tbuckley/cabot-search huggingface dataset:
Abstract 4143728: Pregnancy-Associated Spontaneous Coronary Artery Dissection in the Antepartum Period: Navigating Clinical Uncertainties
Authors: Robyn Goodrich, Patricia Rodriguez-Lozano, Shuo Wang, Olivia Ondigi, Kelly Wingerter
Journal: Circulation (2024)

Description of Case: A 35-year-old G2P1 female with history of drug and tobacco use presented to the emergency department at 25 weeks of gestation with chest pain in the setting of a recent upper respiratory infection. Her vital signs and electrocardiogram (EKG) were normal; however, HS-troponin was elevated at 398 ng/L (normal &lt;5.0 ng/L). An echocardiogram revealed a left ventricular ejection fraction (LVEF) of 55-60% and apical hypokinesis (Figure 1). The initial differential diagnosis included viral myocarditis (supported by elevated inflammatory markers), spontaneous coronary artery dissection (SCAD), and distal atherosclerotic coronary artery disease. Given her hemodynamic stability and preserved LVEF, the risk of invasive angiography outweighed the benefits. She was discharged with medical management and follow-up with maternal-fetal medicine and cardio-obstetric specialists. She underwent planned cesarean delivery at week 37 of gestation. The following day, coronary computed tomography angiography (CCTA) revealed severe stenosis of the mid-left anterior descending (LAD) artery (Figure 2A). Hours later, she had recurrence of chest pain without EKG changes, and HS-troponin increased to 7,000 ng/L. The decision was made to proceed with invasive coronary angiography, which confirmed SCAD in the mid-LAD (Figure 2B). Revascularization was not pursued given her hemodynamic stability, and she was managed conservatively. Discussion: Pregnancy-associated SCAD (PSCAD) is the leading cause of myocardial infarction during pregnancy. The presented case highlights the unique challenges associated with diagnosis and management of antepartum PSCAD, emphasizing the need for a high index of suspicion in pregnant women presenting with chest pain. In PSCAD patients, invasive angiography has been associated with an increased risk of iatrogenic dissections and may pose risks to the fetus, limiting utility. Non-invasive imaging such as CCTA may be considered in clinically stable patients; but there is limited data evaluating the diagnostic accuracy of CCTA in SCAD. Further research is needed to elucidate optimal diagnostic and therapeutic strategies tailored to pregnant women with PSCAD, and to better understand long-term implications of this condition on maternal and fetal outcomes. Given the complexities and unique challenges of managing PSCAD, advancing understanding and developing more specific guidelines is crucial to improving care for these patients.
Abstract 4143729: PTSD-Dependent Acceleration of Aortopathy
Authors: Heather Holman, Ying xiong, Jean Marie Ruddy, Sanford Zeigler, Jeffrey Jones
Journal: Circulation (2024)

Post-traumatic stress disorder (PTSD) is associated with hypertension and increased heart rate, which are risk factors for cardiovascular disease including thoracic aortic aneurysms. A connection between stress and aortopathy has been suggested, yet mechanisms linking the two remain unknown. We hypothesize that PTSD-induced mechanical signals alter thoracic aortic wall homeostasis, which can predispose to aortopathy. C57BL/6 mice underwent traumatization consisting of inescapable foot shock, single prolonged stress, and single housing. PTSD phenotype was assessed through behavioral testing for the DSM-V PTSD criteria. Group-housed control mice did not undergo the traumatization but were subjected to behavioral testing. Z-scores for each behavioral test were generated and mice with z-scores above the 85% confidence interval on all criteria were considered to have a PTSD-like phenotype. This protocol yielded a PTSD phenotype in 30% of mice mimicking the human proportion of PTSD development following a traumatic experience. PTSD mice had significantly higher systolic blood pressures (PTSD (n=10), 149 ± 7mmHg; control (n=10), 123 ± 9mmHg, p&lt;0.05) and lower plasma renin concentrations (PTSD (n=5), 52,233 ± 4,591pg/mL; control (n=5), 80,824 ± 10,797pg/mL, p&lt;0.05) 4-weeks post-traumatization, suggesting a PTSD-induced renin-independent hypertension. Thoracic aortae were harvested 4-weeks post-traumatization and analyzed for changes in compliance by parallel-wire myography and alterations in aortic wall structure by histology. PTSD mice had enhanced thoracic aortic wall stiffness indicating increased extracellular matrix remodeling. Thoracic aortic aneurysms (TAAs) were induced surgically (periadventitial application of 0.5M CaCl 2 to the descending thoracic aorta) at 4-weeks post-traumatization. PTSD mice had significantly larger TAAs 4-weeks post-TAA induction demonstrating an acceleration of aortopathy (PTSD (n=5), 73.9 ± 13% increase from baseline diameter; control (n=5), 29.9 ± 6.9%, p &lt;0.05). Our PTSD model recapitulated the human phenotype showing elevated systolic blood pressure. This hypertension is renin-independent potentially derived from alterations in neural circuits propagating a neurogenic hypertension. PTSD mice demonstrated extracellular matrix remodeling and acceleration of thoracic aortic aneurysm progression. Thus, PTSD can alter thoracic aortic wall homeostasis predisposing to or accelerating existing pathology.
Abstract 4143732: Mitochondrial DNA heteroplasmy and incident cardiovascular disease
Authors: Yun Soo Hong, Wen Shi, Daniela Puiu, Nicole Lake, Eliseo Guallar, Dan Arking
Journal: Circulation (2024)

Background: Variants of mitochondrial DNA (mtDNA) may exist in heteroplasmy and have been associated with increased risk of mortality and cancer. While variation in mtDNA has been associated with cardiomyopathy in mitochondrial disease, the association between mtDNA heteroplasmy and cardiovascular disease (CVD) in the general population has not been well studied. Methods: We quantified mtDNA heteroplasmy from whole genome sequencing data in 476,434 participants in the UK Biobank. We defined a variant allele frequency of 5–95% as heteroplasmic. We functionally characterized mtDNA single nucleotide variants using a constraint-based score, mitochondrial local constraint score sum (MSS). We evaluated the associations of MSS and incident CVD, defined as fatal or non-fatal myocardial infarction (MI) or ischemic stroke (IS), using Cox proportional hazards models adjusted for demographic, lifestyle, and clinical factors in 463,705 participants free of CVD. We further tested the interactions with clonal hematopoiesis of indeterminant potential (CHIP) and leukocyte telomere length (LTL) in the association between heteroplasmy and CVD. We performed additional analysis stratified by MSS for each complex/region in the mtDNA, and subgroup analysis by sex and C-reactive protein (CRP; ≥3mg/L). Lastly, we performed analysis separately for MI and IS. Results: During a median (1 st and 3 rd quartiles) follow-up of 13.6 (13.1–14.5) years, there were 24,723 incident CVD events (16,959 MI and 9671 IS cases). 28.3% of the study population had 1 or more heteroplasmies. We found that higher MSS was associated with CVD (adjusted hazard ratio [aHR] for a 1-unit increase in MSS 1.08; 95% confidence interval 1.00–1.17). In particular, a higher MSS was associated with MI (aHR 1.13; 1.02–1.24) but not with IS (aHR 1.03; 0.90–1.17). The association between MSS and MI was stronger for fatal MI (aHR 1.52; 1.10–2.10) than for non-fatal MI (aHR 1.10; 0.99–1.21). When stratified by complex/region, higher MSS in Complex I increased the risk of MI by 27% (aHR 1.27; 1.06–1.53) but not in other complexes/regions. Although LTL was inversely associated with CVD outcomes, there were no associations with CHIP. Furthermore, there was no interactions by LTL, CHIP, sex, and CRP in the association between MSS and CVD outcomes. Conclusion: These results indicate that mitochondria may have a functional role in the development of CVD, particularly MI, and MSS may serve as a biomarker for CVD risk.
