bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12758: Cardiac Arrest After Cardiac Surgery is Associated With High In-Hospital and Long-Term Mortality
Authors: Voight Jessica , Vakil Kairav , Alraies M Chadi , Garcia Santiago , McFalls Edward , Adabag Selcuk
Published: July 2021

Introduction:
Cardiac arrest is a grave complication after cardiac surgery with a case fatality rate of ~60%. However, the long-term mortality and outcomes of post-operative patients who survived cardiac arrest is less clear.

Methods:
We examined the mortality and outcomes of 6,979 consecutive patients who underwent cardiac surgery from at the Minneapolis VA Medical Center from 1991 to 2014. Data was collected prospectively.

Results:
The mean age was 66 ± 9 years, 99% of the patients were male and 72% had coronary artery bypass graft surgery. In total, 182 (2.6%) patients had a cardiac arrest (median 3 days; range 0-39 days) after surgery. Of these, 93 (51%) died during the same hospitalization and an additional 24 (13%) died within 1 year. Mortality at 30-days (51% vs. 1.9%; p <0.0001), at 1-year (64% vs. 6%; p <0.0001), and after 7.5±5.5 years of follow-up (81% vs. 34%; p<0.0001), was higher in those with vs. without cardiac arrest (Figure 1). After adjusting for age, sex, year, and type of surgery, having an in-hospital cardiac arrest was associated with a 4.7 (95% CI 3.9-5.6; p < 0.0001) times higher risk of long-term mortality in the whole cohort, 2.0 (95% CI 1.6-2.7; p < 0.0001) times higher risk among those who survived 30 days after surgery, and 1.3 (95% CI 0.9-1.9; p = 0.14) times higher risk among those who survived 1 year. Independent predictors of death among cardiac arrest patients who were discharged alive include being discharged to a facility (HR 3.97; 95% CI 1.52-10.32; p=0.005) and renal dysfunction (HR 3.35; 95% CI 1.42-7.89; p=0.006).

Conclusions:
Long-term mortality remains very high in patients who were discharged alive after a postoperative cardiac arrest. Discharge disposition and renal dysfunction may have important prognostic implications in these patients.
Abstract 12763: Adolescents With Type 1 Diabetes Show Early Hemodynamic and Vascular Changes Unrelated to Standard Glucose and Lipid Markers
Authors: Schafer Michal , Truong Uyen , Baumgarter Amy , Cree-Green Melanie , Coe Greg , Hunter Kendall S , Barker Alex J , Nadeau Kristen J
Published: July 2021

Introduction:
Cardiovascular disease (CVD) is the leading cause of mortality in patients with type 1 diabetes (T1D). There is increasing evidence that maladaptive changes in vascular properties occur early in adolescence. Wall shear stress (WSS) plays crucial role in mechanotransduction and tissue remodeling. However, changes in aortic WSS and vascular properties in T1D adolescents and their associations with T1D biomarkers have yet to be determined.

Hypothesis:
We hypothesized that non-invasively MRI derived WSS and vascular markers of stiffness will be altered in T1D adolescents.

Methods:
Fourteen adolescents with T1D and 25 age-matched controls underwent prospective phase-contrast MRI (PC-MRI). Segmented cross sectional planes were selected above the sinotubular junction, transverse to the descending aorta. Maximum WSS values were computed from time specific generated shear fields. Aortic strain (AoS), distensibility (Ds), and stiffness index β (SI) were computed using vessel areas and pulse pressure. All measured hemodynamic and vascular markers were correlated with standard T1D biomarkers: A1C hemoglobin, cholesterol, LDL, HDL, and triglyceride levels. The significance between reported median values was assessed using Wilcoxon Ranked sum method and single linear regression analysis using Spearman rho.

Results:
Subjects with T1D showed significantly increased maximum WSS (dyne/cm2) in both ascending aorta (11.1 vs. 9.02, p = 0.0065) and descending aorta (13.7 vs. 12.3, p = 0.0166). Furthermore, AoS and Ds (mmHg-1) were both decreased in T1D group in ascending aorta (AoS: 25.1 vs. 29.7, p = 0.0352; Ds: 0.49 vs. 0.71, p = 0.0151) and descending aorta (AoS: 20.1 vs. 26.5, p = 0.0002; Ds: 0.41 vs. 0.66, p = 0.0082). Inversely, SI was higher in T1D group in both vessel segments (0.030 vs. 0.018, p = 0.0021 and 0.034 vs. 0.020, p = 0.0017). There were no significant correlations between PC-MRI derived vascular metrics and collected biomarkers.

Conclusions:
T1D adolescents show early aortic stiffness and altered WSS. Neither WSS nor stiffness markers correlated with A1C hemoglobin or lipid biomarkers. This suggests that potential therapeutic targets of the early vascular remodeling are beyond standard glycemic and lipid control.
Abstract 12918: Vitamin D Supplementation Did Not Have an Effect on Serum Total or Subclasses of High-Density Lipoprotein-Cholesterol; A Pilot Study
Authors: Weyland Patricia G , Paul Steven M , Howie-Esquivel Jill
Published: July 2021

Introduction:
Both prevalent and incident CVD are negatively associated with 25-hydroxyvitamin D (25[OH] D) levels but the existence of a causal mechanism has yet to be determined. Vitamin D (D) supplementation may increase total HDL-c or one of the HDL subclasses; HDL2 and HDL3 and decrease CVD. The effect of D supplementation with HMG-CoA reductase inhibitor use on HDL-c, HDL2, and HDL3 also remains unclear. Hypotheses: We assessed the following two hypotheses; 1) HDL-c, HDL2, or HDL3 levels will increase with D supplementation for 12 weeks versus placebo and 2) HDL-c, HDL2, or HDL3 levels will increase with D supplementation for 12 weeks with HMG-CoA reductase inhibitor use versus without HMG-CoA reductase inhibitor use.

