bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 20928: Non-Invasive Mitochondrial Modulation: A Novel Approach to Reduce Brain Injury Following Cardiac Arrest
Authors: Sanderson Thomas H , Wider Joseph M , Gruley Erin , Reynolds Christian A , Przyklenk Karin , Lee Icksoo , Huttemann Maik
Published: March 2022

Loss of oxygen delivery to the brain during cardiac arrest can promote significant brain injury. While prompt resuscitation is critical, the reintroduction of oxygen can potentiate injury by promoting reactive oxygen species (ROS) generation. While mitigating ROS damage may serve as a therapeutic avenue for cerebral reperfusion injury, traditional attempts to scavenge ROS have failed. This failure is thought to be due to inherent difficulties with delivery to the brain and sub-cellular targets within the early minutes of reflow. We found that specific infrared light (IRL) wavelengths penetrate the brain and reversibly reduce the activity of cytochrome c oxidase (CcO). Accordingly, we developed a non-pharmacologic therapy using specific IRL wavelengths to non-invasively modulate CcO and circumvent these delivery barriers. Our previous data shows that IRL wavelengths that reduce CcO activity also directly modulate mitochondrial respiratory rate and membrane potential, block mitochondrial ROS production, and limit neuronal death following oxygen-glucose deprivation. We hypothesized that these wavelengths could be used to inhibit ROS generation following resuscitation from cardiac arrest and thus, provide neuroprotection. IRL therapy was first evaluated for neuroprotection in the rat model of global brain ischemia (bilateral carotid occlusion and systemic hypotension - 8 minutes). Rats were randomly enrolled into IRL treatment groups, initiated immediately upon reperfusion. After 14 days, animals subjected to ischemia demonstrated an 86% loss of neurons in the CA1 hippocampus. Strikingly, for the IRL-treated animals, loss of neurons was significantly less, ranging from 17% with the best treatment to 35% with the least efficacious regimen (n=8-12, p<0.05) and preserved neurologic function, assessed by radial arm maze (n = 10, p<0.05). Finally, preliminary data from a swine model of cardiac arrest/resuscitation show a reduction in neurologic deficit score (0-150 scale 0=no deficit, 150=brain dead) with IRL treatment (Cardiac Arrest/Resuscitation = 112, Cardiac Arrest/Resuscitation + IRL treatment = 1: N = 4-6/group). These data demonstrate that IRL therapy may provide a novel strategy for the treatment of post-cardiac arrest brain injury.
Abstract 20940: PKA-Phosphorylation of Hsp20 Promotes Cardiac Fibrosis Through Upregulation of IL-6
Authors: Gardner George , Travers Josh , Liu Guan-Sheng , Qian Jiang , Jiang Min , Robbins Nathan , Rubinstein Jack , Blaxall Burns , Fan Guo-Chang , Kranias Evangelia
Published: March 2022

Introduction:
Heat shock protein 20 (Hsp20) is the only small heat shock protein that can be phosphorylated by PKA upon β-adrenergic stimulation. Interestingly, phosphorylation of Hsp20 is highly elevated following I/R injury and in human heart failure. However, the functional significance of this phosphorylation
in vivo
is currently unclear.

Results:
Transgenic lines with cardiac overexpression of constitutively phosphorylated Hsp20 (S16D) were generated and we chose one with 10-fold overexpression to mimic the levels observed in human failing hearts. Longitudinal assessment of cardiac function via echocardiography indicated significantly reduced LVEF in S16D mice starting at 3 months of age which progressed to heart failure and early lethality (50% dead by six months). Histological examination revealed interstitial fibrosis as early as 2 months with no evidence of apoptosis. To elucidate the mechanisms underlying fibrosis in S16D hearts, we performed cardiomyocyte-fibroblast crosstalk experiments. Adult mouse cardiomyocytes were infected with GFP, S16D or S16A-Hsp20, cultured for 48 hours, and their supernatant was then used to culture adult mouse fibroblasts. S16D-cultured fibroblasts exhibited enhanced proliferation as well as pro-fibrotic signaling (increased expression of α-SMA, TGF-β and collagen as well as cytokines IL-6 & IL-1β), while GFP or S16A-cultured fibroblasts showed no alterations. At the sub-cellular level, Stat3 phosphorylation and nuclear translocation was increased in S16D-cultured fibroblasts. These pro-fibrotic effects were associated with increased expression and secretion of IL-6 from cardiomyocytes, which were inhibited by inclusion of an IL-6 neutralizing antibody to the S16D-myocyte supernatant upon fibroblast exposure. Consistent with our
ex-vivo
results, the cardiac levels of IL-6 as well as Stat3 activation were upregulated in S16D hearts at two months, concurrent with increased IL-6 levels in the serum.

Conclusion:
Phosphorylation of Hsp20 (P-Hsp20) in cardiomyocytes appears to contribute to fibrosis and ventricular remodeling via upregulation of IL-6. Thus, targeting the observed increases in failing hearts may hold therapeutic potential.
Abstract 20945: Improved Risk Prediction Using a Comprehensive Cta Risk Score That Incorporates All Aspects of Coronary Atherosclerosis Compared With Standard Cta Classification
Authors: van Rosendael Alexander R , Shaw Leslee , Xie Joe , Dimitriu-Leen Aukelien , Smit Jeff , Scholte Arthur , Min James , Bax Jeroen
Published: March 2022

Background:
Risk assessment with coronary CTA is traditionally done with maximal stenosis, but this approach does not use the prognostic value of plaque extent, location and composition. This study assessed whether a comprehensive CTA risk model incorporating all aspects of coronary atherosclerosis provides better risk stratification than the commonly used CTA classification of no CAD, non-obstructive and obstructive CAD.

Methods:
Among 2255 patients with suspected or known CAD the predictive value of the CTA risk score (range from 0-42) was compared with the standard CTA classification. Three risk groups were created based on their best discriminatory performance: 0-5; 6-20; >20.

