tbuckley/cabot-search huggingface dataset:
Abstract 14505: BSCL2/Seipin Deletion Rescues ATGL-Deficiency-Induced Lethal Lipotoxic Cardiomyopathy
Authors: Hongyi Zhou, Huabo Su, Ji Li, Weiqin Chen
Journal: Circulation (2023)

Imbalances in triglyceride (TG) catabolism are associated with cardiac lipid deposition and contractile dysfunction, as manifested in patients with primary triglyceride deposit cardiomyovasculopathy (TGCV) caused by adipose triglyceride lipase (ATGL) deficiency. BSCL2/Seipin is a highly conserved endoplasmic reticulum protein widely implicated in lipid droplet biogenesis and TG metabolism. We previously reported that global Bscl2 –/– mice and mice with cardiac-specific deletion of Bscl2 manifest higher myocardial ATGL expression and develop mild cardiomyopathy with reduced cardiac steatosis. However, the interplay between BSCL2 and ATGL in hearts remains to be further interrogated. In this study, we surprisingly discovered that global BSCL2 deletion completely rescued the lethal lipotoxic cardiomyopathy in the genetic ATGL-deficient TGCV model ( Atgl –/– mice) by drastically reducing cardiac TG deposits, abolishing cardiac hypertrophy, and restoring cardiac contractility. Transcriptomic analyses identified the elevated inflammatory, oxidative stress, and extracellular matrix pathways in Atgl –/– hearts, which were dramatically ameliorated by BSCL2 deletion. Conversely, the severely suppressed cardiac metabolic functions, muscle contraction, and ion transport pathways in Atgl –/– hearts were also normalized by BSCL2 deletion. Heatmap data further revealed that the mRNA levels of Pgc1/Ppara and fatty acid oxidation (FAO) genes were not altered in Bscl2 –/– hearts but were severely repressed in Atgl –/– hearts due to defective TG lipolysis. However, their expressions in Atgl –/– Bscl2 –/– hearts were restored to similar levels as wild-type and Bscl2 –/– hearts. RT-PCR analyses further confirmed such changes. Notably, cardiac-specific deletion of BSCL2 rescues lethal cardiomyopathy in mice with cardiac-specific deletion of ATGL. These data suggest that cardiac BSCL2 cell-autonomously regulates ATGL-independent TG hydrolysis and FAO pathways essential for cardiac function. Our study highlights the presence of BSCL2-mediated ATGL-independent pathways that regulate cardiac TG metabolism and provide novel therapeutic approaches to treat ATGL-deficiency-associated lethal cardiomyopathy.
Abstract 13261: Global T Wave Inversion: Incidence and Implications in Critically Ill Patients
Authors: Garen Kroshian, Christopher Phelan, dennis tighe, Elizabeth Tighe
Journal: Circulation (2023)

Background: Symmetric global T-wave inversion (GTWI) occurs in 0.3% of general hospital admits. As reported by Walder and Spodick, GTWI exhibited a 4:1 female preponderance and was often associated with ACS or central nervous system (CNS) disorders; in-hospital mortality was not affected. Anecdotally we have observed this ECG pattern in critically-ill medical ICU (MICU) patients. We hypothesized that GTWI is more prevalent among MICU patients and may be associated with adverse outcomes. Methods: We reviewed the ECGs, demographic, clinical, and physiological data of 1652 consecutive patients admitted to 2 medical ICUs. Those admitted to CCU and Neuro ICU were excluded as were MICU patients with a primary diagnosis of ACS, acute CNS syndrome, LBBB, ventricular pacing, pre-excitation, and uninterpretable ECG. ECGs performed within 48 hours of ICU admit were reviewed by 2 blinded readers. GTWI was defined by the criteria of Walder and Spodick. The GTWI group was compared to 95 matched patients without GTWI. Results: See Table. GTWI occurred in 75 patients (4.5%); 56% of whom were female. Significant differences between GTWI vs control included history of CAD (p=0.03), cardiomyopathy (p=0.035), CKD (p=0.046), and prior EP procedure (p=0.023). In addition, QT-interval (p&lt;0.0001), QTc (p&lt;0.0001) and BNP (1433±1725 vs 750±978 pg/mL; p=0.032) were greater in the GTWI group. LVEF (52.7±16.2% vs 55.6±14.1%) and cTnI (1.35±2.52 vs 1.25±4.15 pg/mL) were similar. MICU days and APACHE II score were greater in those with GTWI. Total length of stay and in-hospital mortality were similar. Conclusions: In this critically-ill MICU cohort, GTWI was more prevalent compared to previously reported general hospital admits. A distinct female preponderance was not found. This ECG pattern was associated with underlying cardiac disease, greater length of MICU stay and higher illness severity, but was not associated with higher in-hospital morality.
Abstract 17602: Cardiac Structure and Function and Renal Outcomes in Patients With Heart Failure With Preserved Ejection Fraction: Insights From the PARAGON-HF Trial
Authors: Henri Lu, Safia Chatur, Riccardo M Inciardi, Martin Abanda, Finnian R Mc Causland, Amil M Shah, Maja Cikes, Brian Claggett, Narayana Prasad, Carolyn S Lam, Eileen OMeara, John J McMurray, Sheila Hegde, Scott Solomon, Hicham Skali
Journal: Circulation (2023)