Methods:
Serum sample data, including 25(OH) D, HDL-c, HDL2, and HDL3 levels, from a randomized double-blinded placebo-controlled trial conducted between 2008 and 2012 were secondarily analyzed. Statistical analyses included Pearson correlation and Repeated-Measures ANOVA.

Results:
Hypothesis #1; of the 59 participants (mean age=56.0 years), 39 had a deficient (< 20 ng/mL) baseline 25(OH) D level. Hypothesis #2; of the 40 participants (mean age=56.5 years) 23 had a deficient (< 20 ng/mL) baseline 25(OH) D level. Pearson correlation showed 12-week 25(OH) D levels were moderately positively correlated with 12-week HDL-c (0.337, p ≤ 0.05) and 12-week HDL3 (0.356 p ≤ 0.05) levels but not at baseline. Hypotheses #1 and #2; baseline and 12-week levels for HDL-c, HDL2, and HDL3 were moderately to strongly positively correlated with female gender and moderately to strongly negatively correlated with BMI. Some participants did not achieve sufficient 25(OH) D levels. Repeated-Measures ANOVA with one between-subjects factor; group, and one within-subjects factor; time, showed no statistically significant difference in the mean change in HDL-c, HDL2 or HDL3 for D supplementation versus placebo or for D supplementation with versus without HMG-CoA reductase inhibitor use. Conclusions: Future studies may provide more informative results if they include; more participants, deficient 25(OH) D level as an inclusion criteria, and continued D supplementation until sufficiency is attained versus discontinuation after a pre-specified time period.
Abstract 13050: Gender Differences in the Implementation of Secondary Prevention in Patients With Coronary Heart Disease: Results From the EUROASPIRE IV Survey
Authors: Kotseva Kornelia , De Smedt Delphine , Wood David , De Bacquer Dirk ,   on behalf of EUROASPIRE Investigators
Published: July 2021

Objective:
To describe gender differences in lifestyle and risk factor management, and the use of cardioprotective drug therapies in patients with coronary heart disease in Europe.

Methods:
The EUROASPIRE IV survey was a cross-sectional study carried out under the auspices of the European Society of Cardiology, EURObservational Research Programme in 2012-2013 in 78 centers in 24 European countries. Consecutive patients <80 years after acute coronary syndrome or revascularization were identified from hospital records and interviewed and examined at least 6 months later using standardized methods and instruments.

Results:
A total of 7998 patients (24.4% females) were interviewed on average 16 months after having experienced a cardiac event. Women were older (mean age 66.3 years [SD 9.0] vs 63.2 [9.7], p<0.001), had a lower level of education, and had more often unstable angina (14.4% vs 9%, p<0.001) at inclusion than men. Comparing women with men, the prevalence of the risk factors were as follows (p-values adjusted for age and center): current smoking 11.1% vs 17.6% (p<0.001), obesity (BMI ≥ 30 kg/m2) 43.8% vs 35.6% (p<0.001), central obesity (waist circumference ≥ 102 cm in men or ≥ 88 cm in women) 75.2% vs 52.8% (p<0.001), raised blood pressure (BP ≥ 140/90 mmHg, ≥ 140/80 mmHg in patients with diabetes) 43.8% vs 42.4%, (p=0.662), elevated LDL-cholesterol (≥ 1.8 mmol/l) 84.4% vs 79.2% (p<0.001) and self reported diabetes 30.1% vs 25.7% (p=0.013). Reported use of prophylactic drug therapies for the same comparison was: antiplatelets 92.4% vs. 94.3% (p=0.102); beta-blockers 82.5% vs. 82.6% (p=0.858); ACE inhibitors/ARBs 74.6% vs. 75.3% (p=0.187); and statins 83.5% vs. 86.4% (p=0.039). The therapeutic control of blood pressure, LDL-cholesterol and diabetes (HbA1c < 7 mmol/L) was: 53.7% vs 53.1% (p=0.171), 17.3% vs 22.3% (p<0.001) and 49.2% vs 53.8% (p=0.015), respectively.

Conclusion:
The results show that women with coronary heart disease have higher prevalence of obesity, central obesity, LDL-cholesterol and self-reported diabetes than men. Despite similarities in pharmacological treatment women reach less often than men the therapeutic goals of LDL-cholesterol after acute coronary event or revascularization.
Abstract 13101: Subclinical Cardiovascular Abnormalities Exist in Early Rheumatoid Arthritis
Authors: Erhayiem Bara , McDiarmid Adam K , Swoboda Peter P , Kidambi Ananth K , Ripley David P , Musa Tarique A , Dobson Laura E , Garg Pankaj , Andrews Jacqueline , Greenwood John P , Buch Maya H , Plein Sven
Published: July 2021

Introduction:
Cardiovascular disease is the most common cause of premature mortality in rheumatoid arthritis (RA) & CV abnormalities are frequent in established disease. No studies have studied CV changes in treatment naive early RA (ERA).

Hypothesis:
Subclinical CV pathology exists in ERA as assessed by cardiovascular magnetic resonance (CMR).

Methods:
66 ERA patients underwent 3T CMR scan including 355 modified Look-Locker inversion T1 maps before & 15 minutes after contrast administration. Patients had: no current/previous RA therapy; symptom duration <1 year; disease activity score ≥3.2; no known CV disease. 30 healthy controls were matched by age, sex & blood pressure.