Results:
During a mean follow up of 3.6 ± 2.8 years 156 events (death or MI) occurred. Compared with the standard CTA classification, a stronger association with events was observed for the CTA risk score: adjusted HR for 6-20 was: 2.69 (95% CI: 1.55-4.68, P<0.001) and 5.53 (95% CI: 2.82-10.82, P<0.001) for a score > 20 By comparison, adjusted HR for non-obstructive CAD were 1.19 (95% CI: 0.61-2.29, P=0.613) and for obstructive CAD 2.52 (95% CI: 1.33-4.78, P=0.005), Figure 1. Adding the score to a model with clinical variables and the standard CTA classification increased the c-statistic from 0.756 to 0.781 (P<0.001). Furthermore net reclassification analysis confirmed that the novel CTA risk score was able to correctly reclassify a significant proportion of patients compared with the standard CTA classification: categorical NRI 12% (7.4% for events, 4.6% for non-events) using three predicted risk categories 0-5%, 5-15% and >15%

Conclusion:
A CTA risk model incorporating all aspects of CAD provides better discrimination and reclassification of events compared with the standard CTA scoring model including normal, non-obstructive and obstructive CAD. The proposed model allows more precise risk estimation which may further guide patient treatment.
Abstract 20950: An Intrinsic Mechanism for a Gain in Proteasome Activity Preserving Cardiac Function
Authors: Trogisch Felix , Koser Franziska , Jungmann Andreas , Müller Oliver , Hecker Markus , Drews Oliver
Published: March 2022

Cardiac remodeling and heart failure are characterized by misaligned adaptations in protein synthesis and degradation, harboring the therapeutic potential for interventional harmonization. Partial inhibition of protein degradation via the ubiquitin-proteasome system was reported to reduce acute hypertrophic remodeling as well as recover systolic function. The studies are suggestive of an inadequate gain in proteasome activity, contributing to cardiac remodeling and heart failure.

Aim was to identify a common mechanism promoting proteasome activity during cardiac remodeling and heart failure and to test whether it contributes to the pathogenesis.

Incorporation of the inducible proteasome subunit Lmp2 has been described to increase proteasome activity. In fact, it is increasingly expressed and incorporated in proteasome complexes during isoproterenol-induced hypertrophic remodeling, which is associated with a gain in proteasome activity. We found that Lmp2 is also increasingly expressed upon transverse aortic constriction and in a murine model of familial hypertrophic cardiomyopathy. Knock-out (KO) of Lmp2 in mice increased the caspase-like proteasome activity by 19% (n=5, p<0.05), but had no apparent influence on cardiac morphology or function. As predicted, lack of Lmp2 confined the regulatory capacity of proteasomes to gain activity during hypertrophic remodeling induced by isoproterenol. Unexpectedly, the restriction in additional activity did not reduce cardiac remodeling as previously described for proteasome inhibition. In contrast, lack of Lmp2 exacerbated hypertrophic remodeling and caused loss of systolic function (fractional shortening: -32% vs. wildtype, n≥8, p<0.01). Cardiomyocyte-specific expression of Lmp2 via gene transfer into adult Lmp2 KO mice completely rescued the isoproterenol-induced deterioration of cardiac remodeling and function. Interestingly, the deprived gain in proteasome activity in Lmp2 KO hearts rather affected a specific subset than the general pool of ubiquitinated proteins.

In conclusion, a gain in proteasome activity during acute cardiac remodeling is not entirely maladaptive. At least in part, it is dependent on Lmp2, controlling remodeling and preserving cardiac function.
Abstract 20959: Inhibition of Shp2 Ameliorates Systemic Lupus Erythematosus-Associated Cardiac Pathogenesis
Authors: Wang Jianxun , Zeng Li-Fan , Zhang Zhong-Yin , Kontaridis Maria
Published: March 2022

Introduction:
Systemic lupus erythematous (SLE) is a devastating autoimmune disorder affecting multiple tissues, including heart. However, the molecular mechanisms that cause cardiac effects in SLE remain unclear.
PTPN11
, the gene encoding the SH2 domain-containing protein tyrosine phosphatase SHP2, is critical for development and is the first tyrosine phosphatase known to have a functional role in the adult heart. Moreover, gain-of-function mutations in SHP2 have been associated with onset of SLE. Here, sought to identify the mechanistic role for SHP2 in the cardiac pathogenesis of SLE.

Methods and Results:
We analyzed hearts from 18-week old female MRL/lpr (SLE-prone) and MRL/MpJ (control) mice. As compared to controls, MRL/lpr hearts showed substantial interstitial fibrosis and had elevated numbers of infiltrated CD11b
+
leukocytes. Moreover, MRL/lpr hearts displayed decreased fractional shortening and enlarged chamber dimensions, as measured by echocardiography. MRL/lpr heart lysates revealed significantly elevated SHP2 phosphatase activity, as compared to controls. Immunoprecipitation of SHP2 from MRL/lpr hearts revealed Focal Adhesion Kinase (FAK) in complex with SHP2. FAK is required to maintain cardiac function under conditions of stress. Significantly, SHP2 is a negative regulator of FAK, suggesting SHP2 may be involved in cardiac pathogenesis through dephosphorylation of FAK. Here, MRL/lpr heart lysates had decreased pY397-FAK activity, in conjunction with decreased p-ERK levels, suggesting that SHP2 may play a role in cardiac pathogenesis of SLE through aberrant FAK -mediated regulation of ERK. To test whether higher SHP2 activity contributes to the cardiac pathogenesis in lupus, we utilized a potent SHP2 inhibitor, 11a-1, to treat MRL/lpr mice for 6 weeks starting at 12 weeks of age. Hearts from these mice displayed improved cardiac structure and function, with reduced chamber dimensions, had decreased numbers of CD11b
+
leukocytes and lessened cardiac fibrosis. Moreover, pY397-FAK and p-ERK activities were both nearly normalized in response to treatment with the SHP2 inhibitor.