Introduction: Chronic kidney disease is common and associated with a worse prognosis in patients with heart failure (HF). However, the association of cardiac structure and function with renal outcomes in patients with HF with preserved ejection fraction (HFpEF) is not known. Goal: Identify cardiac structural and functional correlates of renal outcomes in HFpEF. Methods: Patients enrolled in the echocardiographic sub-study of the PARAGON-HF trial were included. The endpoint of interest was a composite renal endpoint: a ≥50% decline in estimated glomerular filtration rate (eGFR) relative to baseline, development of end-stage renal disease, or death attributable to renal causes. Multivariable Cox proportional hazards models were used to identify measures of cardiac structural and functional parameters associated with the composite renal endpoint, adjusting for baseline eGFR, systolic blood pressure, NT-proBNP, treatment arm (sacubitril-valsartan or valsartan) and diabetes. Results: In 1,097 patients (53% women, mean age 74±8 years), over a median follow-up of 2.9 years (IQR 2.6-3.4 years) there were 28 composite renal events (0.9 per 100 patient-years). After multivariable adjustment, higher left ventricular (LV) posterior wall thickness and mass index, right ventricular (RV) end-diastolic and end-systolic areas as well as impaired RV function (lower fractional area change and lower absolute RV free wall longitudinal strain), but not LV systolic function (LVEF and global longitudinal strain) were each associated with a significantly higher risk for the composite renal endpoint ( Figure ). Conclusions: In the PARAGON-HF echocardiographic sub-study, evidence of cardiac biventricular remodeling and deterioration of RV function were associated with an increased risk of renal events. These results underscore the close relationship between the heart and kidneys in patients with HF even when LVEF is preserved.
Abstract 13669: Hypertension Subtypes as Predictors of Cardiovascular and All-Cause Mortality
Authors: Kevin S Tang, Jeffrey Jones, Wenjun Fan, Nathan D Wong
Journal: Circulation (2023)

Background: While hypertensive subtypes have been examined in relation to cardiovascular disease (CVD) outcomes in selected earlier cohorts, noting poorer outcomes in those with isolated systolic hypertension (ISH) in particular, contemporary data utilizing newer definitions of hypertension are lacking among US population-representative adults. We evaluated the association between hypertension subtypes with CVD and all-cause mortality. Methods: We included data from the National Health and Nutrition Examination Survey (NHANES) dataset 1999-2008 with follow-up through 2018. Hypertensive subtypes were based on systolic and diastolic blood pressure cut points of 130 and 80 mmHg, respectively. The incidence of CVD and all-cause mortality was examined and compared between hypertension subtypes (isolated systolic hypertension [ISH], isolated diastolic hypertension [IDH], and systolic-diastolic hypertension [SDH]) against patients with normal blood pressure using Cox regression analysis, adjusted for age, ethnicity, gender, tobacco use, use of antihypertensive agents, and comorbidities including diabetes mellitus and dyslipidemia. Results: A total of 23,206 subjects (projected to 194 million US adults) were included at baseline, of which 58% were normotensive, 21% had ISH, 8% had IDH, and 13% had SDH. In the adjusted analysis, ISH and SDH (but not IDH) were significantly associated with increased CVD. Subgroup analyses excluding those not on antihypertensive therapy (26.8%) showed these relationships to persist, except for ISH in relation to CVD mortality. Conclusions: Compared to normotension, ISH and SDH were independently associated with higher risk of cardiovascular and all-cause mortality. This has important implications for the continued necessity of managing systolic hypertension.
Abstract 18873: Microvascular Calcification Varies Across Brain Regions in Humans With and Without Dementia at Death
Authors: KELLY A BORGES, Joseph D Aabye, Isabella Romano, Isabelle Lombardi, Mackenzie Sivilli, Olga V Savinova
Journal: Circulation (2023)