Results:
Patients & controls were well matched: the demographics & RA characteristics are in table 1. CMR measures are in table 2. Left ventricular (LV) mass & remodelling was significantly lower in ERA. There was no difference in LV volume or ejection fraction. Significantly lower aortic distensibility, a measure of increased arterial stiffness & CV risk, was found in ERA. Diffuse myocardial fibrosis, also associated with poorer outcomes & measured by extra-cellular volume, was increased significantly in ERA. Increased amount of non-ischaemic focal scarring was present in ERA but not significantly different compared to controls.

Conclusions:
This is the first CMR study of treatment-naive ERA. This well defined cohort demonstrates abnormalities in vascular function, myocardial tissue composition & LV geometry. This highlights presence of CV risk at the earliest stages of RA. Further investigation will determine the natural history including which effective therapy can modulate these abnormalities.
Abstract 13106: Improved Outcomes of Extracorporeal Cardiopulmonary Resuscitation for Out-of-hospital Cardiac Arrest - A Community-wide Evaluation
Authors: Lin Wei-Shu , Ma Matthew Huei-Ming , Chou Nai-Kuan , Yang Mei-Fen , Chen Yu-Wen , Huang Chien-Hua , Liu Yueh-Ping , Lin Hsien-Tang , Lin Chi-Hung , Chiu Allen Wen-Hsiang , Ko Wen-Je , Chen Yih-Sharng ,   Taipei Fire Dept Med Oversight Committee, KO Patrick Chow-In
Published: July 2021

Introduction:
The patient outcome after OHCA is poor. Return to spontaneous circulation (ROSC) dramatically decreases with the duration of CPR. It has been proposed to implement extracorporeal membrane oxygenation in order to assist CPR (ECPR) in OHCA.

Objective:
To investigate the effects of ECPR in emergency (ED) for OHCA.

Methods:
A prospective 4-year observational database collected from a community-wide OHCA registry in an urban EMS was studied. The EMS ambulance staffs were capable with advanced airway, intravenous (iv) fluid skills, basic and advanced life support and AED techniques. Outcomes included 2-hour and 24-hour sustained ROSC, survival (SD) and cerebral performance category scale (CPC) at discharge. OHCA receiving ECPR were included and their pre-hospital (pre-H) and hospital (H) characteristics and outcomes were evaluated by regression analysis.

Results:
In the 4 years among a total of 7,220 OHCA resuscitated in ED, ECPR was used 88 times (90% male, median age 54 [IQR 44-63]), 90% non-traumatic, 58.6% arrest witnessed, 50.6% with bystander CPR, up to 72.6% initial AED rhythm showing shockable, 54% with LMA (laryngeal mask airway), 5.7% with endotracheal intubation, 18.2% with pre-H iv epinephrine, and 12.5% of them received therapeutic hypothermia. Pre-H time intervals (min:sec, median [IQR]) were 04:38 [03:30-06:08] for response, 13:00 [10:05-16:00] for scene, and 03:08 [02:09-05:00] for transport. Only 10.2% of cases presented pre-H ROSC and 9.1% got ROSC upon H arrival. Outcomes were 88.6% for 2-hr ROSC, 69.3% for 24-hr ROSC, 39.1% for SD, and 21% for good CPC 1or2 respectively. Patients with CPC 1or2 tended to be younger (median age 46.8 vs. 55.9, p=0.04) and less with LMA (29.4 vs. 61.9%, p=0.02).

Conclusions:
ECPR can lead to survival and good neurological outcome in selected OHCA regardless of positive ROSC at pre-H or upon H arrival after EMS resuscitation. Elder age and pre-H LMA may be adverse to neurological outcome for OHCA with ECPR.
Abstract 13115: Nitric Oxide Differentially Regulates White and Brown Adipogenesis Through Effects on Thermogenesis and Mitochondrial Biogenesis
(Best of Basic Science Abstract)
Authors: Huang Paul , Lee-Huang Sylvia
Published: July 2021

Introduction:
In addition to its roles as a vascular signaling molecule, nitric oxide (NO) plays roles in metabolism. Mice deficient in eNOS are overweight and develop insulin resistance. It is not known whether the metabolic effects are due to primary roles of NO, or to increased visceral adiposity, leading to secondary metabolic changes.

Hypothesis:
We hypothesized that NO plays distinct and separable primary roles in white and brown adipogenesis, which underlie the effects on adiposity, energy metabolism, and expression of thermogenic genes.

Methods:
We exposed wild-type and mice carrying specific gain of function and loss of function eNOS mutations to cold at 4C for 48 hours and assessed expression of thermogenic gene programs in white and brown adipose tissue. To study cell autonomous effects, we differentiated adipocyte precursors from brown and white fat in the presence of NOS inhibitors and NO donors, as well as with siRNA to knockdown eNOS expression.

Results:
Cold exposure resulted in upregulation of the thermogenic gene program in brown adipose tissue. Animals carrying a gain of function mutation in eNOS showed increased UCP1 expression even without cold exposure. Induction of thermogenic genes was more pronounced in the animals with gain of function eNOS mutation. Differentiation of adipocyte precursors showed effects of eNOS on adipogenesis. Cells treated with the pharmacologic blockade (L-NAME and L-NA) as well as genetic knockdown (siRNA) showed dose-dependent inhibition of adipocyte differentiation. MitoTracker Red CMXRos staining showed that treatment with the NO donor SNAP increases mitochondrial biogenesis, while L-NAME decreases mitochondrial biogenesis.

Conclusions:
We show that eNOS-derived NO plays distinct and separable roles in white and brown adipogenesis. In brown adipocytes, eNOS regulates the expression of the thermogenic gene program, with upregulation of expression even without cold exposure, and greater increase in response to cold. In white adipocytes, eNOS-derived NO is required for adipocyte differentiation and mitochondrial biogenesis.
Abstract 13162: Post-Cardiac Arrest Serum TNF-α Levels Are Associated With Short-Term Survival in a Swine Model of Ventricular Fibrillation
Authors: Youngquist Scott , Shah Atman , Rosborough John , Niemann James T
Published: July 2021

Introduction:
Most resuscitated victims of out-of-hospital cardiac arrest who survive to hospital expire due to the post-resuscitation syndrome. This syndrome is characterized by a sepsis-like pro-inflammatory state.