Abstract 4143616: A Silent Murmur: Incidental Finding of a Cardiac Paraganglioma
Authors: Kyung Min, Kishan Srikanth, Tann Lien, Salvador Hernandez, Steven Colicci, Amber Wheeler, Jennifer Ting
Journal: Circulation (2024)

Background: Paragangliomas are rare neuroendocrine tumors, arising from neural crest cell lines in the autonomic system. The detection of these tumors has risen in recent years with the growing availability and use of intrathoracic imaging. Case Presentation: A 59-year-old male with a past medical history of HTN, HIV, syphilis, and treated prostate cancer presented to the clinic for a new-patient evaluation and was incidentally found to have a 2/6 diastolic murmur, reportedly present since childhood. He was asymptomatic apart from brief episodes of dizziness when leaning forward or standing during exercise. Family history was notable for an aortic aneurysm in his father and valvular disease in his mother. Clinical Decision Making: A TTE showed a 5.7 x 5.9 cm echogenic mass pushing against the RV and RA. Prospective ECG-gated CT scan of the chest revealed a highly vascular intrapericardial mass (6.0 x 7.7 mm) anterior to the RA and RV with the RCA leading into it. Cardiac MRI showed a large, circumscribed mass moving within the RV-free wall without evidence of depressed RV ejection fraction or significant coronary artery compression. Coronary angiogram found an engorged acute marginal branch feeding the highly vascular mass and the RCA continuing under the mass to give off a small PDA and a small RPL. There were normal filling pressures and no significant obstructive CAD. A multidisciplinary team determined a high concern for cardiac paraganglioma. Serological workup was notable for elevated serum epinephrine (335 pmol/L). 24-hour urinary dopamine was elevated (831.5 ug/TV) while 24-hour urinary catecholamines/metanephrines were normal. A DOTATATE PET/CT scan confirmed presence of a cardiac paraganglioma. Genetic workup did not reveal presence of any succinate dehydrogenase (SDH) mutations. Conclusion: Here we present a highly unusual case of an asymptomatic intra-pericardial paraganglioma in a 59-year-old male. Given the lack of guidelines for management and the complexity of the case due to the location of the tumor, a multidisciplinary team comprising cardiology, endocrinology, and surgery is evaluating the patient, with considerations of surgical removal and CABG to PDA after neurohormonal blockade.
Abstract 4143794: Drug-Coated Balloon Strategy Following Rotational Atherectomy for Calcified Coronary Artery Compared with Drug-Eluting Stent
Authors: Hisanori Yui, Shoichi Kuramitsu, Takuro Sugie, Yutaka Tadano, Umihiko Kaneko, Daitaro Kanno, Yoshifumi Kashima, Tsutomu Fujita
Journal: Circulation (2024)

Background: Drug-coated balloons (DCB) have emerged as an effective treatment for in-stent restenosis and small vessel disease. DCB angioplasty might improve outcomes in heavily calcified lesions, a challenge in the current era of drug-eluting stents (DES). Calcified nodules (CN) also remain problematic due to high incidences of target lesion revascularization (TLR). However, there is limited evidence comparing the efficacy of DCB and DES angioplasty in heavily calcified lesions requiring rotational atherectomy (RA), including those with CN. Methods: From January 2020 to July 2022, 471 patients underwent percutaneous coronary intervention (PCI) for calcified de novo coronary lesions using either DCB or DES (≤ 3 mm) following RA. Among these, 102 cases (21.7%) received DCB angioplasty, while 369 cases (78.3%) received DES angioplasty. The primary endpoint was the cumulative incidence of major adverse cardiac events (MACE), defined as a composite of cardiac death, clinically driven target lesion revascularization (CDTLR), and target vessel-related myocardial infarction (TVMI). We also compared the cumulative one-year incidence of TLR between the DCB and DES groups based on the presence of CN. CN was defined by intravascular ultrasound or optical coherence tomography as a convex