Background: Vascular calcification (VC) is an independent predictor of cardiovascular and cerebrovascular events. While the clinical significance of coronary VC is well recognized, less is known about the prevalence and implications of VC in brain microcirculation. Aims: In this exploratory study, we aimed to compare calcification volume (CV) across brain regions in subjects with and without dementia documented at death. Methods: In a cohort of human donor cadavers (n=14, 57% female, all &gt;70 y/o), brain tissue was sampled bilaterally from basal ganglia (BG), substantia nigra (SN), subventricular zone (SVZ), hippocampus (Hc), and posterior cingulate cortex (PCC), and scanned by microCT at 10 μm resolution. Reconstructed images were segmented into standardized regions of interest (ROI). CV was defined as voxel quantity ≥130 Hounsfield units within each ROI. Findings were confirmed by histologic evaluation. Results: By two-way ANOVA, CV differed significantly by region (p=0.0006) and condition (p=0.0104). Hc and PCC CVs were significantly greater in subjects with dementia compared to age-matched subjects (9.3х10e7 μm 3 vs 1.4х10e7μm 3 , p=0.007; 2.6х10e7 μm 3 vs 4.7х10e6 μm 3 , p=0.017). Conclusions: All subjects in our cohort exhibited VC in at least one brain region, indicating that the prevalence of intracranial VC exceeds published estimates. Subjects with dementia exhibited significantly higher Hc and PCC CVs than age-matched subjects without documented dementia. Although limited by small sample size, our findings support recent reports of hippocampal and BG calcification in post-mortem brain samples from humans with Alzheimer disease.
Abstract 14585: Early Right Ventricular Snail Expression is a Druggable Target to Improve Right Ventricular Function in Pressure-Overloaded Right Heart Failure
Authors: Kenzo Ichimura, Yuqiang Mao, Mario Boehm, Khadem Ali, Adam Andruska, Katharina Schimmel, Fan Zhang, Sushma Reddy, Edda F Spiekerkoetter
Journal: Circulation (2023)

Introduction: Cardiac fibrosis disrupts the myocardial architecture, impairs the exchange of oxygen and nutrients, and puts the heart at risk of failure. Snail (SNAI1) is a transcriptional factor involved in cell plasticity that has been linked to fibroblast-to-myofibroblast transition (FMT) in the hypoxic heart, however, it is unknown whether inhibition of FMT reduces fibrosis and improves right ventricular (RV) function in the pressure overloaded RV. We hypothesized that Snail is necessary for FMT and, as BMP signaling inhibits Snail, that two BMPR2 activators, FK506 and Enzastaurin, reduce cardiac fibrosis and improve cardiac function in a pulmonary artery banding (PAB) mouse model. Methods and Results: We performed PAB surgery on snail-YFP reporter mice and observed transient Snail expression exclusively in the RV 3-7 days after inducing pressure overload (Fig. 1). In PeriostinCre-TdTomato reporter mice we showed that Snail was expressed in proliferating Periostin and vimentin positive fibroblasts representing activated myofibroblasts. In vitro , stimulation of cardiac fibroblasts with TGFbeta resulted in the early expression of Snail at 2 hours, followed by a Snail-dependent Acta2 expression after 24 hours and Col1 after 48 hours, suggesting the critical role of Snail in fibroblast activation. Furthermore, application of stretch and pressure (50kPa) to cardiac fibroblasts, mimicking pressure-overload in vivo , increased Snail expression. FK506 and Enzastaurin inhibited Tgf-b induced Snail expression in vitro as well as in vivo when administered immediately after PAB surgery (Fig. 2). Finally, long-term treatment with Enzastaurin resulted in preserved RV function at week 7 as assessed by cardiac MRI (Fig. 3, N=6). Conclusions: Snail expression is strongly associated with fibroblast activation in the pressure-overloaded RV. Inhibiting Snail with BMPR2 pathway modulators is a promising approach to improve RV function in the pressure-overloaded RV.
Abstract 17617: Toward Improving Diagnosis and Interventional Predictability in Aortic Valve Stenosis Using Computational Modeling
Authors: Vijay Govindarajan, Nils Johnson, Krishnan B Chandran, David D McPherson
Journal: Circulation (2023)