Conclusion:
These data suggest that SHP2 affects cardiac pathogenesis in SLE hearts through regulation of FAK and ERK signaling.
Abstract 20965: Use of Plasma Ceramides to Predict Major Adverse Cardiovascular Events - A Community-Based Analysis
Authors: Medina-Inojosa Jose R , Meeusen Jeffrey , Allan Jaffe , Donato Leslie , rodeheffer Richard J , Lopez-Jimenez Francisco
Published: March 2022

Introduction:
Plasma ceramides (CER) are sphingolipids associated with adverse events and mortality in patients with established coronary artery disease (CAD) and/or risk factors for CAD. The ability of these same specific ratios of CER to predict major adverse cardiovascular events (MACE) in subjects without CAD in the community is less certain. We tested the hypothesis that CER are associated with MACE in a community-based cohort free of CAD at enrollment.

Methods:
In a prospective community-based cohort we performed passive follow-up using a record linkage system to ascertain the composite outcome of MACE, defined as acute myocardial infarction, coronary revascularization (coronary artery bypass grafting or percutaneous coronary intervention), stroke or death. CER were analyzed as continuous variables, ratios and quintiles adjusting for potential confounders.

Results:
We included 1221 subjects, 49% males, mean age ± (SD) 61.1±9.6 years. After a median follow-up of 16 years (IQR 1.7), 297 patients had a MACE: Myocardial infarction (105), coronary artery bypass surgery (53), percutaneous coronary intervention (92), stroke (137) and all-cause death (120). Some had more than one event. Ratios of CER were significantly associated with MACE in unadjusted and adjusted models, see
Figure 1-A.
This association was independent of LDL-C, total cholesterol, Apo-B and traditional CAD risk factors. Those in the highest quintile of (24:1/24:0) CER ratio had more than two-fold risk of MACE, HR 2.32 (95% CI, 1.59-3.46). There was a dose-response association across quintiles of CER ratios and MACE,
Figure 1-B.:

Conclusions:
Elevated CER plasma ratios are associated with MACE in patients with no CAD in the community. The risk conferred by plasma CER is independent of traditional risk factors, including lipids, and has a dose-response.
Abstract 20967: Outcomes and Prevalence of Migraines in Patients With Spontaneous Coronary Artery Dissections: A Cohort Study
Authors: Kok Susan N , Hayes Sharonne N , Cutrer F. Michael , Gulati Rajiv , Best Patricia J , Tweet Marysia S
Published: March 2022

Background:
Spontaneous coronary artery dissection (SCAD) is a nonatherosclerotic cause of myocardial infarction (MI) occurring most often in young women without cardiovascular disease (CVD) risk factors. SCAD is associated with fibromuscular dysplasia (FMD), pregnant/postpartum state, and extreme mental stress or physical exertion. Migraine headaches have been reported common in SCAD and may increase CVD risk. The objective was to assess differences in presentation, clinical factors, and outcomes in SCAD patients with migraines (M-SCAD) compared to those without, and determine M-SCAD prevalence.

Methods:
A retrospective cross-sectional observation study of patients with angiographically confirmed SCAD was conducted using the Mayo Clinic SCAD Registry. Participant-provided data and records were reviewed for migraine history, CVD risk factors, SCAD details, CVD and migraine therapies, and outcomes. Ordinal and nominal variables were compared using Pearson's chi squared test, and continuous variables were compared using Student's t-test. Statistical significance was set at p < 0.05.

Results:
Among 586 patients with complete questionnaires, 236 had a history of migraines; the lifetime and 1-year prevalence of migraines were 40% and 27% respectively. Migraines are more common in SCAD survivors than a comparable population (40% vs 33%, p=0.0002). M-SCAD patients were more likely to be female (99.6% vs 94%, p=0.001), have SCAD at a younger age (45.3 yrs. vs 47.6 yrs., p=0.004), and report a history of aneurysms (7.6% vs 1.7%, p=0.0004), 46% of which occurred in head or neck vessels. There was a trend toward increased head and neck FMD in M-SCAD (32% vs 23%, p=0.095). Prevalence of depression (27% vs 17%, p=0.005), anxiety (32% vs 24%, p=0.038), recurrent angina (62% vs 44%, p=<0.001) and concern for recurrent SCAD (46% vs 37%, p=0.034) were higher in M-SCAD. Triptans were stopped in 39% of migraineurs at the time of MI.

Conclusion:
As compared to SCAD survivors without migraines, those with M-SCAD are younger, more often report a history of depression, anxiety, and aneurysms, and have more chest pain after SCAD. Further investigation into this association and development of safe, effective treatments of both headache and angina after SCAD is needed.
Abstract 20994: Sedentary Behavior Independently Predicts Mortality in the Pacemaker Population
Authors: Cohen Katie E , Tyagi Sudhi , Kapoor Ridhima , Berger Marcie , Fox Judy , Strath Scott , Roth James , Oujiri James , Rubenstein Jason , Kluge Nicholas , Widlansky Michael
Published: March 2022

Introduction:
Embedded accelerometers offer a novel method of measuring physical activity levels in the pacemaker population. In an initial cohort of 96 subjects with pacemakers, we previously showed sedentary behavior significantly correlates with decreased survival. We hypothesize that physical activity of < 2 hours/day correlates with mortality independently of the traditional cardiovascular risk factors in an expanded cohort.

Methods:
Records of 273 individuals with
de novo
Medtronic pacemaker implantation at a single center between January 1, 2005 and December 31, 2012 were reviewed. An accelerometer embedded in these devices measures activity level as above or below a 70 steps/minute threshold and reports the average hours/day of activity exceeding this threshold. Activity levels abstracted from pacemaker interrogations were averaged over a 1 year period following a 6-month blanking period after implantation. Among this cohort, 48.7% were categorized as having failed to reach the activity threshold for ≥2 hours/day (n=140). Survival was compared between groups by Kaplan-Meier estimate and Cox proportional hazards models. Multivariable logistic regression examined predictors of survival.