shape of the luminal side of calcium. Results: The cumulative one-year incidence of MACE was higher in the ROTA+DCB group compared to the ROTA+DES group (12.7% vs. 6.2%, Log-rank P=0.039). ROTA+DCB angioplasty was associated with an increased risk of MACE (inverse probability weighted hazard ratio [IPWHR], 3.02 [95% confidence interval {CI}, 1.063-8.583]; p=0.038) and CDTLR (IPWHR, 6.423 [95% CI, 1.825-22.60]; p=0.004) compared to ROTA+DES angioplasty. In the CN subgroup (n=185), the one-year incidence of TLR was comparable between the DCB and DES groups (10.6% vs. 5.8%, IPWHR, 1.909 [95% CI, 0.414-8.804]; p=0.41). Conversely, in non-CN lesions (n=248), the one-year TLR rate was higher in the DCB group (7.8% vs. 1.0%, IPWHR, 12.42 [95% CI, 1.780-86.59]; p=0.011). Conclusion: In patients with calcified coronary artery disease, the DCB strategy following RA was associated with a higher rate of MACE at one year compared to the DES strategy following RA. However, for calcified nodules in heavily calcified coronary arteries, the DCB strategy alone was comparable to DES following RA. In contrast, non-CN calcified lesions had a higher TLR rate with DCB compared to DES.
Abstract 4143778: ROS-dependent SUMOylation of Copper Chaperone Atox1 Orchestrates Endothelial Inflammatory and Angiogenic Signaling, Promoting Neovascularization Following Ischemic Injury
Authors: Archita Das, Sudhahar Varadarajan, Shikha Yadav, David Fulton, Stephanie Kelley, Malgorzata McMenamin, Junichi Abe, Jack Kaplan, Masuko Ushio-Fukai, Tohru Fukai
Journal: Circulation (2024)

Background: Neovascularization in response to ischemia relies on reactive oxygen species (ROS), inflammatory, and angiogenic signaling in endothelial cells (ECs). Our prior study suggested that the copper (Cu) chaperone Atox1 acts as a Cu-dependent transcription factor for p47phox, facilitating ROS-NFkB-dependent inflammatory responses in ECs stimulated by inflammatory cytokine TNFα. However, the precise mechanism of Atox1’s nuclear translocation during inflammatory angiogenesis is unknown. Posttranslational SUMOylation and deSUMOylation by SENP1 in the cytosol and nucleus play crucial roles in regulating gene expression, protein subcellular localization and signal transduction. In silico analysis identified a conserved potential SUMOylation motif at Lys(K3) of Atox1. Results: Here we show that TNFα or hypoxia stimulation in human aortic ECs, as well as mouse hindlimb ischemia model that promotes inflammatory angiogenesis, significantly increased Atox1-K3 SUMOylation. Mechanistically, ROS induced by TNFα or hypoxia led to the oxidation/inactivation of SENP1 at Cys603 in the cytosol, thereby elevating Atox1 K3-SUMOylation (3.6-fold). Unexpectedly, Atox1siRNA or overexpression of “SUMO-dead” Atox1K3R mutant in ECs inhibited TNFα or hypoxia-induced, activation of NFkB (increased cytosolic p-NFkB and its nuclear translocation) as well as Cu-dependent Atox1 nuclear translocation. Additionally, in the nucleus under reducing conditions, ChIP and promoter analysis revealed that deSUMOylation of Atox1 by nuclear active SENP1 is required for Atox1’s transcriptional activity on inflammatory and angiogenic genes VCAM/ICAM, IL-8 and RANTES. Functionally, siAtox1 and “SUMO-dead” Atox1K3R mutant reduced inflammatory and angiogenic responses, including monocyte adhesion, migration and capillary tube formation. In vivo, EC-specific Atox1 -/- mice or CRISPR/Cas9-generated “SUMO-dead” Atox1K3R knock-in mutant mice exhibited significantly reduced blood flow recovery, Mac3+ inflammatory cells, and angiogenesis (CD31+ capillary) in hindlimb ischemia and sponge implant inflammatory angiogenesis models. Conclusions: SUMOylation of Atox1 via oxidative inactivation of SENP1 in the cytosol promotes p-NFkB and the nuclear translocation of both Atox1 and NFkB. Within the nucleus, deSUMOylated Atox1 and NFkB synergistically enhance the expression of inflammatory and angiogenic genes in inflamed or hypoxic ECs, thereby driving neovascularization in ischemic cardiovascular diseases.
