2021)

Introduction: Tobacco consumption through different forms of smoking is associated with an increased risk of cardiovascular events. Socio-demographic Index (SDI) is a composite index that measures per capita income, fertility, and education and mirrors socio-demographic development, allowing comparisons between locations Objectives: Analyze the association of socioeconomic conditions and trend cardiovascular mortality rates attributable to smoking in Brazil. Methods: Using data from the Global Burden of Disease 2019, we analyzed the age-standardized mortality rate attributable to smoking and the correlation between SDI and the percent variation in mortality rates between 1990 and 2019, for Brazil and each state. SDI values range from 0 to 1 and are higher for better socioeconomic conditions. Results: There was a reduction of 58.8% (95% CI, 61.1 - 56.3%) in mortality rates attributable to smoking, from 199.9/100,000 inhabitants (95% UI, 189.1-210.6) in 1990 to 82.4/100,000 inhabitants (95% UI, 77.9-87.5) in 2019. Mortality rates due to tobacco decreased in all Brazilian states. Overall, larger reductions in smoking-attributable mortality rates were observed in states with higher SDI and smaller reductions in states located in Brazil's North and Northeast regions, with lower SDIs. (Pearson correlation 0.637; p &lt;0.001). Conclusions: The present study points to the improvement of the mortality attributable to smoking in Brazil in the last three decades. However, regional inequities were shown by the association of more significant mortality reductions in states with a better socioeconomic condition.
Abstract 14216: Mitochondrial Dysfunction in Aged Hearts: Role of Mitochondrial Calpain Activation
Authors: Qun Chen, Jeremy Thompson, Ying Hu, Edward J Lesnefsky
Journal: Circulation (2021)

Introduction: Mitochondrial function is impaired in aged hearts. Calpain 1 (CPN1) is a calcium-dependent cysteine protease located in cytosol (cCPN1) and mitochondria (mCPN1). Activation of CPN1 contributes to mitochondrial dysfunction during ischemia-reperfusion. Induction of acute ER (endoplasm reticulum) stress causes CPN1 activation in adult hearts. We find that aging leads to increased ER stress that may favor CPN1 activation. Hypothesis: ER stress induced CPN1 activation leads to mitochondrial dysfunction during aging. Methods: Male adult (3 mo.) and aged (24 mo.) mice were provided by NIA. 4-PBA (1g/kg/day) was dissolved in drinking water with sucrose (0.2 g/100 ml) as sweetener. Sucrose water was used as vehicle control. Mice were treated for two weeks with 4-PBA or vehicle followed by the isolation of cardiac cytosol, SSM (subsarcolemmal mitochondria) and IFM (interfibrillar mitochondria). Results: Oxidative phosphorylation was decreased in IFM from 24 mo. compared to 3 mo. when glutamate + malate was used as complex I substrate (Fig A). The 4-PBA treatment improved oxidative phosphorylation in aged IFM (Figure A). The cCPN1 was activated in 24 mo. as shown by increased spectrin cleavage (Figure B). The α1 subunit of pyruvate dehydrogenase (PDH) is a substrate of mCPN1. The content of the PDH α1 subunit was decreased in 24 mo. compared to 3 mo., indicating that the mCPN1 was activated during aging (Figure C). The 4-PBA treatment decreased the activation of cCPN1 and mCPN1 in aged mice. SSM function is also impaired during aging (data not shown). Conclusions: Aging increased the activation of both cCPN1 and mCPN1. Attenuation of ER stress in 24 mo. mice using 4-PBA decreased cCPN1 and mCPN1 activation. Decreased CPN1 activation was accompanied by improved mitochondrial function . The results support that activation of calpain 1, most likely mCPN1, is a likely cause of increased mitochondrial dysfunction during aging.
Abstract 14257: Ribosome-Profiling Reveals Translational Control of SND1 as a Determinant of Endothelial Homeostasis in a hiPSC Model of Sunitinib-Induced Vascular Dysfunction
Authors: Zhenbo Han, Jordan Jousma, Mehdi Amiri, Negar Tabatabaei, Sarath B Nukala, Youjeong Kwon, Gege Yan, Soroush Tahmasebi, Won Hee H Lee, Sang-Ging Ong
Journal: Circulation (2021)