Introduction: Watchful waiting for symptoms or critical hemodynamics to intervene on aortic stenosis (AS) may delay too long. While stress tests can detect symptoms in allegedly asymptomatic AS patients, image-based computations based on advanced modeling techniques can provide critical biomechanical insights. Hypothesis: Advanced computational modeling techniques utilizing patient data backed by high-performance computing can inform a personalized understanding of disease progression, diagnosis, and anticipated post-op hemodynamics to predict interventional efficacy. Methods: A validated in-house Fluid-structure Interaction (FSI) algorithm that allows easy translation of patient-specific anatomies was utilized to perform "virtual stress test" on a moderate AS with increasing LV contraction to predict systolic ejection dynamics under stress. TAVR was virtually implanted and post-op aortic hemodynamics were quantitatively compared with pre-op (diseased) data. Results: Predictions demonstrated that that aortic flow turbulence in moderate AS (Re = 11,700) during exercise (115 bpm) can be similar to severe AS (Re=10,000) at rest (70 bpm) resulting in a greater dissipation losses rising linearly with heart rates. As LV contraction rose, each valve cusp underwent a distinct non-linear rise (&gt;100%) in mechanical stresses that can accelerate calcification. Interestingly, our evaluation revealed that the heterogenous ΔP vs. Q relationship in AS observed clinically can be attributed to a non-linear rise in aortic valve area occurring during mid-systole. Aortic hemodynamics improved post-TAVR by reducing dissipation losses by ~11 fold and restoring near-normal peak-systolic velocity (1.7 m/s) in the ascending aorta. Conclusions: High-performance based multi-physics algorithms incorporating patient data might offer comprehensive biomechanical insights into diagnosis and interventional suitability for aortic valve stenosis.
Abstract 15818: Association of Clonal Hematopoiesis of Indeterminate Potential With Incident Heart Failure With Preserved Ejection Fraction
Authors: Michael C Honigberg, Alex P Reiner, Mary Roberts, Charles Kooperberg, Pinkal Desai, Alexander G Bick, Pradeep Natarajan, JoAnn E Manson, Eric A Whitsel, Charles Eaton
Journal: Circulation (2023)

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) is the age-related expansion of blood cells with somatic mutations, most commonly in DMNT3A , TET2 , and ASXL1 . CHIP is a risk factor for coronary heart disease as well as heart failure (HF). Experimental HF models suggest a role of CHIP pro-inflammatory myeloid cells on cardiac dysfunction via fibrotic remodeling and hypertrophy. However, whether CHIP associates with incident HF with preserved ejection fraction (HFpEF), HF with reduced ejection fraction (HFrEF), or both is currently unknown. Hypothesis: We hypothesized that CHIP is more strongly related to HFpEF than HFrEF. Methods: We studied a multiethnic sample of postmenopausal women without prevalent HF from the Women’s Health Initiative (WHI). Whole genome sequencing was performed through the NHLBI TOPMed Program, and CHIP was detected based on 74 pre-specified myeloid driver mutations. Participants were followed through March 2020 with physician adjudication of HFrEF and HFpEF. Cox models tested the association of CHIP with incident HFpEF and HFrEF with adjustment for demographic/clinical risk factors and inverse probability weighting to account for the TOPMed sampling scheme. Results: Among 5,214 women, the mean age was 62 years, and 7.8% had CHIP. Over a median follow-up of 15 years, age-adjusted HFpEF incidence rates were 5.86 (95%CI 5.63-6.10) vs. 3.72 (95%CI 3.68-3.77) per 1,000 person-years among CHIP carriers vs. non-carriers. After multivariable adjustment, CHIP was associated with a 42% increased risk of incident HFpEF (HR 1.42, 95%CI 6-91%; P =0.02). In contrast, there was no evidence of association between CHIP and HFrEF ( Table 1 ). HFpEF was more strongly associated with TET2 CHIP (HR 2.50, 95%CI 1.54-4.06; P &lt;0.001) than with DNMT3A or ASXL1 ( Table 1 ). Conclusions: CHIP, especially TET2 CHIP, is associated with incident HFpEF. This finding has potential precision medicine implications for HFpEF prevention and treatment.
Abstract 160: Atrial Fibrillation After Cardiac Arrest is Associated With Increased Risk of Mortality and Stroke
Authors: Kristen Curtis, Aleksander Dombrowski, Steven Wisniewski, Laken Irish, Soufian Almahameed, Ohad Ziv, Joseph S Piktel, Kenneth R Laurita, Lance D Wilson
Journal: Circulation (2023)