Results:
The average age of the study cohort was 71±13 years with CAD prevalent in 34.1% of subjects. Average follow-up time was 3.67±2.43 years. Death occurred in 40 subjects (14.7%). In unadjusted analysis, death was nearly 5 times more likely in the inactive group than the active group [OR 4.81, 95% CI (2.13-10.88), P<0.001]. A multivariate model revealed that < 2 hours of daily activity remained an independent predictor of death [OR 4.39, 95% CI (1.90-10.12), P=0.001] along with age [OR 1.04, 95% CI (1.01-1.08), P=0.02] while sex [OR 0.09, P=0.74] and CAD [OR 0.54, P=0.08] were not predictors.

Conclusion:
Sedentary behavior as measured by an implanted pacemaker correlates with increased mortality independently of traditional cardiovascular risk factors.
Abstract 21000: Interaction Between Mineralocorticoid Receptor Antagonist and Soluble ST2 in Heart Failure With Preserved Ejection Fraction
Authors: Sugano Akinori , Seo Yoshihiro , Ishizu Tomoko , Yamamoto Masayoshi , Aonuma Kazutaka , Iesaka Yoshito , Nogami Akihiko
Published: March 2022

Background:
Mineralocorticoid receptor antagonist (MRA) has a potential to improve clinical outcomes in heart failure with preserved ejection fraction (HFpEF), since MRA inhibits progression of myocardial hypertrophy and fibrosis. Soluble ST2 (sST2) is a novel biomarker reflecting myocardial stress and fibrosis. MRA plays a role in the interleukin-33/ST2 signaling modulation.

Hypothesis:
We hypothesized that the effect of MRA on clinical outcomes in HFpEF differed by sST2 level. This study aimed to evaluate the relationship between sST2 and clinical outcomes and to test for an interaction between the effect of MRA and sST2 level.

Methods:
191 patients with acute decompensated HF and EF ≥50% were prospectively enrolled. The primary endpoint was major adverse cardiovascular events (MACE), which included death from cardiovascular disease, unplanned hospitalization for heart failure, acute coronary syndrome and stroke.

Results:
During follow-up (421±258days), 53 patients (27.7%) met endpoints. In a multivariable analysis, use of MRA and sST2 level were significantly associated with the endpoint (HR 0.48, 95%CI 0.26-0.86, P=0.01, HR 1.02, 1.01-1.03, P=0.01). Patients were divided into 4 groups according to use of MRA and a cutoff value of sST2 (18.5 ng/ml) determined by ROC analysis. Estimated event rate for MACE were significantly higher in patients without MRA compared with those in patients with MRA regardless of category of sST2 level. In a multivariable analysis, MRA was not a significant predictor of outcome in high sST2 group (HR 0.62, 0.28-1.30, P=0.21), whereas MRA was significantly associated with improved outcome in low sST2 group (HR 0.37, 0.13-0.91, P=0.03).

Conclusion:
The present study showed that higher sST2 level was associated with worse prognosis and predictive of less response to MRA treatment in patients with HFpEF, which suggests that sST2 may be used to predict response to MRA treatment.
Abstract 21007: Role of Thick Fibrotic Tissue in the Left Atrium on the Outcome of Atrial Fibrillation Ablation
Authors: Kheirkhahan Mobin , Baher Alex , Siebermair Johannes , Kaur Gagandeep , Steinberg Benjamin A , Han Frederick T , Chelu Mihail G , Marrouche Nassir F
Published: March 2022

Introduction:
Left Atrial (LA) Fibrosis may serve as a substrate for Atrial Fibrillation (AF) and the total percentage of LA fibrosis affects the outcome of ablation therapy. But the role of “thick” (transmural or near transmural) fibrotic tissue, as opposed to superficial fibrosis, in the AF prognosis is not well studied. We assess the amount of LA wall fibrosis thickness on AF ablation outcome.

Methods and Results:
Patients’ parameters were obtained from DECAAF trial. LA fibrosis was quantified with Late Gadolinium Enhancement MRI (LGE-MRI) and when within LA myocardium, 3 or more voxels (each voxel = 0.625mm) were enhanced that area was considered as thick fibrotic tissue. First Cox regression was devised to measure the impact of thick fibrosis on the outcome of AF ablation. Then patients were divided into 2 groups: First group with more than 3.89% of thick LA fibrosis and the second group with less than that. This cut-off was achieved through Receiver Operation Curve analysis of our cohort. Patients were 58.9 ± 10.9 of age and their amount of thick LA fibrosis was 3.5% ± 2.4%. The result of Cox regression showed: 1% increase in the extent of thick LA fibrosis, the recurrence rate of AF increases by 20% after ablation. (HR = 1.2, CI 95% = 1.1 - 1.3, P < 0.0001). The first and second group matched in terms of age, gender, LA volume, and co-morbidities. The first group were 2.9 times more at risk for AF recurrence after the ablation (CI95% = 1.9 - 4.5, P < 0.001) and they had a significantly lower chance of remaining AF free after ablation (0.385 vs 0.621, P < 0.0001)

Conclusions:
We found the percentage of LA wall fibrosis thickness to correlate with a worse AF ablation outcome and an increased risk of AF recurrence. Therefore assessing percentage of thick fibrotic tissue within LA wall may be of a greater interest than assessing total percentage of fibrosis.
Abstract 21008: Effects of Coronary Artery Revascularization With Biofreedom Stent Before Elective Surgery
Authors: Kim Kyu , Jang Ji Yong , Her Ae-Young , Hong Sung-Jin , Ahn Chul Min , Kim Jung-Sun , Ko Young-Guk , Choi Donghoon , Hong Myeon-Ki , Jang Yangsoo , Kim Byeong-Keuk
Published: March 2022

Introduction:
The role of Biofreedom (polymer-free drug coated) stenting compared to coronary artery bypass graft (CABG) for coronary artery revascularization before elective surgery is unclear.

Hypothesis:
Biofreedom stent might be associated with better outcomes than CABG.

Methods:
Between January 2016 and Mar 2017, a total of 21 patients underwent percutaneous coronary intervention with Biofreedom stents before elective surgery (Biofreedom group) and 19 patients underwent CABG in the retrospective, multicenter cohort and we compared clinical outcomes between the Biofreedom group and CABG group. Primary outcomes were the period of planned operation after revascularization and the occurrence of the composite clinical endpoints (including death from any causes, myocardial infarction, stent thrombosis, stroke, any revascularization, or major bleeding).

