bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 18619: Scaffold Protein CARD11 Modulates Receptor Mediated Apoptosis in Cardiomyocytes Following Myocardial Infarction
Authors: Wood Philip , Moon Mark , Zhang Liyong , Dawood Fayez , Liu Youan , Kotaro Naito , Liu Peter
Published: April 2024

Background:
The CARD scaffold family members, named for containing the common caspase-recruitment domain, are important modulators of inflammatory and apoptotic signalling. CARD11, a membrane bound scaffold, is essential for the production of cytokines in the immune cellular response but is present in heart and lung tissue, where its effects are unknown, and described to associate with apoptotic players such as BCL10 and caspase-8. Due to the complex nature of cardiac response to myocardial infarction (MI), we hypothesize that CARD11 can act as a modulator and integrator of receptor mediated apoptotic pathways following cardiac tissue injury.

Methods & Results:
CARD11 expression was increased in neonatal cardiomyocytes by general stress induction by H2O2 (25μM) and death receptor activation by Fas agonist Jo2 (1μg/ml) and TNF-alpha (50ng/ml) in isolated neonatal cardiomyocytes. Annexin V (AV) and propidium iodide (PI) double staining demonstrated decreased levels of apoptotic cells (AV+/PI+) following H2O2, Jo2 and TNF-alpha treatments in CARD11-/- cardiomyocytes to that of placebo levels compared to CARD11+/+ cells, as analyzed by flow cytometry. Pretreatment with caspase inhibitor zVAD-FMK (25μM) blocked this increase in apoptosis. Replacement of CARD11 through plasmid transfection restored the apoptotic phenotype in CARD11-/- cells and it was susceptible to zVAD-FMK inhibition. Experimental MI was created in CARD11-deficient mice (CARD11-/-) and wild-type littermate controls (CARD11+/+) by left coronary artery ligation. Survival over 28 days was significantly improved in CARD11-/- mice which exhibited lower rates of rupture and reduced infarct size post MI. TUNEL staining identified a lower percentage of apoptotic cells in the border zone of CARD11-/- hearts post-MI. Western blot analysis displayed decreased levels of cleaved caspase-3, -8 and -9, as well as pro-apoptotic mitochondrial proteins Apaf1, cytochrome-C and Bid.

Conclusion:
CARD11 up-regulation provides a scaffold for the formation of death receptor signaling through caspase-8 to promote cell death via apoptosis and its removal to increased cardiomyocyte survival in the MI environment.
Abstract 18622: Impact of Chronic Kidney Disease and Anemia on 5-Year Mortality After Acute Myocardial Infarction
Authors: Dai Kazuoki , Inoue Ichiro , Kawagoe Takuji , Shimatani Yuji , Miura Fumiharu , Nishioka Kenji , Nakama Yasuharu , Oka Toshiharu , Ooi Kuniomi , Harima Ayako , Hashimoto Haruki , Shimamoto Keiko , Susawa Hitoshi , Matsui Syogo , Morita Yuuichi , Ishihara Masaharu
Published: April 2024

Background:
Several studies have shown that both chronic kidney disease (CKD) and anemia are risk factors for mortality in patients with acute myocardial infarction (AMI).

Method:
This study was undertaken to investigate prognostic utility of combination of CKD and anemia in AMI. Between January 1996 and December 2005, 878 patients with AMI underwent coronary angiography within 24 hours after the onset of chest pain. Creatinine and hemoglobin were measured on admission in these patients. CKD was defined estimated glomerular filtration rate (eGFR) of less than 60.0 ml/minute/1.73 m2 of body-surface area (stage 3-5). Anemia was defined using World Health Organization criteria (hemoglobin level <13 g/dL for men and <12 g/dL for women).

Results:
Both CKD (81% v.s. 94%, p<0.0001) and anemia (82% v.s. 90%, p=0.006) were associated with lower 5-year survival rate. In patients without CKD, anemia was associated with lower 5-year survival rate (90% v.s. 95%, p=0.03) (Figure 1), but not in patients with CKD (79% v.s. 83%, p=0.46). Multivariate analysis showed that hemoglobin level on admission was an independent predictor for 5-year survival in patients without CKD (OR 1.34, 95%CI 1.06-1.70, p=0.02), but not in patients with CKD (OR 0.92, 95%CI 0.76-1.12, p=0.40).

Conclusion:
In patients without CKD, admission hemoglobin level was an independent predictor for death after AMI. However, in patients with CKD, prognosis after AMI was poor regardless of presence of anemia.
Abstract 18630: Targeting Inhibitor of Protein Phosphatase 2A (I2PP2A) Mediates Plasma Membrane Beta-Adrenergic Receptor Resensitization
Authors: Martelli Elizabeth E , Vasudevan Neelakantan T , Mohan Maradumane L , Gupta Manveen K , Naga Prasad Sathyamangla V
Published: April 2024

βAR downregulation and desensitization are hallmarks of heart failure. Agonist occupied βARs undergo desensitization through phosphorylation by G-protein coupled receptor kinases leading to βAR internalization. Phosphorylated βAR becomes resensitized following dephosphorylation by PP2A in the endosome, a paradigm in receptor resensitization. Our recent studies have suggested that resensitization of βARs can occur on the plasma membrane through the inhibition of PP2A activity by I2PP2A. To test whether I2PP2A regulates βAR and cardiac function we generated transgenic mice with cardiac specific over expression of I2PP2A. Assessment of age dependent cardiac function of these mice showed that transgenic mice have cardiac hypertrophic response followed by dilated cardiomyopathy. These observations are further supported by immunohistochemistry. Since we have observed cardiac dysfunction and βAR desensitization in transgenic mice, we tested whether targeting I2PP2A in cells would allow for plasma membrane resensitization. We generated a stable HEK (Human Embryonic Kidney) cell line expressing short hairpin RNA targeting I2PP2A (shRNA-I2PP2A). Confocal microscopy studies show that cells expressing shRNA-I2PP2A resulted in significant loss of receptor phosphorylation despite the presence of the agonist. Furthermore, radioligand binding and confocal imaging showed marked inhibition of receptor internalization upon depletion of I2PP2A with significant PP2A activation. Consistently, we also observed preservation of βAR function despite the presence of agonist as measured by cAMP generation and adenylyl cyclase activity. Together these studies suggest that targeting I2PP2A may lead to plasma membrane receptor resensitization demonstrating that modulating PP2A function can potentially change desensitization and resensitization dynamics of the receptors on the plasma membrane.
Abstract 18660: A Potential Role of TRPM2 Mediated Inflammation in Heart Disease
Authors: Yue Zhichao , Du Jianyang , Xia Jia , Qin Xin , Zhang Yanhui , He Yanlin , Fusco Daniel , Liang Bruce , Yue Lixia
Published: April 2024

