bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12257: Calmodulin Interacting Genes as a Novel Candidate for Pathogenesis of Long-QT Syndrome
Authors: Aiba Takeshi , Shigemizu Daichi , Nakagawa Hidewaki , Ozaki Kouichi , Miya Fuyuki , Satake Wataru , Toda Tatsushi , Miyamoto Yoshihiro , Fujimoto Akihiro , Suzuki Yutaka , Kubo Michiaki , Tsunoda Tatsuhiko , Kusano Kengo , Yasuda Satoshi , Ogawa Hisao , Tanaka Toshihiro , Shimizu Wataru
Published: July 2021

Background:
Approximately 30% of long-QT syndrome (LQTS) cases remains genetically elusive. Here, we investigated usefulness of the whole exon sequencing (WES) by next-generation sequencing for identification of novel pathogenic candidates which directly or indirectly interact with proteins encoded by known LQTS genes.

Methods:
Of 1815 Japanese LQTS cohort patients, WES was performed in 59 LQTS patients and 61 unaffected individuals from 35 families and 138 unrelated LQTS cases, all were screened major LQTS genes such as KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2 and KCNJ2. After WES, the genes known as inherited arrhythmias were screened by the Human Gene Mutation Database, and the Sanger sequencing was also referred for validation of the mutations and common variants were excluded by the public (1000G, ESP6500 and dbSNP) and Riken database.

Results:
Total 92 candidate mutations including 11 de novo, 5 recessive (2 homozygous and 3 compound heterozygous) and 73 dominant mutations in 88 genes were identified in 23 of the 35 families. Protein-protein interaction network analyses revealed ten new pathogenic candidates (WDR26, RYR2, UBR5, UBR4, KIF21B, CIT, SIRT6, PIK3CG, PI4KA and RIMS1) that directly or indirectly interact with proteins encoded by known LQTS genes. Furthermore, gene based association studies identified an additional novel candidate; SLC2A5. Taken together, mutations in these new candidates or known LQTS genes were identified in 13 of the 35(37%) genotype-unknown LQTS families. Moreover, 5 of the 11 newly identified candidates directly interact with calmodulin (CaM). Subsequent variant analysis in the independent set of 138 cases identified 16 variants in the 11 genes, of which, 14 (87.5%) were in the CaM-interacting genes and 8 of them were in RYR2. Many of the patients with RyR2 mutation had similar exercise-induced cardiac events (3 syncope, 2 VF) as LQTS patients, while the QTc interval was shorter in patients with RyR2 mutation than those with genotype-negative LQTS (441±32 vs. 487±47ms; p=0.01).

Conclusions:
These findings suggest that CaM interacting genes have an important role on the pathogenesis of LQTS. In particular, RYR2 mutations may cause an overlap syndrome between catecholaminergic polymorphic ventricular tachycardia and LQTS.
Abstract 12275: Knock-down of Insulin-like Growth Factor-1 Receptor in the Endothelium Decreases Anti-oxidant Capacity of Aorta, Leading to Increased Atherosclerosis
Authors: Higashi Yusuke , Shai Shaw-Yung , Hou Xuwei , Sukhanov Sergiy , Delafontaine Patrice
Published: July 2021

Systemic infusion of insulin-like growth factor-1 (IGF-1) in Apoe-deficient mice exerts anti-atherogenic effects by reducing oxidative stress and pro-inflammatory responses in lesions, yet precise mechanisms remain elusive. We have shown that smooth muscle specific IGF-1 overexpression does not reduce atherosclerotic burden, suggesting that smooth muscle cells do not mediate anti-atherogenic effects of IGF-1. The endothelium is integral in atherogenesis, however a potential role of endothelial IGF-1 receptor (IGF1R) signaling in atherogenesis is unknown. To investigate, we generated Apoe-deficient/endothelial IGF1R-knockdown (En-IGF1R-KD) mice, which are Igf1r-floxed and express Cre recombinase driven by the Cdh5-promoter. IGF1R expression levels were lower by 60% in endothelial cells isolated from En-IGF1R-KD mice compared to IGF1R-flox cells. After 12 weeks of high-fat diet feeding, En-IGF1R-KD mice had more atherosclerotic plaque than IGF1R-flox control (Oil Red O staining of en face aorta, 33±8% increase, P<0.05), indicating that loss of endothelial IGF1R signaling enhanced atherogenesis. Intriguingly, En-IGF1R-KD did not alter systolic blood pressure (IGF1R-flox; 119.5±2.6 vs. En-IGF1R-KD; 119.1±2.0 mmHg) or plasma nitrate/nitrite levels (index of nitric oxide bioavailability, IGF1R-flox; 8.6±0.4 vs. En-IGF1R-KD; 7.3±0.9 uM). Vasorelaxation to acetylcholine (Ach) was equivalent in aortas of En-IGF1R-KD and IGF1R-flox mice after high-fat diet feeding, suggesting that endothelial function was not affected by En-IGF1R-KD. Intriguingly, high-fat diet feeding made aortas hyporesponsive to Ach both in En-IGF1R-KD and IGF1R-flox mice, and in normal chow fed mice En-IGF1R-KD aortas were more responsive to Ach than IGF1R-flox aortas, indicating that loss of IGF-1 signaling improved endothelial function. On the other hand, anti-oxidant capacity as measured by Hydroxyl Radical Antioxidant Capacity Activity Assay was significantly lower in En-IGF1R-KD aorta by 30.0±6.7%, consistent with anti-oxidant effects of IGF-1 on endothelial cells. In summary, our results indicate that IGF1R signaling in the endothelium is atheroprotective, and that this atheroprotective effect is mediated via an anti-oxidant mechanism.
Abstract 12317: Sex Differences in Lipid Phenotypes Among Young Patients With Acute Myocardial Infarction
Authors: Lu Yuan , Dreyer Rachel , Herbert Peter , Caulfield Michael , Murugiah Karthik , Geda Mary , Jackson Elizabeth A , Lichtman Judith , Lorenze Nancy , D'Onofrio Gail , Spatz Erica , Spertus John , Krumholz Harlan
Published: July 2021