Results:
During follow-up (mean 276.2± 134.3 days), all patients of Biofreedom group underwent planned surgery without delay, but 73.7% of patients in CABG group underwent surgery (p=0.04). Comparing the time to planned surgery, the Biofreedom group showed a greater incidence of performing surgery within 45 days than with CABG (72.7 vs. 31.6%, p=0.02). The Biofreedom group maintained a shorter duration of dual antiplatelet therapy (DAPT) (32.0 ± 10.0 vs 97.8 ± 88.3, p=0.005). During the entire treatment period, incidence of major bleeding after revascularization was significantly lower in Biofreedom group than CABG group (0% vs. 36.8%, p=0.007). There were no occurrence of death or stent thrombosis in the Biofreedom group. The Biofreedom group showed a significantly lower occurrence of primary outcome (7.2% versus 54.8%, HR 0.11, 95% CI 0.01 to 0.93, p=0.01, mainly due to the lower incidence of major bleeding after intervention). However, the statistical significance was not reached when only the perioperative period was observed.

Conclusions:
Biofreedom stent was associated with higher rate of performing planned surgery, shorter DAPT duration and lower incidence of major bleeding without increasing the risks of major cardiac event after surgery. In patients requiring coronary artery revascularization prior to elective surgery, Biofreedom stent might be a good treatment option.
Abstract 21022: Increasing Cav1.2 in Smooth Muscle Cells Induces Both Systemic and Pulmonary Hypertension via Inhibiting Endothelium-Dependent Relaxation
Authors: Zhou Jian , Zhang Xiaoying , Zhang Ying , Chen Zhongjian , Wang Hong , Chen Xiongwen
Published: March 2022

Introduction:
Local activation of the L-type Ca
2+
channel (Cav1.2) in smooth muscle cells (SMCs) may activate big- and small- conductance K
+
channels, leading to hyperpolarization of the cell and vascular relaxation; however, large-scale activation of Cav1.2 increases cytosolic Ca
2+
to enhance muscle contraction.

Hypothesis:
We are testing if and how increasing Cav1.2 in SMCs causes systemic and pulmonary hypertension.

Methods:
Systemic blood pressure in conscious mice were measured with telemetric blood pressure system. Intra-ventricular hemodynamics of the LV and RV were determined in 6-month old SMC-specific Cavβ2a transgenic and control mice. Whole heart, LV and the right ventricular (RV) hypertrophy was assessed by heart weight (HW)/body weight (BW), LV weigth/BW, RV weight/BW, and RV-to-left ventricle+septum (RV/LV+S) ratio. Lung and heart sections were stained with H&E. Mesenteric arteries were isolated for evaluating small arterial contractility and relaxation.

Results:
SMCs from the cerebral iddle arteries of TG mice had increased ICa (by 98.5±5.4%) vs. control. Conscious TG mice had significantly higher systemic systolic (TG vs. control: 145.4±12.1mmHg, n=45 vs. 115.2±7.4mmHg, n=16 ) and diastolic (TG vs control: 116.7±9.1mmHg, n=45 vs. 87.8±8.2mmHg, n=16) pressure (telemetry). Intra-ventricular hemodynamics (anesthestized) showed significantly increased systolic and diastolic pressure in both the LV (systolic: TG vs control: 120.2±7.3mmHg, n=17 vs. 82.3±7.2mmHg, n=16) and RV (systolic: TG vs control: 60.5±6.8mmHg, n=10 vs. 20.4±4.9mmHg, n=9). HW/BW, LV/BW, RV/BW, and RV/LV+S was higher in TG mice than in control mice. Small arteries in the lungs and the heart had increased wall thickness. Mesenteric arteries from TG mice had similar maximum contractility upon 40mM KCl stimulation. Acetylcholine induced relaxation but not NO-depedent relaxation was impaired in TG mesenteric arteries. Western blot and immunostaining showed less small- and large-conductance Ca
2+
-activated K
+
channels in the TG endothelium.

Conclusions:
Excessive calcium ion (Ca
2+
) influx through L-type Ca
2+
channels can lead to both systemic and pulmonary arterial hypertension due to impairment of endothelium-dependent relaxation.
Abstract 21023: Population Attributable Risk for Cardiovascular Disease Associated With Hypertension and Prehypertension in African Americans: The Jackson Heart Study
Authors: Clark Donald , Min Yuan-I , Hall Michael E , Mentz Robert J , Yano Yuichiro , Shimbo Dachi , Colantonio Lisandro D , Ogedegbe Gbenga , Jones Daniel W , Correa Adolfo , Muntner Paul
Published: March 2022

Introduction:
African Americans are disproportionately affected by hypertension (HTN) and cardiovascular disease (CVD). Determining the population attributable risk (PAR) for CVD associated with HTN and prehypertension in African Americans can help inform policymakers and prioritize public health interventions.

Methods:
Among 3770 participants in the Jackson Heart Study without prevalent CVD, we used Cox-proportional hazard analysis adjusted for traditional CVD risk factors to determine the association of HTN and prehypertension with incident CVD and its components including coronary heart disease, heart failure, and stroke. The PAR was calculated as pd*(HR-1)/HR; where pd is the prevalence of the exposure and HR is the hazard ratio for the outcome associated with the exposure. HTN was defined as a systolic blood pressure (SBP) ≥140 mmHg, diastolic blood pressure (DBP) ≥90 mmHg, or self-reported antihypertensive medication use and prehypertension as SBP of 120 to 139 mmHg or DBP of 80 to 89 mmHg.