Abstract 4143757: Adverse Outcomes with Cardiac Contractility Modulation: Insights From the MAUDE Registry
Authors: Aashish Katapadi, Nikhila Chelikam, Aashika Katapadi, Douglas Darden, Rakesh Gopinathannair, Rajesh Kabra, Donita Atkins, Dhanunjaya Lakkireddy, Naga Venkata Pothineni
Journal: Circulation (2024)

Background: Cardiac contractility modulation (CCM) is a device-based heart failure therapy that augments cardiac contractility. One CCM device – the Optimizer Smart Mini System [Impulse Dynamics, Marlton, NJ] – is approved by the Food and Drug Administration (FDA) for clinical use. Research Question: What are real-world and long-term outcomes of the Optimizer Smart Mini CCM system? Objective: We reviewed the United States FDA Manufacturer and User Facility Device Experience (MAUDE) database for adverse events and outcomes associated with the Optimizer Smart Mini System CCM. Methods: On June 3rd, 2024, we performed a MAUDE database search for all reports of CCM devices from January 2019 - when the first pre-market implantation was noted - to the present. Duplicates were removed, and outcomes were noted. Results: A total of 34 total reports were found. The majority of events were reported since 2023. 58.8% (n=20) of events were classified as device malfunctions. This occurred most often due to a computer software problem (35.3%, n=12), failure to charge (14.7%, n=5), and an adverse event without an identified problem (14.7%, n=5). Commonly, error code A09 - a charging error due to incorrect interpretation of a high current during a routine safety self-check - occurred in 38.2% (n=13) of all cases, even in patients without a reported software problem, and was solved by resetting the device in 47.1% (n=16) of cases. This is a known problem. Injury occurred in 35.3% (n=12) of cases due to implant failure (52.9%, n=18) as the most common patient problem. There was a 5.9% (n=2) rate of mortality. Conclusions: Real-world CCM implantation appears to have low device-related adverse risks but suffers from computer software issues that may be solved by resetting the device. Continued monitoring and accurate adverse event reporting are needed with increased use to assess long-term risks.
Abstract 4143772: Genome wide association study meta-analysis of 19,487 individuals with mitral valve prolapse identifies 52 novel genomic regions and highlights pro-fibrosis genes
Authors: Aeron Small, Takiy-Eddine Berrandou, Adrien Georges, Jordan Morningstar, Matthew Huff, Ta-Yu Yang, Jiwoo Lee, Erik Abner, Henning Bundgaard, Quinn Wells, Peter Wilson, Kelly Cho, Daniel Rader, Andrea Ganna, Anna Helgadottir, Hilma Holm, Kari Stefansson, Daniel Gudbjartsson, Ha My Vy, Michael Rosenberg, David Milan, Michael Borger, Maja-Theresa Dieterlen, Amy Kontorovich, Jamie Engert, George Thanassoulis, Eric Farber-Eger, Christopher Gignoux, Patrick Ellinor, Gina Peloso, Russell Norris, Mengyao Yu, Nabila Bouatia-Naji, Pradeep Natarajan
Journal: Circulation (2024)

Introduction: Mitral valve prolapse (MVP) is the most common cause of primary mitral regurgitation and is estimated to affect between 1-3% of the general population. A subset of individuals with MVP develop malignant arrhythmias, often in the context of myocardial fibrosis. The genetics of MVP, and genetic factors explaining why only some individuals with MVP have adverse outcomes, remains poorly understood. Methods: We defined MVP using a combination of claims data and echocardiographic diagnosis across 15 cohorts spanning 5 countries and performed a meta-analysis of genome-wide association studies (GWAS) for MVP including 19,487 MVP cases among 2,247,054 individuals. Causal genes were prioritized using a combination of methods including the identification of variants in active promoters/enhancers