Introduction:
Young women (≤55 years) with acute myocardial infarction (AMI) have higher rates of mortality and morbidity than similarly aged men. An abnormal lipid profile following AMI is a risk factor for recurrent cardiovascular events and may contribute to worse outcomes in young women. However, little is known about the extent to which young women and men with AMI have similar or distinct lipid profiles after hospital discharge. We characterized sex difference in lipid phenotypes in young patients with AMI.

Methods:
We included 2,217 AMI patients (715 men and 1,502 women) aged 18-55 years from the VIRGO study. Standard lipid profile and lipoprotein subclasses were measured 1-month after discharge for AMI. Both sexes were compared on three dyslipidemia phenotypes: 1) increased low-density lipoprotein cholesterol (LDL-C≥100 mg/dL), 2) decreased high-density lipoprotein cholesterol (HDL-C<40 mg/dL for men, <50 mg/dL for women), and 3) increased small/medium LDL particles, decreased large HDL particles, and decreased LDL peak particle size (cutoffs based on sex-specific tertile values of healthy individuals). We also compared patient characteristics between sexes and used t-tests to assess statistical significance.

Results:
The median age was 48 years for both sexes. At baseline, women were more likely than men to be black, single, to have financial strain, obesity and diabetes (all P values<0.001). At 1-month after hospital discharge, women had higher rates of dyslipidemia phenotypes than men, including increased LDL-C (P=0.031, see Table) and an atherogenic phenotype characterized by multiple lipoprotein subclasses (P<0.001). The latter had the largest difference between men and women. The proportion of decreased HDL-C was similar for both sexes (P=0.300).

Conclusion:
Young women have higher rates of dyslipidemia phenotypes than men at 1-month after discharge for AMI. Effective interventions are needed to improve lipid control in young women with AMI.
Abstract 12404: Efficacy and Safety of Apixaban Compared With Warfarin in Patients With Atrial Fibrillation and Normal Renal Function over Time: Insights From the ARISTOTLE Trial
Authors: Hijazi Ziad , Hohnloser Stefan H. H , Andersson Ulrika , Alexander John H , Granger Christopher B , Hanna Michael , Keltai Matyas , Parkhomenko Alexander , Lopez-Sendon Jose L , Lopes Renato D , Siegbahn Agneta , Wallentin Lars
Published: July 2021

Introduction:
It has been recently observed that one oral factor-Xa inhibitor (at the dose studied) might be associated with decreased efficacy in patients with atrial fibrillation (AF) and normal renal function. In the ARISTOTLE trial, apixaban compared to warfarin reduced stroke, mortality, and major bleeding irrespective of renal function at baseline. Our aim was to evaluate the efficacy and safety of apixaban vs. warfarin in patients with normal renal function over time.

Methods:
In ARISTOTLE, 16,971 patients had serial creatinine measurements available after randomization. There were a total of 397 stroke or systemic embolic events, 286 ischemic or unspecified strokes, and 712 major bleed events during median follow-up of 1.8 years. Normal renal function was predefined as an estimated glomerular filtration rate (eGFR) >80 mL/min. The relations between renal function, treatment, and outcomes were investigated by using Cox regression with renal function as a continuous time dependent covariate, fitted using restricted splines. Hazard ratios with 95% confidence intervals (CI) were analyzed based on continuous eGFR level during follow-up using both the Cockcroft-Gault and CKD-EPI equations.