Background:
Inflammation underlies a variety of pathological processes leading to various types of heart disease, including chronic heart failure, arrhythmia, and ischemic cardiomyopathy. The importance of the inflammatory cascade in heart disease has been recognized and thoroughly investigated for the last three decades. However, despite the promising results from experimental studies, attempts to attenuate inflammatory injury in clinical practice have been less successful than expected. A better understanding of the biological process and mechanisms of inflammatory cascade is necessary to identify novel targets for the treatment of inflammatory heart disease. Here we tested the hypothesis that inflammasome activation mediated by the oxidative stress sensitive TRPM2 channels contributes to ischemic cardiomyopathy in I/R mouse model and in human atrial fibrillation (AF).

Methods:
We used both in vivo ischemia-reperfusion (I/R) mouse model and ex-vivo dissociated fibroblasts from control and AF patients. Heart function of I/R mice was assessed by echocardiograph (ECG) and P-V loop catheter.

Results:
We found that TRPM2 is highly expressed in cardiac fibroblasts, and that functional TRPM2 channels were readily detected by patch-clamp in cardiac fibroblasts from mouse and human. In I/R mouse heart, TRPM2 was up-regulated by myocardial infarction. In human fibroblasts, the expression of TRPM2 measured by qPCR was much higher in AF versus control patients. We found that the infarct size of TRPM2-knockout mice was much smaller than wide-type (WT) control mice in I/R mouse model. Heart function measured one week after I/R by ECG was also much better in TRPM2-KO mice than WT mice. To understand the mechanism of the protective effects of TRPM2 deletion in heart function of the I/R model, we investigated the formation of inflammasome and found that TRPM2 deletion largely reduced the inflammasome formation in I/R mouse hearts.

Conclusions:
Fibroblasts from AF patients showed higher expression of TRPM2 detected by qPCR. Moreover, deletion of TRPM2 seems to play an important role in heart protection in the I/R model. Our results suggest that targeting TRPM2 may serve as a potential therapeutic approach for treatment of inflammation associated heart disease.
Abstract 18671: Exercise Training Associated With Testosterone Replacement Decreases Muscle Sympathetic Nerve Activity in Heart Failure Patients With Hypogonadism
Authors: dos Santos Marcelo R , Sayegh Ana Luiza C , Arap Marco A , Barretto Antonio Carlos P , Middlekauff Holly , Negrço Carlos E , Alves Maria-Janieire d
Published: April 2024

Purpose:
Heart failure (HF) is characterized by increase in muscle sympathetic nerve activity (MSNA). Advanced HF can be associated to testosterone deficiency. Study with HF patients and testosterone therapy showed improvement in VO2 and baroreflex sensitivity. The role of exercise with or without testosterone is unknown. Therefore, the aim of the study was to investigate if aerobic exercise with or without testosterone replacement decreases MSNA.

Methods:
24 HF patients (52±2 yr) with low testosterone, FC III (NYHA) and LVEF 26±2%, were divided: Exercise Training (ET,n=9) Testosterone (Testo,n=8) and Exercise Training+Testosterone (ET+Testo,n=7). Total (TT) and free (FT) testosterone and SHBG were measured. Testosterone deficiency was characterized as TT <350 ng/dL and FT <131 pmol/L. Cardiopulmonary exercise was performed on bike. MSNA was measured by microneurography. Both groups Testo and ET+Testo were treated with undecilate of testosterone (intramuscular) at the beginning of the protocol and were monitored monthly. The exercise consisted in three 40-minutes sessions per week on an ergometer bike. Exercise intensity was between anaerobic threshold and respiratory compensation point.

Results:
After 4 months, TT and FT were restored in ET (307±40 to 429±93 ng/dL; p<.001 and 160±26 to 246±50 pmol/L; p<.001), Testo (279±33 to 575±66 ng/dL; p<.001 and 137±18 to 381±55 pmol/L; p<.001) and ET+Testo (223±18 to 497±82 ng/dL; p<.001 and 135±22 to 353±49 pmol/L; p<.001) groups. Peak VO2 increased in ET (14.76±1.60 to 18.06±2.26 ml/kg/min; p=.01), Testo (19.33±1.87 to 20.34±2.08 ml/kg/min; p=.01) and ET+Testo (17.61±1.37 to 20.63±2.72 ml/kg/min; p=.01). Maximal power (watts) was increased only within ET+Testo (75±8 to 129±21 watts; p<.001). MSNA decreased in ET (49±4 to 34±1 bursts/min; p=.02) and ET+Testo (61±4 to 32±2 bursts/min; p<.001) but was not different within Testo (39±4 to 34±3 bursts/min; p=.89).