Hypothesis:
We hypothesized that a relationship exists between the rise of TNF-α, a pro-inflammatory cytokine, following return of spontaneous circulation (ROSC) and early post-arrest survival in a clinically relevant animal model of spontaneous VF.

Methods:
Mixed-breed Yorkshire swine (n=20), weighing 39
+
5 kg, were anesthetized and catheters placed in the right atrium and left ventricle/ascending aorta for continuous pressure monitoring. VF was induced by occluding the LAD with an angioplasty balloon. After 7 min of untreated VF, ALS resuscitation attempts were made for up to 20 min. Animals achieving ROSC were monitored for 3 hrs and fluid and pressor support was administered as needed. TNF-α levels were measured prior to VF and at 0, 15, and 30 min after ROSC using quantitative sandwich ELISA. Exact logistic regression and binomial proportions were used for analysis.

Results:
Twelve (60%) animals experienced early death, expiring during the 3-hour post-arrest period (9 PEA, 2 VF, and 1 asystole). The TNF-α level at 15 minutes post-ROSC was significantly associated with death within the first 3 hours post ROSC with a univariate odds ratio (OR) of 1.4 (95% confidence interval [CI] 1.05-2.2, p=0.01). Using a cutoff TNF-α level of 525 pg/mL at 15 min post ROSC had 100% negative predictive value (95% CI 0-37%) and 67% positive predictive value (95% CI 35-90%) for early death.

Conclusions:
The pro-inflammatory cytokine TNF-α increases shortly after ROSC and is predictive of early death. Early identification of resuscitated victims at greatest risk for hemodynamic collapse and recurrent arrest might facilitate the use of early hospital-based interventions to decrease the likelihood of a poor outcome.
Abstract 13189: CV-Ecosystem Model: Workplace Wellness With Individualized Medicine
Authors: Krittanawong Chayakrit , Kermott Cindy A , Wang Zhen , Zhang HongJu , Marysia Tweet S , Chirapongsathorn Sakkarin , Hayes Sharonne
Published: July 2021

Introduction:
At-work stress is rapidly becoming a significant contributory cause of occupational disease, while sedentary work and dietary indiscretion, taken together, have contributed to cardiovascular disease, known to be associated with substantial morbidity and mortality. The aim of the CV-Ecosystem Model is to provide an individual approach by systematic environmental modification of the work site.

Methods and Results:
Our model which we term the CV-Ecosystem Model includes two basic tenets: 1) Workstation technologic design 2) Flexible physiologic activity.

Workstation technologic design utilizes the services of a certified Ergonomist to engineer a comfortable, safe, and effective work environment. It is tailored to the unique physiologic needs of the worker while enhancing productivity within different environments. Computer aided design software would evaluate ergonomics to maximally mitigate the risk and incidence of eye strain, musculoskeletal disorders, repetitive movement disorders such as Carpal Tunnel Syndrome, etc unique to that work activity.

Flexible physiologic activity would permit a worker to actively focus on basic needs during work time, on site; this would include exercise activity and food intake, channeled into healthy options. Exercise time would provide a sense of calm during stressful projects and enhance emotional well-being. In this regard, a three hour period of time, weekly, could be allocated to fitness or meditation. Conveniently located food stations could provide a variety of healthy, plant-based, fresh food options. Both would come with flexible, relative control and scheduling of these activities, within a social environment and context.

Conclusions:
The CV Ecosystem Model, due to its simple technology and relative low cost, could be successfully implemented in a number of enterprises, including all healthcare facilities, with benefit to employee health, wellbeing, and favorable to the business bottom line.
Abstract 13272: Efficacy and Safety of Non-invasive Renal Denervation Study Using Externally Delivered Focused Ultrasound in Severe Resistant Hypertension
Authors: Schmieder Roland E , Ormiston John A , Neuzil Petr , Stárek Zdenek , Kay Patrick , Dawood Omar , Anderson Thomas L , Gertner Michael , White William B
Published: July 2021

Background:
Invasive catheter based techniques for renal denervation have been extensively examined in treating patients with resistant hypertension, with mixed results and some periprocedural complications. New evidence suggested that not all renal nerves are in the range of invasive procedures limited to a distance 4 to 6 mm from the lumen.

Aims:
To evaluate the safety and efficacy of an entirely non-invasive approach to renal denervation using externally delivered focused ultrasound to the peri-renal artery tissue with real time Doppler-based image guidance.

Methods and results:
Twenty-seven patients with severe, treatment resistant hypertension, defined as persistent systolic blood pressure (BP) > 160 mmHg despite 3 or more antihypertensive medications, were treated non-invasively with the Kona Medical Surround Sound System™. Focused ultrasound energy was delivered to the renal arteries bilaterally and surrounding tissue using Doppler-based imaging and continuous tracking with automatic correction for kidney motion throughout treatment. Patients received conscious sedation during the treatment period.

At this time, all patients have completed 24 weeks and 23 patients 52 weeks of follow up. Post-denervation, the mean changes from baseline BP (175/92 mmHg) were -16.8/-8.6 mmHg at 3 weeks, -23.2/-10.8 mmHg at 6 weeks, -29.7/-13.1 mmHg at 12 weeks, -21.6/-8.7 mmHg at 24 weeks and -25.6/-10.1 mmHg at 52 weeks . No serious device-related events have been reported to date. Forty-one percent of subjects (11/27) reported mild back pain immediately following the denervation treatment. The majority of cases (7/11) completely resolved within three days post treatment without any significant intervention and no case was associated with any motor, sensory deficits.