Results:
The relative risk of stroke or systemic embolism was consistently lower in participants randomized to apixaban compared with warfarin. The patterns were similar for the ischemic or unspecified stroke outcome as well as for major bleeding (Table).

Conclusions:
Apixaban, relative to warfarin, demonstrated preserved efficacy and safety in AF patients with normal renal function over time.
Abstract 12414: The Impact of Frailty on Cause Specific Mortality Among Elderly Patients Undergoing PCI
Authors: Orme Nicholas M , Lennon Ryan J , Lewis Bradley R , Gulati Rajiv , Sandhu Gurpreet , Spertus John , Roger Veronique L , Singh Mandeep
Published: July 2021

Background:
The presence of frailty increases the risk of long-term mortality for a myriad of reasons, but its association with cardiac-specific mortality among the elderly undergoing percutaneous coronary intervention (PCI) is unknown. We sought to determine the relationship between frailty and cause-specific (cardiac versus non-cardiac) mortality among elderly patients undergoing PCI.

Methods:
A prospective cohort of elderly (>65 years) patients undergoing PCI at Mayo Clinic between October 2005 and September 2008 were tested for frailty using the Fried criteria. Vital status was prospectively monitored including evaluation of death certificates, telephone interviews and review of autopsy/medical records.

Results:
Frailty data was obtained in 428 (84%) of 508 elderly patients (median age 74.2 years [SD 6.4, range 65-100]; 59% male). Of these, 92 (21%) patients were frail while 231 (54%) had intermediate frailty and 105(25%) were not frail. Frail patients were older than intermediate and non-frail patients (77.6 vs 74.3 vs 71.0 years; p<0.001) and had more comorbidities (mean Charlson index 4.6 vs 3.9 vs 2.8; p<0.001). There were 113 deaths (26% of cohort) during 5.1 median years of follow-up, of which 77 (68%) were classified as non-cardiac and 36 (32%) which were classified as cardiac. Frailty at baseline was associated with poor overall survival compared to non-frail patients (HR 6.1, 95% CI 3.2, 11.6; p<0.001). The estimated effect of frailty was nearly 3 times greater for cardiac mortality (HR 13.1, 95% CI 3.0, 57.0; p=0.001) than non-cardiac mortality (HR 4.6, 95% CI 2.2, 9.7; p<0.001). These findings remained significant following multivariable adjustment.

Conclusions:
Frailty is common among elderly patients undergoing PCI and is associated with poor overall survival and both cardiac and non-cardiac causes of death.
Abstract 12518: MicroRNA 139-5p Coordinates APLNR-CXCR4 Crosstalk During Vascular Maturation
Authors: Papangeli Irinna , Kim Jongmin , Maier Inna , Kang Yujung , Tanaka Keiichiro , Ju Hyekyung , Lee Aram , Kojima Yoko , Siekmann Arndt , Chun Hyung
Published: July 2021

Rationale:
Sprouting angiogenesis is governed by the concept of tip/stalk cells that guides our understanding of the transition from vascular sprouting to maturation and ultimately quiescence. The VEGF and Notch signaling pathways have been extensively described in regulating the discrimination between these two cell populations. However, several additional tip and stalk cell specific genes have been identified. To date, unresolved questions remain, and our understanding of the mechanisms by which these signaling processes are integrated is incomplete.

Objective:
We set out to investigate novel mechanisms by which signaling pathways involving two G protein coupled receptors (GPCRs), expressed in a mutually exclusive fashion in the tip/stalk cell populations, are intricately linked in vascular development.

Methods/Results:
Using a combination of in vivo and in vitro techniques, we demonstrate the critical role of crosstalk between APLNR and CXCR4 in vascular maturation. We show robust flow induced expression of the stalk cell specific APLNR, that leads to marked suppression of CXCR4 expression, a mechanism to achieve tip cell restricted expression of the latter. Retinas from Apln (ligand), Aplnr (receptor) and endothelial specific Aplnr deleted mice show retarded vascular expansion, reduced vascularized area and fewer vascular branch points. These phenotypes are in part due to increased expression of Cxcr4 in Apln-/- and Aplnr-/- retinal vessels as Cxcr4 inhibition through a selective inhibitor can ameliorate the Aplnr phenotype. The crosstalk between the two GPCRs was found to involve a key shear responsive microRNA, miR-139-5p, which is upregulated by APLN/APLNR signaling and directly targets CXCR4 in endothelial cells. In accordance, Apln-/- and Aplnr-/- retinal endothelial cells showed depleted levels of miR-139-5p. Lastly, we demonstrate that atorvastatin, an HMG-CoA reductase inhibitor shown to enhance APLNR signaling, can induce miR-139-5p expression and rescue the vascular phenotypes associated with APLN/APLNR deficiency.