Conclusion:
Functional capacity increased in all groups, but only ET+Testo improved muscle strength. Interestingly, exercise alone was able to restore testosterone. In addition, ET and ET+Testo reduced MSNA. These findings emphasize that ET and testosterone together should be included in the treatment of HF patients with hypogonadism.
Abstract 18681: Association Between Type of Coronary Artery Anomaly, Cardiac Surgery, and Death in Adults
Authors: Cotney Kristen , Brown Todd M , Nath Hrudaya , Lloyd Steven
Published: April 2024

Introduction:
Anomalies of coronary artery origin where the artery arises from the opposite aortic cusp are associated with adverse cardiac events; those of the left main and the left anterior descending coronary arteries (LMCA and LAD) are thought to be at particular risk. However, there are few outcomes data on anomalies identified in adulthood; existing outcomes data are derived from the pediatric population. We determined the relationship between anomaly type, cardiac surgery, and death in adults.

Methods:
73 individuals ≥19 years of age with anomalies of coronary artery origin were identified from the institutional imaging and catheterization databases. Anomaly type and whether surgery was performed were ascertained by chart review. Anomalies were grouped into 3 categories: 1) left circumflex coronary artery arising from right cusp (n=26); 2) right coronary artery (RCA) arising from left cusp (n=32); and 3) all other anomalies (n=15). Vital status was ascertained from the Social Security Death Index. Association between type of anomaly and mortality was investigated by Cox proportional hazards models, adjusting for surgical management and age at diagnosis.

Results:
Mean age at diagnosis was 56±14 years (55% male, 59% white). As of November 5, 2012, 27 had died. The relationship between anomaly type, surgical management, and mortality is in the table. After adjustment, RCA anomaly (hazard ratio [HR] 3.5, 95% confidence interval [CI] 1.2, 9.9) was associated with increased mortality; undergoing surgery (HR 0.07, 95% CI 0.01, 0.56) was associated with decreased mortality.

Conclusion:
This represents the largest outcomes study of adults with anomalous coronary artery origin. In this group, anomalous RCA is associated with higher incidence of overall mortality than other types of anomalies, including those of LMCA and LAD. This finding is surprising, since the prevailing view suggests that RCA anomaly carries less risk than those of the LMCA or LAD.
Abstract 18684: Extracorporeal Shockwave Myocardial Revascularization: A Novel Therapy for Refractory Angina Pectoris
Authors: Prasad Megha , Cassar Andrew , Rodriguez-Porcel Martin , Reeder Guy S , Karia Darshak , DeMaria Anthony , Lerman Amir
Published: April 2024

Background:
Treatment options for refractory angina not amenable to revascularization are limited. Extracorporeal shockwave myocardial revascularization (ESMR) is a novel non-invasive application of low intensity shock waves that stimulates angiogenesis to improve ischemia. We aimed to determine the safety and efficacy of ESMR in patients with refractory angina.

Methods:
A single-arm multicenter U.S. prospective trial was implemented to assess safety and efficacy of ESMR therapy in patients with Class III/Class IV refractory angina. Each patient received 9 sessions of ESMR to ischemic areas over 9 weeks. Efficacy was assessed at baseline and 4 months after treatment by maximal treadmill exercise time and ischemic burden on pharmacological single photon emission computed tomography (SPECT). Safety was assessed by incidence of adverse events, electrocardiography, echocardiography, laboratory markers, and pain questionnaires.

Results:
Fifteen patients with medically refractory angina were enrolled. Exercise treadmill time from baseline to last follow-up after ESMR increased significantly (38%) by 122.3±156.9 seconds (319.8±157.2 vs. 422.1±183.3 seconds, p=0.016) (Figure 1). There was no difference in the mean summed stress score (SSS) on pharmacological-SPECT 4 months after treatment vs. baseline (17.8±14.9 vs. 21.2±15.3, p=0.233). However, SPECT SSS revealed that untreated areas had greater progression in ischemic burden vs. treated areas (3.69±6.2 vs. 0.31±4.5, p=0.038). There was no significant change in the mean summed echo score from baseline to post treatment (0.4±5.1, p=0.79).There were no changes in electrocardiography, echocardiographic parameters, or laboratory markers. No serious adverse events or complications occurred, and pain with ESMR was minimal (score of 0.5±1.2 to 1.1±1.2 out of 10).

Conclusions:
We find that ESMR is a safe and efficacious treatment which may be clinically feasible for patients with refractory angina pectoris.
Abstract 18725: Exercise Capacity and Level of Physical Activity in a Broad Population of Adults With Congenital Heart Disease
Authors: Ashman Linda K , Johansson Linda M , Zetterström Anna-Klara , Cider åsa , Eriksson Peter , Dellborg Mikael
Published: April 2024

Purpose:
To evaluate exercise capacity and physical activity level in a broad population of Swedish men and women with adult congenital heart disease (ACHD).

Material and Methods:
From April 2009 to December 2012, 1176 patients with ACHD, seen at regular visits in an ACHD-unit were assessed for the possibility and individual need to take part in tests of physical fitness. The patients performed a submaximal ergometer bicycle test to evaluate exercise capacity and filled in the International Physical Activity Questionnaire (IPAQ) to assess the level of physical activity.

Results:
Four hundred and seventy three patients (40.2 %) performed the tests and the demographics of these patients and the results of the tests are presented in table 1.

Conclusions:
The correlation between exercise capacity and the level of physical activity is low in patients with ACHD and this finding is in congruence with former studies in healthy persons. To judge exercise capacity of a patient with ACHD using self reported physical activity should therefore be used with caution before exercise capacity is objectively assessed.

Table 1. Demographic data of patients with ACHD categorized according to the physical activity level assessed by IPAQ.
Abstract 18727: Atrial Fibrillation is an Independent Predictor of Higher Coronary Atherosclerosis Burden
Authors: Khaleel Bala Sayf , Alchalabi Sama , Elferjani Belqis , Chaikriangkrai Kongkiat , Mahwash Kassi , Nabi Faisal , Chang Su Min
Published: April 2024

Introduction:
Atrial fibrillation (AFIB) and coronary artery disease (CAD) share common risk factors. It’s unknown if AFIB is an independent predictor of subclinical CAD.