Conclusions:
This is the first study in humans using a non-invasive renal denervation system in severe resistant hypertension. Results showed clinically meaningful reductions from baseline in office BP through 52 weeks post-denervation. The procedure was well-tolerated with no serious adverse events. This technology should enable patients to benefit from renal denervation therapy without the invasive risks associated with catheter based techniques.
Abstract 13330: Depression is Associated With Cardiovascular Events in Male but Not Female Patients With One or More Cardiovascular Risk Factors: Japan Morning Surge Home Blood Pressure (J-HOP) Study
Authors: Kabutoya Tomoyuki , Hoshide Satoshi , Kario Kazuomi
Published: July 2021

Introduction:
Depression is associated with cardiovascular events, and the frequency of depression is higher in females than in males. However, the association between depression and cardiovascular events in patients with cardiovascular risk factors and the gender difference of the association remains unclear.

Hypothesis:
We assessed the hypothesis that depression was associated with a poor prognosis in patients with cardiovascular risk factors, and that the association is different in males and females.

Methods:
We enrolled 3,216 patients in the Japan Morning Surge Home Blood Pressure Study who had one or more cardiovascular risk factors. We conducted the Beck Depression Inventory (BDI). Depression was defined as having a BDI score ≥ 16. The primary endpoints were fatal/nonfatal cardiovascular events (myocardial infarction, stroke, hospitalization for heart failure, aortic dissection).

Results:
The mean follow-up period was 47±24 months, and 134 patients suffered primary endpoints. In male patients, depressive patients (N=184) were more likely to suffer cardiovascular events than non-depressive patients (N=1439) (log rank 6.79, p=0.009). In female patients, cardiovascular events were similar in depressive (N=347) and nondepressive patients (N=1246,log rank 0.06, p=0.81). A Cox proportional hazards model including age, history of hypertension, dyslipidemia and diabetes revealed that depression was a significant, independent predictor of primary endpoints in male patients (hazard ratio 2.01, 95% confidence interval 1.20-3.37, p=0.008).

Conclusions:
Depression is associated with cardiovascular events in male but not female patients with one or more cardiovascular risk factors.
Abstract 13368: Acetylation of VGLL4 Tdu Domain Modulates Its Activity to Regulate Postnatal Cardiac Growth
(Best of Basic Science Abstract)
Authors: Lin Zhiqiang , Guo Haidong , Zhou Pingzhu , Ma Qing , Zhang Jin , Stevens Sean , Liang Feng , Quan Qimin , Clapham David , Pu William T
Published: July 2021

Mammalian cardiomyocytes (CM) largely exit the cell cycle shortly after birth, limiting the heart’s capacity to recover from injury. The mechanisms that enforce neonatal CM cell cycle withdrawal are largely unknown. CM proliferation is stimulated by interaction of the co-activator YAP, the terminal effector of Hippo signaling, with the transcription factor TEAD1, but YAP’s mitogenic potency declines in the adult compared to fetal or newborn heart. Here we show that VGLL4, a CM-enriched TEAD1 binding protein, inhibits CM proliferation by competing with YAP for TEAD1 binding. Moreover, VGLL4 activity is regulated by acetylation of the lysine 225 (K225) residing in its first Tondu (Tdu) domain. Acetylation at K225 antagonized its interaction with TEAD1 in the neonatal heart. Overexpression of VGLL4 with a point mutation that blocks its acetylation enhanced VGLL4-TEAD1 interaction and limited CM proliferation, resulting in lethal cardiac hypoplasia. Our study defines a novel acetylation-mediated, VGLL4-dependent switch that regulates Hippo-YAP signaling and that restrains CM proliferation. These insights may enable more effective approaches to cardiac regeneration.
Abstract 13473: Refinement of a Risk-Standardization Model for Adverse Outcomes Following Congenital Cardiac Catheterization: Insights From from the NCDR
®
IMPACT
TM
Registry
Authors: Jayaram Natalie , Spertus John A , Kennedy Kevin F , Vincent Robert N , Martin Gerard R , Curtis Jeptha P , Nykanen David , Moore Phillip , Bergersen Lisa
Published: July 2021

Background:
Risk-standardization for adverse events following congenital cardiac catheterization is needed to equitably compare patient outcomes among different hospitals as a foundation for quality improvement. We sought to refine and update the risk-standardization methodology for the NCDR
®
IMPACT
TM
(Improving Pediatric and Adult Congenital Treatment) Registry.

Methods:
We identified 39,725 consecutive patients within IMPACT undergoing cardiac catheterization between January 2011 and March 2014. New procedure type risk categories were derived by empiric data and expert opinion and markers of hemodynamic vulnerability were empirically explored and identified. A multivariable hierarchical logistic regression model to identify patient and procedural characteristics predictive of a major adverse event (MAE) or death following cardiac catheterization was derived in 70% of the cohort and validated in the remaining 30%.

Results:
The rate of MAE or death was 7.1% and 7.2% in the derivation and validation cohorts, respectively. Six independent indicators of hemodynamic vulnerability and six procedure-type risk groups were identified. The final risk adjustment model included procedure type risk group, hemodynamic vulnerability, renal insufficiency, single-ventricle physiology, and coagulation disorder (See Figure). The model had good discrimination with a C-statistic of 0.76 and 0.75 in the derivation and validation cohorts, respectively. Model calibration was excellent with a slope of 0.97 (standard error [SE] 0.04; p-value [for difference from 1]= 0.53) and an intercept of 0.007 (SE 0.12; p-value [for difference from 0]= 0.95).