Conclusions:
These findings provide key mechanistic insights into a critical microRNA based crosstalk between two GPCR signaling cascades, which regulates important steps in vascular maturation.
Abstract 12535: Interaction Between Gene Polymorphism of Alpha Adducin (ADD1) and Alcohol Habit on the Risk of Essential Hypertension in A Japanese Population
Authors: Eto Masahiko , Okayama Masanobu , Takeshima Taro , Kumada Maki , Aonuma Takanori , Nakamura Yoshikazu , Kajii Eiji
Published: July 2021

Objectives:
To evaluate the interactions between single nucleotide polymorphism (SNP) of alpha adducin gene(ADD1) and alcohol habits on the risk of hypertension (HT) in Japanese.

Methods:
We analyzed 19284 Japanese subjects enrolled in the genome banking project at Jichi Medical University, including 8711 HT cases and 10573 non-HT controls.Diagnosis of HT was based on BP≥140/90mmHg or anti-HT medications. We divided the subjects into four groups according to gender and age (≤49 or ≥50) and performed statistical analyses in each group. SNP rs4961(GG/GT/TT, Gly460Trp) of ADD1 was genotyped by TaqMan method. Alcohol habits were categorized to never, sometimes, and daily drinker for frequency of drinking. To assess the contribution of genotypes, alcohol habits, and the combinations of both to HT risk, we compared the frequencies of them between cases and controls by chi-squared test. The strength of the associations was estimated by odds ratios(ORs) and 95% confidence intervals(CI) by using logistic regression analysis. For the interaction, we assessed the joint ORs, which were calculated for each of nine combined categories created by cross-classification. Non-risk reference was never drinker carrying GG.

Results:
(1)Although genotype distributions did not significantly differ between cases and controls in all groups, the frequencies of alcohol habits and the combinations of both significantly differed in all groups.(2)Compared to GG, the ORs (95%CI) of TT were 1.11(0.83-1.49) in M≤49, 1.00(0.86-1.17) in M≥50, 0.83(0.58-1.17) in F≤49, and 0.99(0.85-1.15) in F≥50. Compared to never drinker, the ORs (95%CI) of daily drinker were 1.77(1.32-2.37, p<0.001) in M≤49, 1.64(1.44-1.87, p<0.001) in M≥50, 1.26(0.88-1.80) in F≤49, and 1.13(0.90-1.43) in F≥50. Compared to never drinker with GG, the ORs (95%CI) of daily drinker with TT were 3.43(1.74-6.73, p<0.001) in M≤49, 1.83(1.41-2.39, p=0.001) in M≥50, 0.77(0.37-1.59) in F≤49, and 1.41(0.92-2.17) in F≥50.

Conclusions:
The interactions between ADD1 rs4961 and alcohol habits had significant effects on HT risk in Japanese males≤49 years. The interactions between ADD1 genotypes and alcohol habits may contribute to young-onset hypertension in Japanese males.
Abstract 12556: Prospective Association of Incident Atrial Fibrillation With Resting Heart Rate: The Henry Ford Hospital Exercise Testing (FIT) project
Authors: Aladin Amer I , Al Rifai Mahmoud , Rasool Shereen H , Keteyian Steven J , Brawner Clinton A , Blumenthal Roger S , Al-Mallah Mouaz H , Blaha Michael J , McEvoy John W
Published: July 2021

Objective:
Autonomic nervous system dysfunction plays an important role in atrial fibrillation (AF) initiation. Research suggests that vagal tone may mediate paroxysmal AF, such that a low resting heart rate (RHR) is associated with incident AF. However, conflicting reports also suggest that elevated RHR identifies risk for AF. Thus, we sought to further clarify the link between RHR and AF, independent of cardiorespiratory fitness (CRF).

Methods:
We analyzed 51,451 individuals without a history of AF who underwent a clinically-indicated exercise stress test between January 1991 and May 2009. Persons on nodal blocking medications were excluded. Adjusted hazard ratios (HRs) for AF were estimated using Cox models with baseline RHR categorized by <70, 70-85 (reference) and >85 beats-per-minute (bpm) (sensitivity analyses used quartile of RHR). Incident AF was defined by coding for new AF on claims files on ≥three subsequent encounters. We tested for effect modification by age (<60 vs. ≥60 years) and CRF (determined metabolic equivalents [METs] achieved on stress testing).

Results:
Mean age was 53 ± 13 years, 53% were men and 28% were black. Subjects in the lowest RHR category (<70 bpm) were older, more likely to be male diabetic and hypertensive, but had higher CRF. Compared to RHR 70-85, those with RHR <70 were at increased risk of AF [HR (95% CI), 1.15 (1.06-1.25)] (Table). While there was a trend for higher risk with RHR >85, this was non-significant after full adjustment. The association between low RHR and AF was independent of CRF and, in the sensitivity analysis using RHR quartile, appeared to be driven by excess risk in persons with RHR <64 bpm. There was no interaction by age or CRF level.