Objectives:
Evaluate the association of AFIB with subclinical CAD as determined by coronary artery calcium scoring (CACs)

Method:
430 consecutive AFIB patients without angina, known CAD, systolic heart failure, valvular heart disease and cardiomyopathy underwent CACs with Multi-detectors CT. Results were compared to 1) Age, gender and race predicted CACs using MESA (Multi-ethnic study of atherosclerosis) calculator 2) Age and gender matched cohort of 430 patients presented with chest pain and suspected CAD.

Results:
The mean age of the population was 63±10, 65% male and 16% diabetics, 63% hypertensive. Prevalence of CAD (CACs > 0) was 76 % of patients with AFIB and significantly higher than predicted by MESA calculator (Figure).Among AFIB patients, 64% had higher CACs than MESA predicted CACs at 50
th
percentile (P <0.001) while 13 % had higher CACs than MESA predicted CACs at 90
th
percentile (P =0.05). In 320 AFIB patients with CACS > 0, estimated arterial age was higher than the actual biological age. (68.8± 12 Vs.64.1±8.9, mean difference of 4.7 ±13 years, median of 5. P < 0.001).

Compared to the chest pain cohort, prevalence of CAD (CACs > 0) and severe CACS (>400) in patients with AFIB was significantly higher (Figure).Multivariable -analysis adjusted to Framingham 10 years risk showed that the presence of AFIB is independently associated with the presence of CACs (OR 1.81; 95% CI 1.34-2.44; P<0.001) and severe calcification (OR 2.32; 95%CI 1.43-3.74; p0.001)

Conclusion:
Presence of AFIB without other known cardiac disease appears to have higher prevalence and more advanced CAD when compared to both epidemiological data and symptomatic patients with suspected CAD.
Abstract 18863: Emerging Role of Cytoglobin in Cardiovascular Function and Regulation: Evidence From Cytoglobin Knockout Mice
Authors: Talukder M A Hassan , Ismail Raed S , El-Mahdy Mohamed A , Thuy Le T , Kawada Norifumi , Zweier Jay L
Published: April 2024

Cytoglobin (Cygb), a recently identified globin protein, is reported to play an important role in O
2
-dependent nitric oxide (NO) removal, nitrite reduction and NO production; and it is thought to be involved in vascular function. However, there is no report on the effect of Cygb in cardiovascular (CV) function. Recently, a genetically modified mouse model with global absence of Cygb was developed. Therefore, to investigate the role of Cygb in CV function and regulation, we utilized this mouse model to explore the role of Cygb for in vivo (echocardiography) and in vitro (isolated perfused hearts) cardiac hemodynamics. Tail-cuff BP measured in conscious animals was >20 mmHg lower in Cygb-knockout (Cygb-KO) mice than in age-matched (6-months) wild-type (WT) mice. Importantly, echocardiographic parameters in Cygb-KO mice were markedly different from WT mice (Table). Cardiac chambers in Cygb-KO mice were significantly larger with increased end-systolic and end-diastolic volumes; however, there was septal hypertrophy with large stroke volume, but no differences in heart rate or fractional shortening. In isolated hearts, coronary flow was significantly higher in Cygb-KO hearts, but other parameters were comparable (Table). Thus, the absence of Cygb results in marked hypotension, ventricular chamber dilatation and dysfunction yet with preserved cardiac contractile function. Collectively, these data from both in vivo and in vitro studies provide direct evidence that Cygb plays a critical role in CV pathophysiology, and its absence during stressful conditions may lead to progressive high output cardiomyopathy or heart failure that warrants in-depth investigation.
Abstract 18913: Regional Variation in Heart Transplant Outcomes in the United States: Trends Over Time
Authors: Mujib Marjan , Gupta Tanush , Mazumder Nabila K , Khera Sahil , Kolte Dhaval , Palaniswamy Chandrasekar , Garg Jalaj , Sule Sachin , Fonarow Gregg C , Ahmed Ali , Frishman William H , Aronow Wilbert S
Published: April 2024

Background:
Clinical outcomes after heart transplant have improved considerably in the United States over the past several decades. However, the degree to which this has occurred uniformly across the country is unknown.

Methods:
We used the Nationwide Inpatient Sample (NIS) databases to identify patients who received heart transplant (ICD 9 procedure codes 37.51) during the years 2003 through 2010. Using discharge weights an estimated 13,084 nationwide heart transplant patients were identified. Patients were stratified on the basis of hospitals’ census region as obtained from the AHA Annual Survey of Hospitals: Northeast (17%), Midwest (23%), South (29%), and West (31%). Multivariable logistic regression models were used to estimate the association of hospital region and in-hospital mortality. To estimate trends over time, a subsequent analysis was performed within strata of three time-periods: time-period 1 (2003-2005), time-period 2 (2006-2007) and time-period 3 (2008-2010).

Results:
Overall, in-hospital mortality was lowest in the West (4.2% versus 5.2% in the South, 5.6% in the Midwest, and 7.3% in the Northeast; P<0.001). After adjusting for patient demographics, co-morbidities, pay status, median household income status, and hospital characteristics, compared to the West, in-hospital mortality remained higher in the South (OR; 1.27; 95% CI, 1.01-1.60; P=0.037), Midwest (OR; 1.39; 95% CI, 1.10-1.76; P=0.006) and the Northeast (OR; 1.77; 95% CI, 1.39-2.27; P<0.001). When stratified by three time-periods, in-hospital mortality rates during time-period 1 were similar across all regions. Compared to the West, Northeast (OR, 5.84; P<0.001) and Midwest (OR, 1.91; P=0.019) had significant higher mortality rates during time-period 2. During time-period 3, Northeast (OR, 2.57; P<0.001), Midwest (OR, 1.92; P=0.002) and South (OR,1.67; P=0.019) regions had higher in-hospital mortality compared to the West.