Results:
At baseline, 52.4% of the cohort had HTN and 77.1% had prehypertension or HTN. Over a median of 9.9 years follow-up, 349 (9.3%) participants developed CVD. The HR for CVD and PAR associated with HTN was 2.17 (95% CI 1.63, 2.89) and 0.28 (95% CI 0.20, 0.35), respectively (Table). The HR for CVD and PAR associated with HTN and prehypertension pooled together was 2.21 (95% CI 1.41, 3.47) and 0.42 (95% CI 0.25, 0.56), respectively. In the pooled group there were significant associations with incident coronary heart disease, heart failure, and stroke. Sex-specific sensitivity analysis demonstrated PAR for CVD associated with HTN and prehypertension was 0.40 (95% CI 0.07, 0.62) in men and 0.43 (95% CI 0.19, 0.61) in women.

Conclusions:
Approximately 40% of incident CVD is attributable to HTN and prehypertension among African Americans in the southeastern United States. Preventing HTN and prehypertension in this population is a major public health priority.
Abstract 21025: Wnt/beta Catenin Signaling Regulates Lymphatic Vascular Development
Authors: Srinivasan Sathish , Cha Boksik
Published: March 2022

Lymphatic vasculature regulates fluid homeostasis by returning interstitial fluid to blood circulation. Lymphatic endothelial cells (LECs) are the building blocks of the entire lymphatic vasculature. LECs originate as a homogeneous population of cells predominantly from the embryonic veins and undergo stepwise morphogenesis to become the lymphatic capillaries, collecting vessels or valves. The molecular mechanisms underlying the morphogenesis of the lymphatic vasculature remain to be fully understood. Here we show that canonical Wnt/β-catenin signaling is necessary for lymphatic vascular morphogenesis. Lymphatic vascular-specific ablation of β-catenin in mice prevents the formation of lymphatic and lymphovenous valves. Additionally, lymphatic vessel patterning is defective in these mice, with abnormal recruitment of mural cells. We found that oscillatory shear stress (OSS), which promotes lymphatic vessel maturation, triggers Wnt/β-catenin signaling in LECs. In turn, Wnt/β-catenin signaling controls the expression of several molecules, including the lymphedema-associated transcription factor FOXC2. Importantly, FOXC2 completely rescues the lymphatic vessel patterning defects in mice lacking β-catenin. Thus, our work reveals that mechanical stimulation is a critical regulator of lymphatic vascular development via activation of Wnt/β-catenin signaling and, in turn, FOXC2.
Abstract 21029: Achieving High Retention in Mobile Health Research Using Design Principles Adopted From Widely Popular Consumer Mobile Apps
Authors: Tison Geoffrey H , Hsu Kaiyu , Hsieh Johnson T , Ballinger Brandon M , Pletcher Mark J , Marcus Gregory M , Olgin Jeffrey E
Published: March 2022

Introduction:
While mHealth platforms can enable rapid participant recruitment, the first 5 ResearchKit apps retained less than 10% of daily participants after the first 90 days, whereas well-optimized consumer mobile apps like Instagram and Twitter retain 31% and 48%, respectively. We proposed to apply design principles from the world of consumer internet to achieve high engagement and retention in a mHealth study.

Methods:
We enrolled 14,011 users of Cardiogram for Apple Watch app into the Health eHeart Study, an IRB-approved study at UCSF. We applied 3 key design principles to drive engagement and retention. First, give valuable insights back to user—e.g., notify users of abnormal heart rate spikes, and show when exercise caused a lower resting heart rate trend—using Gottman’s ratio: for every negative insight, give 5 positive ones. Second, minimize latency so users’ data updates many times per day. Third, use simple user interfaces that easily visualize trends and provide insights in small digestible formats.

Results:
Mean age was 42.3 ± 12.1, 31% were women. Seven days after app install, 64% of participants were active; 63% were active after 30 days, and 54% after 90 days. Retention was consistent across age groups—day 90 retention was 52% for 20-40 y.o., 55% for 40-60, and 49% for above 60. Refreshing data as frequently as possible had the highest impact on user engagement—in A/B testing, where heart rate visualizations were updated less frequently, we saw 20.9% drop in daily active users (51951 to 41094) within 7 days. The ratio of daily to monthly active users, a key measure of engagement, is 69.8% in our study, while average mHealth app is 8%.

Conclusions:
By applying design techniques from consumer mobile apps, we achieved day 90 retention 5x higher than the best ResearchKit app, showing that mHealth studies can retain large cohorts of participants and collect unique ambulatory health data with high engagement, improving the impact of mobile health interventions.
Abstract 21031: Paroxysmal Supraventricular Tachycardia is Associated With Atrial Enhancement Detected With Late Gadolinium Enhanced MRI
Authors: Kheirkhahan Mobin , Baher Alex , Siebermair Johannes , Kaur Gagandeep , Steinberg Benjamin A , Han Frederick T , Chelu Mihail G , Marrouche Nassir F
Published: March 2022

Introduction:
Paroxysmal supraventricular tachycardias (PSVT) are among common cardiac arrhythmias. Atrial fibrosis correlates with several cardiac dysrhythmias and while its role is well described in atrial fibrillation, its role in PSVTs is less clear. We sought to investigate the extent of left atrial (LA) and right atrial (RA) enhancement in patients with supraventricular tachycardia (SVT) without a history of atrial fibrillation.

Methods and Results:
In our case-control study the information of 212 patients was collected. 30 patients with PSVT (age 48.6 ± 20.1 and 43% male) and 182 patients with no known arrhythmic disorder as the control group (age 50.3 ± 14.7 and 66% males) matched for age, LA volume, left ventricular ejection fraction (LVEF) and other comorbidities such as hypertension, hyperlipidemia, diabetes, coronary artery disease, heart failure, and smoking. LA and RA fibrosis were quantified by the Late Gadolinium Enhanced Magnetic Resonance Imaging (LGE-MRI) using signal intensity analysis. The average % LA wall enhancements were 15.2% ± 6.3% in the SVT group and 10.7% ± 6.5% in the control group (p = 0.001) while for RA enhancement they were 11.1% ± 5% and 8.1% ± 4.1% for the SVT and control groups respectively (p = 0.009). Our logistic regression analysis showed that for each 1% increase in LA and RA enhancement, there was a 19% and 16% greater chance of having PSVT (p = 0.006, p = 0.013 respectively).