Conclusion:
We found that low RHR had a robust association with incident AF. Persons with low RHR, particularly in the presence of other AF risk factors, may benefit from AF screening and heart rhythm surveillance.
Abstract 12582: The Origin of Hypertension and Sympathetic Regulation in Diet Induced Obesity
Authors: Lim Kyungjoon , Barzel Benjie , Burke Sandra L , Head Geoffrey A
Published: July 2021

Obesity is closely associated with a greater risk of developing hypertension and there is a strong link between bodyweight gain and greater blood pressure (BP). Plasma leptin levels correlate with BP and renal sympathetic nerve activity (RSNA). The central effects of leptin are mediated primarily through the arcuate (ARC) nucleus of the hypothalamus from which peripheral signals are relayed downstream, to other hypothalamic nuclei, via a network of second order neurons. Dense projections of both Neuropeptide Y (NPY) and alpha-melanocyte stimulating hormone (α-MSH) containing neurons ascend from the ARC and terminate in several hypothalamic nuclei such as the ventromedial hypothalamus (VMH) which are the key centres of energy homeostasis, hemodynamics and sympathetic tone to brown adipose and renal vasculature. It is therefore possible that a change in the activity of either POMC or, NPY neurons or both may underlie the mechanism by which sympathetic output is increased in obesity, leading to hypertension.

In the present study we assessed the contribution of α-MSH and NPY neurons in the VMH on development of diet-induced neurogenic hypertension.

New Zealand White rabbits were instrumented with a VMH cannula and a renal sympathetic nerve electrode. Blood pressure (BP) was measured by means of an intra-arterial catheter. Rabbits were injected with α-MSH, SHU9119 (MC3/4R antagonist), NPY or Leptin receptor antagonist into the VMH, 60 minutes apart using an injector.

Following 3 weeks of a high fat diet (HFD, 13.5% fat), conscious rabbits had higher BP (+7.6 ± 0.5mmHg, P<0.001) and RSNA (+4.6 ± 0.4nu, P<0.001) compared to control group (3.5% fat). α-MSH injection into the VMH increased BP (+7%) and RSNA (+35%) (P<0.001) and SHU9119 injection showed reduction (P<0.05) in BP (-7%), HR (-5%) and RSNA (-23%) in HFD rabbits. Leptin antagonist or NPY injection showed dose dependant reduction in BP (-7%), HR (-5%) and RSNA (-11%) (P<0.05) when given to HFD rabbits. NPY injection reduced BP in all groups.

We conclude that the HFD feeding may induce pathway-specific changes in the VMH and VMH is the likely origin of leptin-mediated sympathoexcitation, α-MSH hypersensitivity and altered central responsiveness to NPY.
Abstract 12613: Apurinic/apyrimidinic Endonuclease/redox Factor-1 Gene Enhances Anti-apoptotic Function of Cardiac Progenitor Cells via TAK1-Activation and Promotes Cardiac Regeneration in Myocardial Infarction
Authors: Aonuma Tatsuya , Takehara Naofumi , Maruyama Keisuke , Kabara Maki , Matsuki Motoki , Yamauchi Atsushi , Kawabe Junichi , Hasebe Naoyuki
Published: July 2021

Introduction:
Overcoming the poor survival of cell grafts is an indispensable mission in cell therapy. Apurinic/apyrimidinic endonuclease/redox factor-1 (APE1) is known as a multifunctional enzyme to encourage cell survival, whereas the role of APE1 in cardiac cell therapy is still unknown.

Hypothesis:
APE1 overexpression in cardiac progenitor cells (CPC) ameliorates the effect of cardiac cell therapy.

Methods:
CPCs from 8-10 week-old C57BL/6 mice hearts were transfected with APE1-DsRed gene (APE1-CPC) or DsRed gene (Control [Ct]-CPC). The apoptosis induced by oxidative stress was assessed in APE1-/Ct-CPCs, and in neonatal rat cardiomyocytes (NRCM) within the co-culture system of APE1-/Ct-CPCs. Western blot analysis indicated the cellular signal to protect CPC via APE1 enzyme. To evaluate the effect of APE1 overexpression in cell therapy, we transplanted APE1-CPCs and Ct-CPCs into the mice myocardial infarction (MI) model and assessed the pathophysiological role of APE1 with functional and histological analysis.