Conclusions:
Regional differences in in-hospital mortality after heart transplant were not prevalent until 2006. The inpatient mortality remained worse in the Northeast, Midwest and South regions compared to the West. Further prospective studies are required to identify factors responsible for these regional differences.
Abstract 18986: Collateral Flow In the Canine Heart Derived From Coronary Wedge Pressure Overestimates Actual Collateral Flow Measured by Fluorescent Microspheres
Authors: van den Wijngaard Jeroen P , van Horssen Pepijn , Hoefer Imo E , Piek Jan J , Spaan Jos A , Siebes Maria
Published: April 2024

Purpose:
In severe coronary artery disease, coronary collateral flow may prevent distal ischemia. Clinically the ratio between coronary wedge pressure and aortic pressure is used as index of collateral flow. The aim of this study was to validate this method by selective microsphere injections in the LAD during obstruction of LCX flow.

Methods:
The study was conducted in ten mongrel dogs and was performed in accordance with the Principles of laboratory animal care (NIH) as well as local IACUC. Under anesthesia a thoracotomy was performed and a guide wire equipped with both a pressure and a Doppler velocity sensor was introduced in the LCX. Fluorescent microspheres were injected into the LAD with partial and full occlusions of the LCX. Collateral flow derived from pressure was expressed as the fractional flow reserve, FFRcoll_p calculated according to its definition as; FFRcoll_p = FFRmyo - FFRcor where FFRmyo is the assumed true myocardial FFR. FFRcor_p is zero by definition during full occlusion and unity in the absence of any stenosis resistance. At full occlusion FFRcoll_p equals the ratio between distal wedge pressure, Pw, and aortic pressure Pa. At partial occlusion FFRcoll_p can be calculated from distal pressure, Pd, and Pa by means of the linear FFR model. With microspheres, FFRcoll_m is measured as the ratio between microsphere density in the LCX and that in the LAD perfusion territory but corrected for the estimated contribution of septal 28%, and right, 21%, coronary contribution to LCX collateral flow as derived from literature data.

Results:
Both, FFRcoll_p and FFRcoll_m were inversely related to the ratio between LCX flow velocity by the maximal hyperemic coronary flow velocity in the LCX. FFRcoll_p overestimated FFR_m at all occlusion degrees by a factor of 3 in average. At full occlusion this difference was significant according to Wilcoxon paired test with P<0.0005.

Conclusions:
These results show that during severe occlusion pressure-derived measurement of collateral flow overestimates collateral flow as determined from microsphere distributions. Pressure based assessment of collateral flow may thus yield an incorrect estimate of collateral flow.
Abstract 19007: Lineage Reprogramming of Mouse Fibroblasts to Induced Cardiac Progenitor Cells by Defined Factors
Authors: Lalit Pratik A , Lea Martin , Jackson Steven A , McIntosh Brian E , Kyba Michael , Thomson James A , Garry Daniel J , Kamp Timothy J
Published: April 2024

Several studies have reported reprogramming of mouse fibroblasts to induced cardiomyocytes (iCMs). However, reprogramming to cardiac progenitor cells (CPCs), which may be more favorable for cell therapy because of their proliferative properties and multipotency, remains to be accomplished. This study aims to reprogram mouse fibroblasts to induced CPCs (iCPCs) by transcription factor (TF)-mediated reprogramming. We have cloned a library of 25 genes including cardiac-related TFs and chromatin remodeling agents into a novel, inducible piggyBac transposon vector. Fibroblasts were derived from a Nkx 2.5- YFP cardiac progenitor reporter mouse model. We first confirmed efficient transcription/translation of our piggyBac TF library. Next, as a control experiment neonatal cardiac fibroblasts were transfected with Gata4, Mef2c, Tbx5 or Gata4, Mef2c, Tbx5, Hand2 (published factors) and monitored for appearance of beating cells. Spontaneously beating, YFP- iCMs were observed only after application of doxycycline (25 days) for both combinations of factors, demonstrating a robust reprogramming system. We then transfected neonatal cardiac fibroblasts with entire library of 25 factors and observed YFP+ cells on doxycycline treatment. The TF pool was subsequently narrowed down to 11 essential factors. On transfection with 11 factors, YFP+ cells were first observed 4 days after doxycycline treatment. By day 20 these YFP+ cells developed into two-dimensional, highly proliferative YFP+ colonies of cells that lost their parental fibroblast morphology and exhibited a high nucleus to cytoplasmic ratio. Similar reprogramming was later accomplished using adult cardiac and adult lung fibroblasts. Untransfected/iPSC factors transfected control fibroblasts yielded no beating or YFP+ cells. qPCR analysis of these YFP+ colonies revealed an upregulation of CPC markers including Mesp1, Mef2c, Irx4 accompanied with down regulation of fibroblast specific genes such as Fsp1, consistent with reprogramming towards an iCPC state. These results support the ability of inducible piggBac-based TFs to reprogram fibroblasts to iCPCs. Current experiments are focused on optimizing culture conditions to maintain iCPCs in a proliferative state and defining their potency.
Abstract 19010: Exercise but Not Pacing Affects Coronary-Cardiac Interaction via Reflected Waves From the Aorta
Authors: Rolandi M. Cristina , Lockie Tim , Verhoeff Bart-Jan , Perera Divaka , de Silva Kalpa , Redwood Simon , Marber Mike , Piek Jan J , Spaan Jos A , Siebes Maria
Published: April 2024

Background:
Not only the interaction with cardiac mechanics, but also the systemic circulation determines coronary hemodynamic waveforms. Coronary wave intensity can distinguish between forward (FW) waves entering from the aorta and backward (BW) waves originating from the microcirculation. The aim of this study was to assess contributions of the systemic circulation to cardiac-coronary interaction by comparing exercise, having a profound influence on the systemic circulation, with right atrial pacing where the systemic circulation is minimally affected.