Conclusion:
We updated and refined a risk-standardization model for outcomes following congenital cardiac catheterization using the large, multicenter IMPACT Registry. Our model can be used for quality reporting back to sites participating in IMPACT to guide quality improvement initiatives.
Abstract 13513: MitraClip
®
for Functional Mitral Regurgitation: Outcomes in Over 600 Patients
Authors: Ailawadi Gorav , Lim D. Scott , Kron Irving L , Trento Alfredo , Kar Saibal , Mack Michael J , Grayburn Paul , Glower Donald D , Wang Andrew , Foster Elyse , Weissmann Neil J , Pearson Paul , Feldman Ted
Published: July 2021

Background:
The treatment options for degenerative or primary mitral regurgitation (DMR) include mitral surgery and transcatheter edge-to-edge repair (MitraClip). However, the optimal therapy for patients with functional or secondary MR (FMR) remains unclear. The purpose of this study was to evaluate the 1 year outcomes of all patients with FMR undergoing MitraClip in the United States as part of the EVEREST (Endovascular Valve Edge-to-Edge Repair STudy) II study.

Methods:
Patients treated in the EVEREST II trial (randomized trial and continued access registries) with severe FMR were evaluated. Outcomes at 30 days and 1 year were analyzed and adjudicated by an independent core laboratory. Patients were further stratified by surgical risk (High risk= STS mortality score ≥12% or pre-specified risk factors).

Results:
A total of 619 patients (mean age=73.4 years) with FMR were treated with MitraClip. Comorbidities were common including coronary artery disease (81.1%), NYHA functional class III/IV (80.3%), and previous coronary artery bypass grafting (55.7%). Device implantation was achieved in 96.4% with a mean hospital stay of 3.3 days and an 87.2% discharge to home. At 30 days, mortality was 3.6% with a major adverse event rate of 9.2%. At 1 year, the survival was 78.3%, while the majority of survivors had MR≤2+ (84.5%) and significantly improved symptoms (83.2% NYHA Class I/II). The left ventricular end diastolic volume (LVEDV) improved from 162.5ml to 152.6ml (P<.001). When comparing high surgical risk patients (n=485; mean STS score=10.6±6.9%) to non-high risk patients (n=134), the 30 day mortality was similar (4.1% vs. 1.5%, P=.19), but the 1 year mortality was worse (22.7% vs. 13.4%, P=.02). Nevertheless, at 1 year, there were similar rates of MR reduction (MR≤2+: 83.9% vs. 87.3%) and improvement in LVEDV (-9.0ml vs -12.6ml). The non-high risk cases had greater symptom improvement (NYHA Class I/II: 91.2% vs. 80.2%, P=.001).

Conclusions:
MitraClip in patients with severe FMR is associated with excellent safety, positive ventricular remodeling, symptom improvement, and stable MR reduction at 1 year independent of surgical risk. Compared to high surgical risk patients, non-high risk patients may derive the greatest survival and symptom benefit.
Abstract 13555: Acute Efficacy of Sodium Zirconium Cyclosilicate (ZS-9) in Patients on Mineralocorticoid-Receptor Antagonists: Analysis From Two Phase 3 Studies
Authors: Kosiborod Mikhail , McCullough Peter A , Rasmussen Henrik , Singh Bhupinder , Lavin Philip T , Deedwania Prakash
Published: July 2021

Introduction:
Although mineralocorticoid-receptor antagonists (MRAs) are strongly recommended by guidelines for chronic management of patients with heart failure (HF), less than 1/3 of eligible patients receive these cardio-protective medications due to the risk of hyperkalemia (hyperK; potassium [K+] ≥5.1 mEq/L). Sodium zirconium cyclosilicate (ZS-9) is a highly selective K+ ion trap that binds K+ throughout the GI tract. We examined the effectiveness of ZS-9 in treating hyperK in patients receiving MRAs using pooled data from 2 recently completed Phase 3 clinical trials.

Methods:
Data were pooled from 2 Phase 3 trials of patients with hyperK: ZS003 (N=753) and HARMONIZE (N=258). In both trials, patients receiving MRAs at baseline, and treated with 10 g, three times daily (TID), ZS-9 for 48 hrs were selected. Per protocol, MRA doses remained stable for the duration of the study. We examined absolute change in K+ from baseline, proportion of patients who achieved normokalemia by 24 and 48 hrs, and time to K+ normalization.

Results:
Across studies, 19 patients were on MRAs (age 73y; 74% HF; 90% eGFR <60; 74% diabetes mellitus). Mean baseline K+ was 5.7 mEq/L. ZS-9 significantly reduced K+ during 48 hrs after treatment initiation (Figure): by 0.3, 0.5, 0.5, 0.7 and 1.1 mEq/L at 1, 2, 4, 24 and 48 hrs, respectively (P<0.005 for each time point vs. baseline). Normokalemia was achieved in 84% and 95% of patients by 24 and 48 hours, respectively. Median time to K+ normalization was 3.8 hrs. During the initial 48 hrs of treatment of the overall population treated with 10 g ZS-9, the adverse event rate was 9% compared to 11% among patients who received placebo.

Conclusions:
In patients with hyperK while on MRA therapy, ZS-9 rapidly lowered K+ to normal range, with 95% of patients achieving normokalemia by 48 hrs. If confirmed in future studies, these results suggest that ZS-9 may enable optimization of cardio-protective MRA therapy in HF patients with or at high risk for hyperK.
Abstract 13585: The Relationship Between Dietary Magnesium Intake and Incident Heart Failure Among Older Women: The Women’s Health Initiative
Authors: Huang Mengna , Wu Wen-Chih H , Taveira Tracey H , Liu Simin , Roberts Mary B , Martin Lisa W , Wellenius Gregory A , Johnson Karen C , Manson JoAnn E , Eaton Charles B
Published: July 2021

Background:
Heart failure (HF) causes substantial burden and cost in older women. Low intake of dietary magnesium (Mg) has been associated with cardiac arrest, sudden cardiac death, fatal coronary heart disease, and stroke, although little is known about how Mg affects risk of HF.