Results:
Under the oxidative stress condition, APE1 overexpression inhibited the apoptosis of CPCs and accelerated TAK1 activation (Ct-CPC : APE1-CPC = 1.5±0.4 : 3.3±1.6 fold, p<0.05), and consequently NfKB phosphorylation in CPCs. In the co-culture system, the apoptosis of NRCMs was inhibited with APE1-CPCs compared to that with Ct-CPCs. In vivo, in the mice MI model, the number of total CPC grafts and cardiac α-actinin-positive graft CPCs were significantly larger in APE1-CPC injected mice (APE1 mice) compared to Ct-CPC injected mice (Ct mice) at 7 days after implantation. Eventually, the left ventricular ejection fraction of APE1 mice was significantly improved compared to Ct mice (Ct mice : APE1 mice = +3.1±6.7 : +11.3±4.0%, p<0.05) and was accompanied with the attenuation of fibrosis at 28 days after implantation.

Conclusions:
APE1 gene inhibited the apoptosis of CPCs and host cells against oxidative stress via the activation of TAK1-NFkB pathway, which is a novel insight into the stress response of APE1 enzyme. Furthermore, APE1-CPC grafts that effectively survived in the ischemic heart restored cardiac dysfunction and attenuated myocardial infarct size, and may be an innovative strategy to reinforce cardiac cell therapy.
Abstract 12632: Impact of Systolic Pressure Response on Measurement of Fractional Flow Reserve
Authors: Ikeda Tomoyuki , Ueno Masafumi , Ikuta Shinichiro , Fujita Kosuke , Yasuda Masakazu , Nakamura Takashi , Kobuke Kazuhiro , Iwanaga Yositaka , Miyazaki Shunichi
Published: July 2021

Background:
Fractional flow reserve (FFR) is calculated as the ratio between distal coronary pressure(Pd)and aortic pressure(Pa)during whole cardiac cycle at stable hyperemia. In clinical practice, we experience various Pd wave pattern during hyperemia, such as decreasing equally in systolic and diastolic phase, or mainly decreasing in diastolic phase.

Purpose:
The aim of the study was to evaluate the impact of systolic and diastolic pressure response during hyperemia in patients with coronary stenosis and an FFR of less than 0.8.

Methods:
A total of 35 patients (40 stenosis)had FFR of less than 0.8 were enrolled. FFR measurements were performed using a standard technique. Based on Pa and Pd wave forms, the decreasing area in systolic and diastolic were calculated by integrating Pa-Pd pressure gradient during hyperemia using the RadiView2.2 software. %Sys value was defined as the percentage of delta systolic area during the whole cardiac cycle (Figure). The results of %Sys values were divided into tertiles to evaluate the most significant factors for systolic pressure response.

Results:
Vessel distribution was as follows: LAD (60%), CX (20%) and RCA (20%). There was a significant difference of vessel distribution in coronary arteries in the upper tertile compared with the other two tertiles of %Sys values (p=0.028). However, the other factors such as FFR value, lesion length and severity, history of diabetes mellitus and previous myocardial infraction were not affected by the %Sys values. In addition, there was a significant difference of %Sys values among three major coronary arteries (LAD 49.4±18.5%, CX 81.5±38.7%, RCA 67.5±20.2%, p=0.006). %Sys values were significantly higher in non-LAD lesions compared with LAD lesions (74.5±30.7% vs 49.4±18.5%, p=0.003).

Conclusions:
There was a significant difference of decreasing pattern of Pd wave during hyperemia among the three coronary arteries. These findings suggest that iFR might not be accurate in non-LAD lesion.
Abstract 12650: Activity of Serum Angiotensin Converting Enzyme 2 is Decreased During Acute Ischemic Stroke in Humans
Authors: Bennion Douglas M , Rosado Christian A , Haltigan Emily H , Sumners Colin , Waters Michael F
Published: July 2021

Introduction:
The expression and activity of angiotensin converting enzyme 2 (ACE2), a cardio and neuro-protective carboxypeptidase, has recently been shown to be dynamically altered during and after stroke in animal models.

Hypothesis:
The aim of this study was to characterize the previously unexplored changes in activity of ACE2 in the serum of patients experiencing acute ischemic stroke.

Methods:
Serum samples were obtained from patients presenting with acute ischemic stroke (n=20) and again at three days post-stroke and enzyme activity levels were analyzed by fluorometric assay and compared to levels from non-stroke control patients (n=20).

Results:
Ischemic stroke resulted in a significant decrease in serum ACE2 at an average of 3.5 hours after stroke, which was followed by a rebound increase by three days later (Fig 1). ACE activity was also significantly decreased following stroke, but without rebound increases. Tumor necrosis factor-alpha converting enzyme activity was not significantly different from control. ACE2 activity was negatively correlated with systolic blood pressure (SBP) among stroke patients (Fig 2), while activity was positively correlated with SBP among a cohort of healthy young adults (n=16).