Methods:
During cardiac catheterization we recorded aortic pressure (Pa), distal coronary pressure (Pd) and flow velocity (U) in diseased coronary arteries. In 10 subjects heart rate (HR) was increased by right atrial pacing at 120 bpm. 11 other patients exercised using a supine cycle ergometer at increasing workload. Net wave intensity was computed as dI= (dPd/dt)(dU/dt) and the energy of the FW and BW waves was derived by the areas under the curve.

Results:
Resting values of systemic and coronary hemodynamic were similar in both groups, with HR = 73 ±4 bpm, Pa = 104 ±5 mmHg, Pd = 85 ±10 mmHg and U = 16.2 ±2.1 cm/s. Exercise increased HR to 108 ±7 bpm which did not differ from that during pacing. Pa and Pd increased with exercise by 20 mmHg and 8 mmHg, resp. (p<0.05), whilst pacing raised Pa by only 5 mmHg (p<0.05) at unchanged Pd. U similarly increased to 23.1±3.0 cm/s by pacing and exercise. Coronary wave energy at rest was the same for both groups. The BW compression wave more than doubled with both pacing and exercise, while the early FW compression wave was unchanged by exercise and much reduced by pacing from 1.9 ± 0.6 to 0.3±0.1 Jm
-2
s
-2
(p<0.05). The FW expansion wave at the onset of relaxation increased from 1.6±0.5 to 3.5±1.0 Jm
-2
s
-2
(p<0.05) with exercise but was not altered by pacing. The BW expansion wave that drives diastolic coronary flow more than doubled with exercise, but only increased by 63% with pacing.

Conclusion:
Exercise more profoundly affects cardiac-coronary interaction than pacing and improves the energy of FW and BW waves during cardiac relaxation. This is likely due to increased contractility, assisted by added reflection from the systemic circulation that enters the coronary arteries via the aorta.
Abstract 19020: Angiotensin Converting Enzyme-2 Activation Attenuates Right Ventricular Hypertrophy and Dysfunction After Pulmonary Artery Banding in Rats
Authors: Shenoy Vinayak , Qi Yanfei , Katovich Michael , Raizada Mohan
Published: April 2024

Background:
Right ventricular (RV) hypertrophy and dysfunction are important prognostic factors in pulmonary hypertension. Pharmacological therapies aimed at improving RV function reduce symptoms, enhance cardiac hemodynamics, and potentially increase survival in pulmonary hypertensive subjects. We hypothesized that activation of angiotensin-converting enzyme 2 (ACE2) using Diminazene (DIZE) will improve RV function in a chronic pressure overload model of pulmonary artery banding (PAB).

METHODS:
Chronic pressure-overload RV hypertrophy and dysfunction was induced by PAB in adult male rats (9 weeks of age). A subset of rats was treated with DIZE (15mg/kg/day, subcutaneous injection) following PAB. After 5 weeks of banding, right ventricular hemodynamics and cardiac functions were evaluated.

RESULTS:
Five-weeks of PAB resulted in significant increase in right ventricular systolic pressure, which was not affected by DIZE treatment (Control: 31± 1mmHg; PAB: 49± 3mmHg; PAB+DIZE: 44± 2mmHg). However, DIZE injection significantly improved RV function. Specifically, DIZE decreased right ventricular end diastolic pressure (RVEDP; Control: 3.55± 0.71mmHg; PAB: 10± 0.92mmHg PAB+DIZE: 7.51± 0.83mmHg), reduced +dP/dt (Control: 2466± 62mmHg/s; PAB: 3055± 172mmHg/s; PAB+DIZE: 2670± 193mmHg/s) and -dP/dt (Control: -1735± 54mmHg/s; PAB:-2628± 166mmHg/s; PAB+DIZE: -2281± 144mmHg/s). In addition, DIZE decreased RV hypertrophy as measured by RV/LV+S ratio (Control: 0.24± 0.01; PAB: 0.42± 0.02; PAB+DIZE: 0.37± 0.010).

CONCLUSIONS:
Treatment with DIZE, an ACE2 activator led to significant improvements in RV function and decreased hypertrophy in a chronic pressure-overload rat model. Thus, DIZE may represent a novel treatment for RV dysfunction and failure.
Abstract 19050: Accelerated Neointimal Hyperplasia in a Diabetic Mouse Model via Elevated microRNA-221/222
Authors: Lightell, Jr. Daniel J , Woods Thomas C
Published: April 2024

Introduction:
Neointimal hyperplasia is increased in the diabetic population, promoting accelerated plaque development and an increased risk of stroke and myocardial infarction. Two microRNA, miR-221/222, that are known to promote neointimal hyperplasia in response to vascular injury through down regulation of the cyclin dependent kinase inhibitor, p27Kip1, are elevated in the internal mammary arteries of diabetic subjects. We hypothesized that miR-221/222 would be elevated in the arteries of a mouse model of diabetes and that this increase in miR-221/222 would promote a decrease in p27Kip1 and an increase in neointimal hyperplasia following vascular injury.

Methods:
Femoral artery wire injury coupled with perivascular local delivery of a low dose of either non-targeting (NT) or miR-221/222 targeting antisense oligonucleotides (AS) was performed in NONcNZO10 mice fed a diabetes inducing diet (DM) or normal chow (ND). We compared neointimal hyperplasia and the expression of miR-221/222 and p27Kip1 in DM and ND mice in the presence and absence of AS treatment.

Results:
DM mice exhibited a ~2 fold elevation in expression of miR-221/222 both pre- and post-injury compared to ND mice. This was coupled with significant decreases in p27Kip1 mRNA and protein as well as the decreases in the mRNA for two additional targets of miR-221/222, c-Kit and p53 up-regulated modulator of apoptosis. In DM mice AS treatment reduced miR-221/222 expression (Figure 1A) and restored normal p27Kip1 mRNA and protein levels, with no effect in the ND mice. Similarly, neointimal hyperplasia was significantly elevated in the NT treated arteries of the DM mice, but AS treatment reduced neointimal hyperplasia to levels comparable to the ND mice (Figure 1B).