Methods:
We included 88,752 postmenopausal women of the prospective Women’s Health Initiative-Observational Study (WHI-OS). Incident hospitalized HF was adjudicated by medical record abstraction of self-reported hospitalization. Dietary intake of Mg was measured at baseline by a 122-item validated semi-quantitative food frequency questionnaire. We adjusted dietary Mg intake with calibrated total energy using the residual method. Cox proportional hazards models were used to evaluate the association adjusting for potential confounding factors, including demographics, traditional risk factors, dietary intake, and Mg-containing medications and multivitamins. Additional analyses were conducted in the subset of all black and Hispanic participants and those in the hormone therapy trial of WHI, for whom HF cases were re-adjudicated and classified into HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF). Since there are great differences in risk factors and pathology between the two subtypes of HF, we explored the potential different associations of dietary Mg with both in 40,969 participants of this subset.

Results:
Among participants in the OS, women in the lowest quartile of residual Mg intake (median: 154 mg/day) had 1.44 (95% CI: 1.11-1.86) times the hazard of incident HF compared to those in the highest quartile (median: 366 mg/day). Total Mg combining unadjusted dietary and supplemental Mg intake showed a similar but non-significant result (HR = 1.22, 95% CI: 0.98-1.51 comparing lowest to highest quartile). Low dietary Mg intake was also associated, although not significantly, with increased hazards of both HFpEF (hazard ratio (HR) = 1.42 comparing lowest to highest quartile, 95% CI: 0.92-2.18) and HFrEF (HR = 1.35 comparing lowest to highest quartile, 95% CI: 0.84-2.17).

Conclusions:
Low dietary Mg intake at baseline was associated with higher long-term risk of incident HF. Results were similar for incident HFpEF and HFrEF.
Abstract 13594: Impact on Clinical Outcomes of Randomization at Community Hospitals Versus Pre-hospital location in STEMI Patients: Insights From the STREAM Study
Authors: Welsh Robert C , Goldstein Patrick , Carvalho Antonio , Ostojic Miodrag C , Nanas John , Zheng Yinggan , Gershlick Anthony , Danays Thierry , Van de Werf Frans , Armstrong Paul W
Published: July 2021

Objectives:
The STREAM study randomized STEMI pts <3 hrs from symptom onset to primary PCI (pPCI) or a fibrinolysis pharmacoinvasive approach (PI) with rescue for failed fibrinolysis and scheduled angiography for the remainder within 24h. Although most pts were randomized pre-hospital (PH) and admitted to pPCI centres, selected community hospitals (CH) within STEMI networks also participated. Given the inherent delays with inter-hospital transfer, we examined outcomes accordingly to randomization location.

Methods:
CH pts 358/1866 (19.2%) were compared to PH pts. Results are further categorized according to pts receiving pPCI, PI rescue, PI with scheduled angiography (%’s and medians with 25th-75th percentiles).

Results:
Overall compared to PH, CH pts had more diabetes (17.8% vs. 11.5%, p=0.001), higher Killip Class >1 (9.4% vs. 5.0%, p=0.002) and TIMI Risk Score ≥5 (18.2% vs. 12.4%, p=0.005). 30-day primary composite endpoint (death, CHF, shock, re-infarction) for CH was 14.9% vs. PH 13.2% (p=0.403). PI pts within CH received less rescue PCI than PH pts (35.1% vs. 42.8%, p=0.062) (table) and it was delayed by approximately 43 min. CH pts undergoing pPCI also had an approximate 31 min delay. After adjusting for TIMI risk score and time from symptom onset, CH pts requiring rescue had worse outcomes compared to PH (OR 2.3, 95% CI, 1.2-4.6); However no difference in outcomes existed between CH and PH pts in those undergoing pPCI (p interaction=0.027). PI pts receiving scheduled cath from CH and PH had comparable times to cath (17.7 vs. 18.7 hours) and low primary composite event rates (6.2% vs 8.0%).

Conclusion:
Within STREAM CH pts had higher baseline risk but overall similar outcomes to those randomized PH. Despite higher baseline risk, CH pts with successful fibrinolysis and scheduled angiography or those who underwent primary PCI had similar outcomes to PH. The worse outcomes in CH rescue pts emphasizes the need to identify and expeditiously treat those pts needing rescue PCI.
Abstract 13600: Patients Identified as Low Risk May Be Safely Discharged From the Emergency Department After Presentation With Chest Pain
Authors: Adeola Oluwaseun , Ruthmann Nicholas , Boshard Barbara , Geltman Joshua , Ardhanari Sivakumar , Dohrmann Mary L
Published: July 2021

Background:
Chest pain accounts for over 8 million visits to the emergency department (ED) annually in the United States. However, only a minority of these patients are eventually diagnosed with acute myocardial infarction.

Hypothesis:
A protocol may be safely utilized to identify and evaluate low risk patients upon presentation to the ED with chest pain.

Methods:
A prospective study at a large academic medical center evaluated the safety of a protocol to schedule outpatient stress testing and follow-up for low risk patients discharged from the ED after presenting with chest pain. Patients were low risk if they were pain-free in the ED, had negative cardiac enzymes, non-ischemic electrocardiogram and TIMI risk score < 1, or if a cardiologist deemed patient low risk for acute myocardial infarction. Selected patients were discharged from the ED and scheduled for stress testing within 1-3 business days. Patients with positive test results were evaluated by a cardiologist for medical management or coronary angiography as needed.