Conclusions:
The characterization of the dynamic and novel changes in serum ACE2 activity in human stroke, which follow observations from preclinical studies, along with the demonstration of a negative association with SBP, provides new insight for the development of therapies that target this protective system in the context of ischemic stroke. Data are mean ± SEM. RFU: relative fluorescence units; *p<0.001 vs. control; †p<0.05 vs. 4h post stroke.
Abstract 12680: A Comparative Assessment of Echocardiographic Parameters for Determining Mitral Regurgitation Severity
Authors: Uretsky Seth , Argulian Edgar , Marcoff Leo , Koulogiannis Konstantinos , Supariwala Azhar , Rosenthal Mark , Brown John M , Jagarlamudi Ashadevi , Chaudhry Farooq , Awan Hira , Gillam Linda D , Wolff Steven D
Published: July 2021

Introduction:
Guidelines suggest the use of several echocardiographic (Echo) parameters to assess mitral regurgitation (MR) severity using an integrated approach without guidance as how to weight each parameter. The aim of this study is to develop a hierarchy for Echo parameters of MR severity.

Methods:
This prospective study included 80 patients (63 ± 13 yrs, male 57%) with MR. Echo parameters including in this analysis were effective regurgitant orifice area (EROA), vena contracta (VC), LV EDD, color Doppler jet/LA area, the presence of a flail leaflet, and the presence of pulmonary vein wave systolic reversal. MR volume by MRI was calculated as the difference between the LV stroke volume and forward flow. A backward elimination multivariate linear regression analysis was used to determine which Echo parameters predicted regurgitant volume by MRI.

Results:
Individual Echo parameters that correlated best with MR volume by MRI were EROA (r = 0.68, p <0.0001), VC (r = 0.62, p < 0.0001), and the presence of a flail (r = 0.48, p < 0.0001) (figure 1). In the linear regression analysis, significant predictors of MR volume by MRI were EROA, VC and the presence of a flail with a moderate correlation with MR volume by MRI (overall model r = 0.72. p <0.0001). LV EDD, color Doppler jet/LA area, and the presence of reversal of the pulmonary systolic wave having no effect on the model. Of the 3 parameters in the model, EROA correlated the best with MR volume by MRI, followed by VC and the presence of a flail leaflet.

Conclusions:
Echocardiographic parameters for assessing MR had only a moderate correlation with MR volume by MRI. The model that best predicted MR volume by MRI included EROA, VC, and the presence of a flail leaflet. EROA was the best at predicting MR volume by MRI, followed by VC and the presence of a flail leaflet. Not all of the recommended echocardiographic measures of MR severity were helpful in predicting MR volume by MRI. .
Abstract 12714: Aldosterone Activates Raptor to Promote Pulmonary Artery Smooth Muscle Cell Proliferation and Pulmonary Arterial Hypertension
Authors: Stephens Thomas E , Arons Elena , Zhang Ying-Yi , Zaman Paula , Aghamohammadzadeh Reza , Polach Kevin J , Matar Majed , Brown Marcel G , Loscalzo Joseph , Leopold Jane A , Maron Bradley A
Published: July 2021

In pulmonary arterial hypertension (PAH), elevated levels of aldosterone (ALDO) induce a vasculopathy that is characterized by dysregulated pulmonary artery smooth muscle cell (PSMC) growth. Upregulation of the mammalian target of rapamycin complex 1 subunit Raptor induces PSMC growth; however, the factors regulating Raptor in PAH are not known. We hypothesized that Raptor activation by ALDO induces PSMC proliferation, hypertrophic vascular remodeling, and PAH. To test this hypothesis, PSMCs were exposed to vehicle (V) control or ALDO (10
-7
mol/l) for 1 h. Compared to V-treated cells, ALDO increased expression of P-Raptor(Ser792) and the Raptor target P-p70S6K(Thr389) by 68% (P<0.01) and 50% (P<0.01), respectively, without affecting total Raptor/p70S6K levels. Raptor upregulation in ALDO-treated cells also increased PSMC proliferation by 19% (P<0.01), assessed by BrdU incorporation. To explore the relevance of ALDO-Raptor signaling
in vivo
, we studied the monocrotaline (MCT) model of PAH, which is characterized by hyperALDO. In a prevention protocol, MCT-PAH rats were treated with spironolactone (SP)(25 mg/kg/d) in the drinking water to inhibit ALDO and/or intravenous Staramine-mPEG labeled with Raptor-siRNA (2 mg/kg dose x4)(si-Raptor). Anti-Raptor and anti-α-SM actin immunohistochemistry showed that compared to controls (N=4), Raptor expression and vessel thickness was increased in MCT-PAH rats (N=5) by 87% (P<0.01) and 5.8-fold (P<0.01), respectively, and pulmonary artery systolic pressure (PASP) was increased significantly (25 ± 4 vs. 77 ± 12 mmHg, P<0.01) as assessed by catheterization. Compared to MCT-PAH, MCT-si-Raptor (N=5) decreased Raptor levels by 31% (P<0.05), arteriole thickness by 41% (P<0.05), and PASP (77 ± 12 vs. 46 ± 5 mmHg, P<0.05) without affecting central blood pressure significantly. A further benefit was observed in MCT-si-Raptor+SP rats (N=5) for arterial thickness (-57%, P<0.01) and PASP (46 ± 5 vs. 39 ± 5 mmHg, P<0.05) compared to MCT-si-Raptor. Taken together, Raptor activation by ALDO induces PSMC proliferation
in vitro
to promote PAH
in vivo
. Identifying ALDO-Raptor signaling as a pathobiological mechanism underlying pulmonary vascular remodeling may have novel therapeutic implications for PAH patients.
Abstract 12739: Microrna-294 Modulates Cardiomyocyte Proliferation Following Myocardial Infarction
Authors: Khan Mohsin , Nickoloff Emily , Johnson Jennifer , Verma Suresh K , Garikipati Venkata N , Zhou Jibin , Alderfer Cynthia B , Kishore Raj
Published: July 2021