Conclusions:
We conclude that diabetes is accompanied by an increased arterial expression of miR-221/222 that in turn accelerates neointimal hyperplasia in response to arterial injury.
Abstract 19067: Rehospitalization Characteristics in Patients With Continuous Flow Left Ventricular Assist Devices
Authors: Thomas Sunu S , Han Jason , Nahumi Nadav , Lippel Matthew , Garan Arthur R , Yuzefpolskaya Melana , Colombo Paolo , Takayama Hiroo , Naka Yoshifumi , Uriel Nir , Jorde Ulrich P
Published: April 2024

Background:
Readmission diagnoses, timing and hospital length of stay have become a major clinical and health policy focus in the management of patients with continuous flow left ventricular assist devices (CF-LVADs). The aim of this study was to characterize CF-LVAD rehospitalizations at a large volume center.

Methods:
We performed a retrospective analysis of patients implanted with HeartMate II (Thoratec, Pleasanton, CA) CF-LVADs from March 31, 2004 to September 20, 2012. Readmission metrics were evaluated in discharged patients following CF-LVAD placement as either a bridge to transplant (BTT) or destination therapy (DT) strategy. Data are reported as median and interquartile range, unless otherwise stated.

Results:
HeartMate II CF-LVADs were implanted in 205 patients (BTT 150; DT 55). Total time on LVAD support was 247.0 yrs (BTT 147.4 yrs; DT 99.6 yrs). Of 741 non-transplant readmissions, the majority were due to cardiac (BTT 27%; DT 24%), bleeding (BTT 12%; DT 29%), infection (BTT 19%; DT 11%) and device (BTT 12%; DT 9%) related diagnoses. Freedom from readmission at 30 days post-discharge following device implantation was 73.5% (SE 0.03). Table 1 lists 30 day and 1 yr event rates for common readmission diagnoses. DT patients had significantly higher 1 yr gastrointestinal bleeding (GIB) event rates than BTT (0.41 vs 0.21, p<0.01). Median length of stay per readmitting diagnosis included drive-line infection (10.5 days (6.8-17.0)); heart failure (9.5 days (5.0-15.0)); device malfunction (7.0 days (2.0-18.8)); and GIB (7.0 days (3.0-11.0)) for all CF-LVAD patients.

Conclusion:
Readmissions following CF-LVAD implantation are frequent and consume significant hospital inpatient time. Bleeding, cardiac, infection, and device related diagnoses contribute to the greatest burden of CF-LVAD rehospitalizations.
Abstract 19116: Depletion of T Lymphocytes Exerts Cardioprotection and Antifibrotic Effect in Streptozotocin-Induced Type 1 Diabetic Mice
Authors: Abdullah Chowdury S , Li Zhao , Jin Zhu-Qiu
Published: April 2024

Background and Aims:
T lymphocytes infiltration into myocardium has been observed in both type 1 and type 2 diabetic patients. However, effects of T cells on cardiac function and survival as well as fibrosis in a diabetic model remain to be determined.

Methods:
In this study, depletion of T cells was achieved by using pharmacological approach (fingolimod, a sphingosine 1-phosphate receptor modulator) and genetic approach (Rag1 knockout mice without mature lymphocytes). Type 1 diabetes was induced by intraperitoneal injection of streptozotocin (STZ) for five consecutive days with small dose (50 mg/kg) in both C57BL/6J mice and Rag1 mutant mice. Treatment with Fingolimod (0.3 mg/kg/day, i.p.) was performed in STZ diabetic mice. Body weight of mice was monitored twice a week. Fasting blood glucose level was detected after 4 weeks and 11 weeks of STZ administration. At the end of 11 weeks, blood T cells (CD4+ and CD8+) counting was conducted with flow cytometry. Serum insulin content was measured with ELISA. Infiltration of T cells (CD3+ positive staining) into the myocardium of mice was observed with immunohistochemistry method in paraffin sections. The fibrosis of myocardium was quantified by using trichrome staining. Cardiac contractile force was recorded with Langendorff heart perfusion system. Apoptosis of hearts was detected with TUNEL staining.

Results:
Fingolimod had no effects on body weight and glucose level (478+/-20 mg/dl vs 426+/-34 mg/dl in vehicle group, p=n.s.). Fingolimod significantly reduced the blood T cells (CD4+ cells: 0.16+/-0.12% vs 7.07+/-0.68% in vehicle group, P<0.01, n=4-5 per group) in C57BL/6J mice. Fingolimod also enhanced cardiac contractility and reduced fibrosis as well as apoptosis of the myocardium in C57BL/6J mice. Compared to wild-type (B6), Rag1 mutant mice remained the high blood glucose level in STZ model (447+/-36 mg/dl, n=11). However, cardiac fibrosis was reduced and cardiac contractile force was enhanced in Rag1 mutant mice.

Conclusions:
Depletion of T cells in the circulation with pharmacological agent-Fingolimod or Rag1 mutation without mature lymphocytes renders hearts more resistant to the cardiac injury caused by diabetes.
Abstract 19119: Augmentation Index is Associated With Renal Function in Black but Not in White Young Adults: The Bogalusa Heart Study
Authors: Fernández Alonso Camilo , Chen Wei , Srinivasan Sathanur R , Berenson Gerald S
Published: April 2024

Background:
Increased Augmentation Index (AI) has been associated with kidney damage in patients with hypertension and underlying cardio-metabolic diseases. However, information is scant on the association between AI and renal function/performance in non-institutionalized asymptomatic young adults.

Hypothesis:
Race-specific differences exist on the association between AI and renal function (as defined by estimated glomerular filtration rate (eGFR)), in asymptomatic young adults.