Introduction: The advent of tyrosine kinase inhibitors in cancer therapies has contributed towards the lowered mortality rate from cancer deaths; however, resulting vascular toxicity from such drugs increases the risk for fatal heart disease in cancer survivors. Thus, a better understanding of the mechanisms related to adverse cardiovascular effects is needed to improve mortality rates in cancer survivors. Hypothesis: The objective of this study is to identify previously unrecognized molecular targets that are regulated at a translational level which may contribute to sunitinib-induced vascular toxicity. Methods and Results: A human induced pluripotent stem cell-derived endothelial cells (hiPSC-EC) model of sunitinib-induced vascular dysfunction was established. Ribosome profiling which allows the selective sequencing of translated RNA regions identified Staphylococcal nuclease domain-containing protein 1 (SND1) as a translationally-repressed gene caused by sunitinib exposure. Mechanistically, we identified that sunitinib repressed SND1 by inhibiting mTOR which in turn dephosphorylates 4E-BP. Double-knockdown of 4E-BP1/2 reversed sunitinib-induced repression of SND1. Loss-of-function studies revealed that SND1 inhibition led to endothelial dysfunction as measured by reduced cell viability, impaired angiogenic capability, and reduced wound healing; effects which were blunted in reciprocal SND1 gain-of-function studies in the presence of sunitinib treatment. Furthermore, our results revealed that SND1 transcriptionally regulates UBC13, an E2-conjugating enzyme that mediates K63-linked ubiquitination. Pharmacological inhibition of UBC13 also led to endothelial dysfunction similar to the detrimental effects of sunitinib or SND1 inhibition. Conclusions: Our study demonstrates that translational control of SND1 which acts through UBC13 is a previously unidentified mechanism that can potentially be manipulated for therapeutic benefits to reduce sunitinib-induced vascular toxicity.
Abstract 14133: Hepatic Deletion of the Cargo Receptor <i>Surf4</i> Causes Marked Hypocholesterolemia in Mice
Authors: Vi T Tang, Brian T Emmer, Joseph McCormick, David Ginsburg
Journal: Circulation (2021)

Introduction: High plasma concentration of low-density lipoprotein (LDL) is a strong risk factor for coronary artery diseases. Circulating LDL level is a balance between the secretion of its precursor, very low-density lipoprotein (VLDL), and LDL uptake by tissues. Central to these processes are the secretion of APOB - a protein component of VLDL, and PCSK9 - a negative regulator of LDL uptake. We previously demonstrated that the cargo receptor SURF4 mediates the secretion of PCSK9 heterologously expressed in HEK293T cells. We now report the generation and characterization of hepatocyte-specific Surf4 knockout ( Surf4 LKO ) mice. Methods and Results: Hepatic deletion of Surf4 results in a marked reduction of plasma cholesterol (5.1 mg/dl vs. 71.3 mg/dl, n=5) and triglycerides (17.6 mg/dl vs. 80.4 mg/dl, n=5) as compared to wild-type (WT) littermate controls. Despite modest increases in liver mass (1.14±0.03 g vs. 0.94±0.03 g, n=5) and liver lipid content (3.54±0.46% vs. 0.80±0.57% liver mass, n=4), Surf4 LKO mice show no signs of liver dysfunction or hepatosteatosis as evaluated by serum liver function markers and histology. Consistent with a role for SURF4 in PCSK9 secretion, plasma PCSK9 levels are reduced in Surf4 LKO mice (17.8±2.6 μg/ml vs. 46.0±7.7 μg/ml, n=6) while liver PCSK9 levels remain unchanged. Given that Pcsk9 -/- mice exhibit an approximately 50% reduction in plasma cholesterol, the magnitude of hypocholesterolemia in Surf4 LKO mice suggests that other cargoes involved in lipoprotein metabolism might also depend on SURF4 for secretion. Indeed, an unbiased secretomic study by mass spectrometry revealed that secretion of several lipoproteins, including APOA1, APOA2, and APOB, is reduced in SURF4 null Huh7 cells. As expected, Surf4 LKO mice show reduced APOB and lipoprotein secretion rate. In contrast to Huh7 cells, which demonstrate broad transcriptional changes in response to SURF4 deletion, the livers from Surf4 LKO mice exhibit few transcriptional changes, including the downregulation of genes involved in fatty acid synthesis. Conclusions: These results indicate that the cargo receptor SURF4 has pleiotropic functions in mammalian lipoprotein regulation and may represent a promising target for therapeutic development.
Abstract 14178: Artificial Intelligence (AI)-ECG Derived Biological Age Identifies Accelerated Aging in the Lamin A/C Gene ( <i>LMNA</i> ) Mutations
Authors: Shahar Shelly, Margherita Milone, Audry Chacin-Suarez, Michal Cohen-Shelly, Jose Medina-inojosa, Suraj Kapa, Zachi Attia, Anwar Chahal, Virend K Somers, Paul Friedman, Francisco Lopez-Jimenez
Journal: Circulation (2021)