Conclusions:
Our study suggests that the extent of atrial fibrosis (either in the left or right atrium), quantified using LGE-MRI, is higher among patients with PSVT. The impact of increased atrial fibrosis in this patient population, could be correlated with other major adverse cardiac events.
Abstract 21033: Effect of Baseline Antiarrhythmic Drug on Outcomes With Ablation in Ischemic Ventricular Tachycardia: A Vanish Substudy
Authors: Parkash Ratika , Nault Isabelle , Rivard Lena , Gula Lorne , Essebag Vidal , Nery Pablo , Tung Stanley , Raymond Jean-Marc , Sterns Laurence , Doucette Steve , Wells George , Tang Anthony , Stevenson William , Sapp John
Published: March 2022

Introduction:
The VANISH trial enrolled patients with prior myocardial infarction, an implanted defibrillator and ventricular tachycardia (VT) despite antiarrhythmic (AAD) drugs and compared the effectiveness of escalated AAD therapy to catheter ablation. We sought to compare the effectiveness of these interventions in patients with sotalol-refractory VT versus amiodarone-refractory VT.

Methods:
All patients enrolled in the VANISH study were included (n=259). VT recurrence was compared in patients despite amiodarone (amio-refractory) as compared to non-amiodarone drugs (sotalol-refractory). Outcomes were a composite of death, VT storm, appropriate ICD shock, each of these components and any ventricular arrhythmia.

Results:
At baseline, 169 (65.2%) were amio-refractory and 90 (34.7%) were sotalol-refractory (1 patient was enrolled with VT despite procainamide). Amio-refractory patients had more renal insufficiency (23.7% vs 10%, p=0.0008), worse NYHA class (82.3% II/III vs 65.5%, p=0.0003), and lower ejection fraction (29 ± 9.7% vs 35.2 ± 11%, p<0.0001). After adjusting for these baseline differences, there was no difference in mortality between the two groups. When examined within the escalated drug therapy arm, amio-refractory patients had a higher incidence of the composite outcome (HR 1.94, 95%CI (1.14, 3.29), p=0.0144), and a trend to higher mortality (HR 2.40, 95%CI (0.93, 6.22), p=0.07), while no difference in outcomes were observed within the ablation treatment group. Within the amio-refractory group, ablation resulted in significant reduction of any ventricular arrhythmia (HR 0.53, 95%CI (0.31, 0.9), p=0.020). Sotalol-refractory patients had trends towards higher mortality and VT storm with ablation, with no effect on ICD shocks.

Conclusions:
The benefit of catheter ablation is greater for patients with amio-refractory VT than for patients with sotalol-refractory VT who are then switched to amiodarone.
Abstract 21040: MicroRNA-144 Antagonism Promotes Regression of Atherosclerosis
Authors: Tarling Elizabeth J , Cheng Joan , Cheng Angela , Wu Judy , Sallam Tamer , Baldan Angel , de Aguiar Vallim Thomas Q
Published: March 2022

Introduction:
Removal of cholesterol from atherosclerotic lesions remains an unmet therapeutic need. The ATP Binding Cassette Transporter A1 (ABCA1) plays a key role in the efflux of cholesterol from macrophages, therefore strategies that increase macrophage ABCA1 levels are likely to be atheroprotective.

Methods and Results:
To determine the long-term efficacy of anti-microRNA-144 (miR-144) therapy on the progression of atherosclerosis, we first treated

Ldlr
-/-

mice with saline, control anti-miR, or anti-miR-144 oligonucleotides once a week for 16 weeks. Second, to determine the potential of miR-144 antagonism as an interventional atherosclerosis therapeutic, we treated Low-density lipoprotein receptor null (

Ldlr
-/-

) mice with established atherosclerotic plaques with anti-miR-144 for 4 weeks, in a model of atherosclerosis regression. All anti-miR-144-treated mice showed an increase in circulating high-density lipoprotein (HDL) levels. In the model of atherosclerosis regression, anti-miR-144-treated mice also showed enhanced reverse cholesterol transport to the plasma, liver, and feces. Consistent with these observations, anti-miR-144-treated mice showed reductions in atherosclerotic burden. Notably, in addition to increasing circulating HDL levels and reverse cholesterol transport, miR-144 antagonism significantly remodeled the HDL particle proteome in both progression and regression models of atherosclerosis.

Conclusions:
These studies establish that raising HDL levels and altering HDL particle properties by anti-miR-144 treatment promotes reverse cholesterol transport and atherosclerosis regression, and suggest it may be a promising interventional therapeutic strategy to treat atherosclerotic disease.
Abstract 21051: The Incidence of Common Post-Procedural Complications After ICD and Crt-d Placement Using the Nationwide Inpatient Sample 2009-2013
Authors: Shanbhag Anusha G , Chatterjee Kshitij , Goyal Abhinav , Pothineni Naga venkata K , Alzghoul Bashar , Innabi Ayoub , Paydak Hakan
Published: March 2022

Introduction:
With the increasing burden of patients undergoing ICD and CRT-D placement, we attempted to determine the incidence of common in-hospital post-procedural complications (cx) after ICD and CRT-D placement and independent predictors of post-procedural mortality. Post-procedural cx after placement of ICD and CRT-D devices have been sparsely studied.

Methods:
Using the Nationwide Inpatient Sample, hospitalizations with placement of new ICD (ICD-9 procedure code 37.94) or CRT-D (ICD-9 procedure code 00.51) devices were identified between 2009 and 2013. Hospitalizations involving generator or lead changes or those with additional procedures like cardiac cath, cardiac surgery, pacemaker or catheter ablation during the same hospital stay were excluded. Only adults (age≥18 years) were included and cases with missing data on age or gender were excluded. A multivariate regression model was created with demographics, post-procedural cx (cardiac, vascular, neurologic, respiratory) and Elixhauser co-morbidities as covariates.