Results:
A total of 1,735 patients were enrolled in the protocol. Of the 1,036 patients completing a follow-up stress test, only 6.4% (66/1,036) had an abnormal result. Forty-two of these 66 patients (63.6%) were either determined to be false positive by the cardiologist or underwent medical management. The remaining 24 (36.4%) had coronary angiography, of which only 20.8% (5/24) had significant coronary artery disease requiring percutaneous coronary intervention. All patients were followed for 30 days after their ED visit. During this period, 1.9% (33/1735) of patients returned to the ED per protocol, and 1% (18/1735) were admitted to the hospital for chest pain or other cardiovascular presentation. Only 3 patients (0.2%) had myocardial infarction. No mortality was recorded during this period. With this protocol, patients and insurers avoided over $16 million in professional and facility charges and over $3 million in payments. Estimated cost savings from reducing hospitalization in our patient population was about $3.77 million.

Conclusions:
Our data support that an outpatient evaluation protocol for low risk patients presenting to the ED with chest pain is safe, avoids unnecessary hospitalization and reduces healthcare cost.
Abstract 13698: Comparative Long-term Outcomes of Endovascular versus Open Revascularization for Lower Extremity Peripheral Arterial Disease
Authors: Wiseman Jason T , Fernandes-Taylor Sara , Saha Sandeep , Havlena Jeffrey , Rathouz Paul J , Smith Maureen A , Kent K. Craig
Published: July 2021

Introduction:
Restoring circulation to patients with symptomatic lower extremity peripheral arterial disease (PAD) is traditionally achieved with open surgery. However, endovascular techniques have enhanced the armamentarium available to patients. No long-term, population-based results exist on which of these provides the optimal approach to symptomatic PAD.

Methods:
We identified patients who underwent an inpatient endovascular or open lower extremity revascularization for PAD (including those with claudication and limb threat) for 2006 through 2009 from the Centers for Medicare & Medicaid Services Chronic Conditions Warehouse, a 5% national sample of Medicare beneficiaries. The primary outcome was amputation free survival. The secondary outcome was the relative rate of subsequent intervention. Propensity score matching ensured similar baseline characteristics amongst cohorts.

Results:
Among 14,685 eligible patients, 5,928 endovascular revascularization patients and 5,928 open revascularization patients were included in a matched analysis. Patients undergoing endovascular repair had improved amputation free survival compared to open repair at 30-days (7.4 vs. 8.9%, p=0.002). This benefit persisted over the long-term: At 4-years, 49% of endovascular patients had died or received major amputation compared to 54% of open patients (p<0.001). An endovascular procedure was associated with a risk-adjusted 19% decreased risk of amputation or death compared to open over the study period (hazard ratio: 0.84; 95% confidence interval, 0.79-0.89; p<0.001). The rate of subsequent intervention at 30-days was 7.4% greater for the endovascular versus the open revascularization cohort. At 4-years, this difference remained stable at 8.6%.

Conclusions:
Using a population-based dataset, we show that an endovascular approach is associated with improved amputation free survival over the long-term. Moreover, we show a modest initial increase in the risk of reintervention after endovascular procedures; the differential rate of reintervention for endovascular patients was less than 10% over four years. The observed benefit associated with endovascular intervention may have significant implications for the millions of patients with PAD.
Abstract 13742: PDE3 Inhibitor, Cilostazol, Ameliorates Ischemic Hindlimb Through cAMP and PPARγ Activation
Authors: Sanada Fumihiro , Taniyama Yoshiaki , Muratsu Jyun , Ikeda-Iwabu Yuka , Otsu Rei , Rakugi Hiromi , Morishita Ryuichi
Published: July 2021

Peripheral arterial disease (PAD) is highly prevalent in the elderly and subjects with atherosclerotic risk factors. Approximately 2-4% of those affected with PAD commonly complain of intermittent claudication (IC) that is a strong indicator for the development of systemic atherosclerosis. Cilostazol (CSZ) has been shown to be of benefit in improving pain-free walking distance and quality of life in patients with IC. CSZ may be the most clinically effective pharmacologic option for IC. However, the underlying mechanism for amelioration of IC by CSZ remains largely unclear.

Here, we demonstrate that CSZ increases expression of hepatocyte growth factor (HGF) in vascular smooth muscle cells (SMCs) via two distinct pathways, PPAR γ and cAMP pathway. Activation of PPAR γ and cAMP activates HGF promoter leading to increase in capillary density and improvement of perfusion in mouse ischemic hind limb model. Enhancement of angiogenesis by CSZ involves Akt/eNOS activation in endothelial cells by HGF secreted from SMCs. However, this process was essentially absent in aspirin treatment group and CSZ with HGF neutralizing antibody treatment group. As CSZ also increases HGF protein production in interstitial area of skeletal muscle where satellite cells reside, we postulated that CSZ stimulates myogenesis. To proof this hypothesis, BrdU was injected every day for 7days in mouse hind limb model, and animals were sacrificed at day 7 and 28. Embryonic form of myocyte heavy chain (eMHC), BrdU positive myocyte, and nuclear centralization was measured. As predicted, CSZ increases the number of newly formed myocyte in ischemic leg compared to control and Aspirin treated mouse. This beneficial effect of CSZ was blunted by the administration of HGF neutralizing antibody. Additionally, Heart specific HGF overexpression mouse in which serum level of HGF is 4-5 times higher than wild type mouse were generated to proof the role of HGF in angiogenesis and myogenesis. Similar to the data obtained from CSZ treated mouse, HGF Tg mouse ameliorates ischemic hind limb via both angiogenesis and myogenesis.

Altogether, our date demonstrates that CSZ improves ischemic hind limb via angiogenesis and myogenesis. This results may account for the beneficial effect of CSZ in PAD patients with IC.