Introduction: LMNA encodes the nuclear envelope proteins lamin A/C that are involved in ageing processes. Mutations in LMNA cause a spectrum of phenotypes which include muscular dystrophy, arrhythmogenic dilated cardiomyopathy, peripheral neuropathy, progeroid syndrome and overlap syndrome. Early diagnosis is crucial to prevent sudden cardiac death. We hypothesized that LMNA mutations result in an ECG biological age older than chronological age. Methods: In this study, we used AI-enabled ECG network to investigate standard digital 12-lead ECGs in genetically characterized LMNA patients. Results: We identified 33 LMNA patients with 331, 12-lead ECG available for analysis. Median age at symptoms onset was 23.5 (range: &lt;1 to 61 years;15 females). Mean follow up time was 86 months (range: &lt;1 to 367 months). Symptoms at onset included muscle weakness (n=10) or cardiac symptoms (n=18) and asymptomatic (n=5). We included a total of 1532 age sex matched controls. We found significant differences in positive age-gap (biologically older than chronological age) comparing LMNA patients (median of 17.5) versus controls (4.9 years; p&lt;0.001, Figure 1 ). AI-ECG age with 10 years or higher age-gap was observed in 73% of LMNA patients compared to 27% in the controls (p&lt;0.001). Consecutive serial analysis for all ECG’s in the study versus predicted age showed faster aging when comparing the rates of age-gap overtime in the LMNA group compared to controls (p&lt;0.0001, Figure 2 ). Moreover, the subset analysis of 23 ECG in the 5 asymptomatic patients versus controls also showed significantly higher AI-ECG age-gap (p=0.004) Conclusions: An AI-ECG algorithm to detect biological age effectively demonstrates accelerated aging in patients with LMNA mutations related to physiological aging. Our findings further validate the role of AI-ECG to detect accelerated aging, expanding previous studies demonstrating higher mortality among individuals with in increased positive age-gap.
Abstract 14147: Septal Native T1 is Higher in Patients With Pre-Capillary Pulmonary Hypertension Compared to Post-Capillary Pulmonary Hypertension
Authors: John W Cerne, Ashitha Pathrose, Roberto Sarnari, Daniel Gordon, Bhargav Devabhaktuni, Kelvin Chow, Bradley D Allen, Ryan Avery, Michael Markl, James C Carr
Journal: Circulation (2021)

Introduction: Right heart catheterization (RHC) is used to diagnose and classify pulmonary hypertension (PH). Because RHC is invasive, there is growing interest in non-invasive PH evaluation techniques, such as cardiac magnetic resonance (CMR). Hypothesis: CMR-derived fibrosis indices [native T1 (NT1) and extracellular volume (ECV)] differ between pre-capillary PH (PRE-PH), post-capillary PH (POST-PH) and controls. Methods: RHC-defined PH patients and healthy controls (N=25, age=52+/-13 years) underwent CMR. A cardiologist classified patients into PRE-PH (N=29, age=55+/-8 years) and POST-PH (N=19, age=66+/-13 years) based on RHC measurements and clinical history. T1 maps of the left ventricle were acquired using a Modified Look-Locker Inversion Recovery sequence before and after administration of gadolinium contrast. T1 maps were manually segmented using the AHA 16 segment model to obtain segmental native and post-contrast T1. Segmental ECV was calculated using NT1, post-contrast T1, and hematocrit. Global ECV and NT1 were calculated by averaging all segments. Results: PRE-PH had higher NT1 than POST-PH in segments 8 (1077+/-39 vs 1046+/-36 ms, p=.01), 9 (1082+/-47 vs 1051+/-44 ms, p=.03), and 14 (1080+/-74 vs 1028+/-53 ms, p=.01). Global ECV and NT1 were higher in PRE-PH (31+/-4% and 1056+/-36 ms) than controls (28+/-4% and 1013+/-29 ms) (p=.017 and p=.000, respectively). Conclusions: NT1 was different between PRE-PH and POST-PH in mid- and apical-septal segments, however segmental ECV and global measures were not. NT1 may reflect more than just ECV expansion, providing additional insight into the myocardium. Regional NT1 may complement RHC for classifying PH.