Results:
There were a total of 280,144 hospitalizations for placement of ICD or CRT-D between 2009-2013 with a mean age of patients being 66.6 (SD=13.4) years; 71.5% were males and 71% were Caucasians. Post-procedure, around 9.1% patients had cardiac cx like pericardial effusion, tamponade, hematoma, post-op MI; 5.9% had vascular cx like hemorrhage and injury to blood vessels. Respiratory cx like pneumothorax, hemothorax and respiratory failure were reported in 1.2% and neurological cx in 1.9% patients. In-hospital death was reported in 1,526 (0.5%) patients. The independent predictors of post-procedural mortality were cardiac cx (OR 2.38, p<0.001), respiratory cx (OR 3.01,p<0.001) and history of chronic kidney disease (OR 2.09,p<0.001). There was no association of age or gender with mortality after adjusting for other variables. The mean charge for all hospitalizations was $141792 (SD $92866).

Conclusions:
Post-procedural complications have been reported to increase costs by 20% over an uncomplicated hospitalization. Closer monitoring of patients with above stated cx and initiatives like QI projects to curb the load of cx may be beneficial.
Abstract 21053: Single Centre Experience of Portico
TM
Transcatheter Aortic Valve Implantation
Authors: Chokka Ramesh G , Delacroix Sinny , Cosgrove Claudia , Sinhal Navin , Montarello Nicholas , Nelson Adam , Deans Renae , Copus Barbara , Contibas Michael , Fragnito Kristen , Montarello Joseph , Worthley Stephen G
Published: March 2022

Background:
The Portico
TM
nitinol based self-expanding transcatheter aortic valve implantation (TAVI) system has the capability of being fully repositioned and retrieved in situ. This study investigates the feasibility and performance of Portico
TM
valve in subjects with severe symptomatic aortic stenosis up to 6 months post procedure.

Hypothesis:
The Portico
TM
system is safe and feasible in the treatment of patients with severe aortic stenosis.

Methods:
TAVI with the Portico
TM
system was performed in 83 subjects with severe AS using transfemoral (n=78), subclavian (n=4) and transaortic (n=1) access. Valve sizes included 23mm (n=5), 25mm (n=12), 27mm (n=31) and 29mm (n=35). Transthoracic echocardiography (TTE) was conducted pre and post-procedure and at 1mth and 6months in outpatient clinical follow-ups to evaluate aortic valve (AV) gradients and paravalvular regurgitation. Major stroke, vascular complications and mortality were also assessed in this cohort.

Results:
The mean age was 82±9yrs, with mean STS score of 5.0% and mean Euroscore II of 5.7%. The mean AV gradient improved significantly from baseline 47±17mmHg to 11±6 mmHg at 1mth and this decrease was sustained at 6 months post procedure; p<0.0001. There were no cases of severe paravalvular regurgitation by TTE at 6 months. The 30-day mortality was 1.2% (n=1) and 6 months mortality was 6.0% (n=5). Two patients (2.4%) had post procedure stroke and both were treated with intravenous thrombolysis with improvement in their symptoms, one patient (1.2%) had major vascular complications requiring vascular intervention and 10 patients (12%) required permanent pacemaker implantation. With regards to patients with impaired LV function, 12 patients (14.4%) had an EF < 55% prior to the TAVI procedure. In this group, there was a 15% improvement in EF at 6 months. Furthermore, 89% of all subjects improved at least one NYHA class at 30 days post procedure and 84% of the subjects improved at least one NYHA class at 6 months follow up.

Conclusion:
From our single center experience, the repositionable transcatheter Portico
TM
valve is feasible, safe and promising in the management of severe symptomatic aortic stenosis.
Abstract 21054: Hematopoietic Factors Are Sufficient to Increase AF in Aged, Atherosclerotic Mice
Authors: Ramos-Mondragon Roberto , Tyrrell Daniel , Guerrero-Serna Gudalupe , Valdivia Hector , Jalife Jose , Goldstein Daniel
Published: March 2022

Rationale:
Aging is a strong risk factor for atrial fibrillation (AF), the most common sustained arrhythmia in the clinical practice. Atrial inflammation correlates with increased AF susceptibility but whether chronic age-related inflammation that occurs with atherosclerosis contributes to AF is unknown.

Hypothesis:
Hematopoietic factors contribute to AF inducibility in aged atherosclerotic mice.

Methods:
We used burst electrical stimulation (tachypacing) of the right atrium to test susceptibility to AF
in-vivo
in young and aged atherosclerotic, low density lipoprotein receptor knockout (C57BL/6
Ldlr
-/-
) mice, and young and old wildtype (C57BL/6 WT) mice. We also determined the role of the stroma vs. the hematopoietic system, by creating bone marrow chimeras in which aged or young
Ldlr
-/-
mice were transplanted with age-matched or mismatched bone
Ldlr
-/-
bone marrow. We used whole-cell patch-clamping investigate atrial sodium currents. Confocal microscopy and patch-clamping in current clamp mode was used to simultaneously record action potentials and Ca
2+
transients.

Results:
Upon atrial tachypacing, aged atherosclerotic mice underwent longer and more frequent AF episodes than young (incidence, 0.47±0.09 vs 0.12±0.02 episodes/attempts;
p<0.05
) and aged WT mice (0.47±0.09 vs 0.16±0.07 episodes/attempts;
p<0.05
). Importantly, young-to-old bone marrow chimeric mice exhibited reduced AF incidence (0.23 ± 0.05 episodes/attempts), whereas old-to-young chimeric mice exhibited increased AF incidence (0.45 ± 0.08 episodes/attempts). Atrial myocytes from aged atherosclerotic mice presented a 50% reduction in the cardiac inward sodium current (I
Na
). Moreover, compared to young, aged atherosclerotic mice showed prolonged action potential duration (APD90: 34.0±5.0 ms vs 48.1±7.0ms; p<0.05), post-pacing spontaneous calcium releases (25% vs 81.8%; p<0.05) and triggered activity (0% vs 27.2 %; p<0.05).

Conclusions:
Aged atherosclerotic prone mice are susceptible to AF induction. Hematopoietic factors are sufficient to increase AF propensity with aging in the atherosclerotic host possibly by causing electrophysiological remodeling and intracellular Ca
2+
handling abnormalities.