using mitral valve ATAC-seq data from an external dataset. To determine whether prioritized genes may be differentially expressed in myocardial fibrosis, we compared single-cell RNA sequencing between fibrosed papillary muscles and normal left ventricular among two individuals with severe MVP. Results: There were 67 unique genome-wide significant (GWS; p&lt;5x10 -8 ) genomic regions, of which 52 were novel. Of these, 38 GWS regions included either missense variants or variants overlapping a promoter active in valve tissue as suggested by mitral valve ATAC-seq data. Pathway analysis of prioritized genes highlighted etiological roles for extracellular matrix and cardiomyocyte biology. 33 prioritized genes were differentially expressed between fibrotic papillary muscle tissue and normal left ventricle, the majority of which were specific to cardiomyocytes. One of these genes, CAMK2D , was also observed as sub-GWS in a recent GWAS of myocardial interstitial fibrosis and has notable pleiotropy for arrhythmia traits including atrial fibrillation and atrioventricular block. Conclusions: We performed the largest GWAS of MVP to-date, discovering 52 novel GWS regions, and prioritized genes relevant to myocardial fibrosis, an important risk factor for adverse outcomes among individuals with MVP.
Abstract 4143448: Obesity Prevalence Differs by Asian Ethnicity across the Adult Lifespan
Authors: Anika Naidu, Nancy Gordon, Nirmala Ramalingam, Veronica Njuguna, Edward Shin, Inaya Majid, Joan Lo
Journal: Circulation (2024)

Background: The US Asian population comprises diverse ethnic subgroups with distinct cultural and dietary profiles that influence their health outcomes. However, most research has focused on obesity trends among general populations, and little is known about trends within Asian ethnic subgroups. We examined the variation in obesity prevalence among the four largest US Asian subgroups in comparison with White, Black, and Hispanic groups across five age decades of the adult lifespan. Methods: This retrospective study used electronic health record data for 101,837 Filipino, 98,281 Chinese, 76,916 South Asian, 28,764 Vietnamese, 805,051 White, 124,412 Black, and 328,064 Hispanic adults aged 30-79y who were members of a Northern California health plan in 2019 and had a measured BMI. Obesity was defined as body mass index (BMI) ≥27.5 kg/m2 for Filipino, Chinese, South Asian, and Vietnamese adults and ≥30 kg/m2 for White, Black, and Hispanic adults. Obesity prevalence was compared by sex in Asian and non-Asian groups at ages 30-39y through 70-79y. Results: Among Asian men and women, obesity prevalence was consistently higher among Filipino and South Asian adults than among Chinese and Vietnamese adults ( Figure ). Obesity prevalence in Asian adults peaked at 58-59% for Filipino men at age 30-49y, 43-44% for Filipino women at 30-49y, and 42-46% for South Asian women at 50-69y. At age ≥40y, obesity prevalence was similar in South Asian and White men, whereas Filipino men tracked higher, in the range of Black and Hispanic men. For women, obesity prevalence was higher among Filipina than South Asian women under age 50y. However, this trend reversed in women age ≥50y, when prevalence was similar among Filipina and White women, and higher for South Asian women who tracked closer to Hispanic women. Black women had the highest obesity prevalence across all age decades. Conclusion: Across five age decades, obesity prevalence was substantially higher among Filipino and South Asian than Chinese and Vietnamese ethnic groups. These trends point to an alarmingly high obesity burden among Filipino and South Asian adults and underscores the importance of using disaggregated Asian ethnic subgroup data to study health risks and outcomes.