Introduction: The presence of atrial fibrillation (AF) in the first 2 days after resuscitation from cardiac arrest has been associated with increased mortality. However, whether new onset AF diagnosed in the first days to weeks after ROSC is associated with mortality or stroke is unknown. Our aim was to determine the incidence of new AF diagnoses after cardiac arrest and its impact on mortality and ischemic stroke. Methods: Retrospective observation cohort study using COSMOS, an Epic-based EHR database with &gt;190 million deidentified patients from 5/18/2020 to 4/1/2023. Patients with an ICD-10 diagnosis of cardiac arrest (ICD-10 I46.*) without prior history of AF were included. Two groups were examined: 1) AF diagnosis (ICD 10 I48*) made within 48 hours and 2) within 14 days after index cardiac arrest. We examined mortality and incidence of ischemic stroke at 1, 3, 6, and 12 months. Statistical comparisons were made using Chi-squared analysis. Results: Among 410,850 cardiac arrest patients without prior history of AF, 16,498 received a new AF diagnosis within 14 days (4%). The mean age was 68 yrs. with 64% male, 72% white. Mortality at one year in patients who developed AF by post-arrest day 14 was 54.5% vs. 39.5% in patients with no AF diagnosis (p&lt;.00001). The one-year incidence of stroke in patients with AF at 48 hours was 7.9%, similar to patients who had AF at 14 days (7.3%, p=NS). Moreover, stroke was diagnosed within 14 days of cardiac arrest in 5.4% of AF patients. Importantly, in these patients with stroke, 7% received anticoagulation with warfarin or direct oral anticoagulation, while the remaining 93% were not anticoagulated (p&lt;.00001), suggesting that consideration of early anticoagulation is imperative. Conclusion: AF diagnosed after cardiac arrest is associated with increased mortality. Patients who develop AF after cardiac arrest have significant short and long-term ischemic stroke risk, which is markedly decreased by anticoagulation. These data suggest that vigilance is required for patients who develop persistent AF after cardiac arrest, particularly stroke risk and prevention, as well as the consideration of an early rhythm control strategy.
Abstract 17810: Sustained Natural Heart Regeneration After Myocardial Infarction in One-Week-Old Rats Without Significant Cardiomyocyte Proliferation
Authors: Hanjay Wang, Hye Sook Shin, Stefan Elde, Danielle Mullis, Sabrina Walsh, Seung Hyun Lee, Camille Hironaka, Haley Lucian, Akshara Thakore, Nicholas Tran, Jinsuh Jung, Matthew Wu, Yuanjia Zhu, Y Joe Woo
Journal: Circulation (2023)

Introduction: Newborn mammals are capable of natural heart regeneration after cardiac injury during the first week of life, but whether a decline in cardiomyocyte (CM) proliferation directly leads to the loss of regenerative potential is unknown. We hypothesized that, after myocardial infarction (MI) in neonatal rats, the extent of regeneration is directly correlated with the degree of CM proliferation. Methods: Neonatal Wistar rats, including both males and females, underwent left coronary artery ligation to induce MI on postnatal day 1 (P1, n=12), day 7 (P7, n=14), day 8 (P8, n=14), or day 9 (P9, n=15). Sham surgery was performed at each age (n=14, 13, 12, 16, respectively). CM proliferation was assessed using Ki67 staining in a subset of each age group, sacrificed 1 week after MI (n=4, 3, 5, 4) or sham surgery (n=4, 3, 3, 5). At 9 weeks post-MI, echocardiography was performed, and the hearts were explanted for Masson’s trichome staining. Results: At 9 weeks after surgery, left ventricular (LV) end-diastolic diameter (Fig 1A) and ejection fraction (EF, Fig 1B) were similar for P1 MI vs P1 sham (EF 62.5±5.2% vs 62.4±3.3%, p=0.941), as well as for P7 MI vs P7 sham (EF 61.4±3.3% vs 63.3±3.3%, p=0.210), consistent with robust natural regeneration. Progressive LV remodeling, dysfunction, and scar formation were observed after P8 MI (EF 50.1±2.6% vs 63.5±3.6%, p&lt;0.001) and P9 MI (EF 39.4±3.4% vs 63.1±3.9%, p&lt;0.001), but minimal scar was observed after P1 MI and P7 MI (Fig 1C). While the proportion of Ki67-positive CM was increased after P1 MI vs P1 Sham (4.0±2.0% vs 0.5±0.5%, p=0.013), CM proliferation was not significantly increased after P7 MI (1.0±0.4% vs 0.3±0.4%, p=0.105), or after P8 or P9 MI (Fig 1D). Conclusions: In rats, CM proliferation is not significantly stimulated after P7 MI, but the hearts develop with preserved geometry, normal function, and minimal infarct. Further studies are needed to examine non-CM-related mechanisms influencing the extent of natural heart regeneration.