Methods:
As a part of the Bogalusa Heart Study, a long term community based study, 884 non-institutionalized participants with a mean age of 43.5 years (29.4-51.3), 68.3% whites and 41.9% male were considered. AI was estimated non-invasively by applanation tonometry of the radial artery. eGFR was calculated using the MDRD study equation. Race-specific independent association of AI with eGFR was tested through multivariable adjusted linear regression analyses.

Results:
Black participants had higher AI and eGFR levels compared to whites. Of note, black females had significantly higher levels of AI and eGFR compared to black males (p<0.01). No significant sex differences were noted in white participants. In multivariable adjusted linear regression analyses, controlling for age, sex and traditional cardiovascular risk factors, AI was significantly and directly associated with eGFR in blacks (B=1.12, p<0.001), but not in whites (B=0.039, p=0.34)

Conclusion:
The observed differences in the impact of AI on renal function help support the hypothesis that underlying mechanisms for cardiovascular disease related-end organ damage differ among race groups. Further, this may aid to enhance race-specific approaches on prevention and screening of cardiovascular disease and complications.
Abstract 19137: Association of Pulmonary Hypertension and Left Ventricular Dysfunction: Impact of Demographics
Authors: Sharif Roozbeh , Kumar Arnav , Khan Adnan , Parekh Trisha , Kohli Anjali , Hoang Van , Morsy Mohammad , Khalife Wissam
Published: April 2024

The association between left ventricular diastolic dysfunction (LVDD) and pulmonary hypertension (PH) is shown in the literature, studies on the linear association between LVDD and PH severity and effect of demographics on this association are lacking. We aimed to investigate the correlation of LVDD with presence and/or severity of PH and to examine whether patient’s demographics modifies this association.

Methods:
Study population included 2702 randomly selected patients with ejection fraction (EF) ≥ 50%, who presented to the echocardiographic lab at a tertiary care academic center between 2008 and 2011. Diastolic function was assessed based on echocardiographic characteristics. PH was diagnosed if right ventricle systolic pressure (RSVP) was ≥ 40 mmHg. Using logistic regression analysis, the association between diastolic function and presence and severity of PH was examined after adjusting for potential demographic and clinical confounders. Then, we examined the interaction term of demographics (age, sex and combination of age and sex) in regards to the association between LVDD and PH.

Results:
Among 2702 patients, 1301 (48.4%) were female, 842 (31.2%) had normal LVDD and 694 (25.7%) had PH. Patients with LVDD had higher frequency of PH compared to those with normal diastolic function (28.1% vs. 18.6%, OR: 1.7; 95%CI: 1.4, 2.1; p< 0.0001). RVSP increases at higher stages of LVDD (p<0.0001). Among patients with LVDD, PH was found in 24.7% patients with impaired relaxation, 44.5% of pseudonormal, and 52.5% of those with restrictive.

Subgroup analysis showed that in patients 60 (OR: 1.9 vs. 0.9, p<0.0001 and 0.8820, respectively). Besides, the association of LVDD and PH was higher among female patients < 60, compared to males <60 (OR: 2.5 vs 1.5, p<0.0001 and 0.0800, respectively). Sex did not modify the association between LVDD and PH.

Conclusion:
Patients with LVDD have higher risk of PH, compared to those patients with normal diastolic function. The severity of PH also increases with higher stages of the LVDD. In addition, these findings were more pronounced in middle age females.
Abstract 19147: Time From First Medical Contact to Aspirin in ST Elevation Myocardial Infarction: An International Survey of Acute Coronary Syndromes in Transitional Countries (ISACS-TC) Study
Authors: Bugiardini Raffaele , Cenko Edina , Dorobantu Maria , Kedev Sashko , Vasiljevic Zorana , Bozidarka Knezevic , Milicic Dabor , Ricci Beatrice , Majstorovic Stakic Marta , Manfrini Olivia
Published: April 2024

BACKGROUND:
A significant number of patients who suffer from STEMI do not reach a hospital within the recommended timeframe in the South Eastern European countries. Unequal dispersion of PCI-capable facilities throughout this area results in transport distances that can exceed 100 miles, while response times vary greatly dependent upon volunteer ambulance services.

METHODS:
The aim of the International Survey of Acute Coronary Syndromes in Transitional Countries (ISACS-TC /
NCT01218776
) registry was to assess whether initial antiplatelet/ anticoagulant treatment at the point of prehospital first medical contact impacts in-hospital outcomes. To assess the value of this strategy were compared: prehospital versus in-hospital first medical contact; those arriving at the hospital by ambulance versus those whose initial hospital care was an ambulatory/community center.

RESULTS:
Of the 2295 patients enrolled in the study, 392 received fibrinolysis, 753 primary PCI, 86 facilitated PCI, and 1064 standard medical therapy having overcome the golden hours for reperfusion therapy. Compared with the in-hospital group, patients who underwent facilitated PCI (7%, n=34) experienced 9.6 % reduction in cardiovascular mortality (odd ratio [OR] 0.096 coefficient interval [C.I] 0.012-0.69 P=0.004). Arrival by an ambulatory/community center incurred a substantial delay from first medical contact to reperfusion (fibrinolysis 76 min [63 min to 105 min] and PCI 35 min [224 min to 612 min]) compared with arrival by ambulance (fibrinolysis 47 min [32 min to 68 min] and PCI 108 min [85 min to 150 min]).

CONCLUSIONS:
These findings support prehospital antiplatelet/ anticoagulant treatment followed by reperfusion therapy in patients presenting early with STEMI, who do not have access to hospital care within the recommended time-frame of 60 minutes from first medical contact. Those activating the prehospital medical response system without receiving prehospital ambulance assignment experienced the longest delay from first medical contact to reperfusion, indicating a lost opportunity to enhance ST elevation myocardial infarction patient outcomes.