Rationale:
Embryonic heart is characteristic of rapidly dividing cardiomyocytes that give rise to sufficient numbers required to build a working myocardium. In contrast, cardiomyocytes retain some proliferative capacity in the neonates but lose most of it in adulthood. Embryonic stem cell cycle (ESCC) miRs are a class of microRNAs regulating the unique cell cycle of ESCs and their characteristic pluripotency. Nevertheless, expression of miR-294, a member of the ESCC miRs is lost during developmental transitions from the ESCs to mature cells. Effect of miR-294 to induce cardiac proliferation and heart function has not been previously studied.

Objective:
To determine whether miR-294 drives cardiomyocyte cell cycle reentry leading to augmentation of cardiac function after myocardial infarction.

Methods and Results:
miR expression analysis in the heart during development revealed elevated levels of miR-294 in the prenatal stages while the expression was lost in the neonates and adults as confirmed by qRT-PCR. Neonatal ventricular cardiomyocytes (NRVMs) were treated with miR-294 mimic to determine the effect on proliferation and cell cycle. Elevated mRNA levels of cyclins A2, E1, CDK2 together with c-myc, E2F1 and E2F3 was observed in NRVMs treated with 25nM mimic for miR-294. Additionally, miR-294 treated NRVMs showed in AKT phosphorylation along with enhanced protein levels of cyclin D1 and E2F1. Increased expression of p-histone 3, Ki67 and Aurora B kinase (G2/M) was confirmed by immunocytochemistry in NRVMs after miR-294 treatment compared to control cells. Administration of miR-294 in mice subjected to myocardial infarction demonstrated augmentation of cardiac function in mice receiving miR-294 8 weeks after injury. Increase myocyte proliferation was observed in the heart after miR-294 treatment as analyzed by BrdU uptake, p-Histone 3 and Aurora B expression by immunostaining. Concurrently, a decrease in infarct size along with decreased apoptosis was observed in the miR-294 hearts compared to the control.

Conclusion:
Ectopic expression of miR-294 recapitulates embryonic signaling and enhances cardiomyocyte ability to proliferate and reenter the cell cycle leading to augmented cardiac function in mice after myocardial infarction.
Abstract 12754: Infused CD34 Cell Dose, not Bone Marrow CD34+ Cell Content, Improves Clinical Outcomes and LVEF in Patients With Left Ventricular Dysfunction post STEMI: Results of the PreSERVE-AMI Trial
Authors: Quyyumi Arshed , Kereiakes Dean J , Shavelle David M , Henry Timothy D , Abdel-Latif Ahmed , Toma Catalin , Barsness Gregory , Frohwein Steve C , Schatz Richartd A , Cohen Martin , Davidson Charles , Dib Nabil , Klapholz Marc , Schaer Gary L , Vasquez Alejandro , Moss Thomas J , Kanakaraj AnnaMaria , Druker Vitaly , Harper Ken , Chung Amy , Junge Candice , Preti Robert , Smith Robin , Mazzo David J , Pecora Andrew , Losordo Douglas W
Published: July 2021

Background:
Prior studies suggest an association between naturally high circulating levels of CD34+ cells (CD34) and better outcomes following ischemic events. Pts in the treatment arm of the PreSERVE-AMI study were infused with all CD34 yielded from their bone marrow harvest, resulting in pts with naturally higher CD34 cell counts being infused with a higher cell dose. To determine whether selection bias may have influenced results, we performed an analysis of the relationship between BM CD34 content and outcomes in PreSERVE-AMI.

Methods:
PreSERVE-AMI is a Phase 2, randomized, double-blind, placebo-controlled trial of autologous, BM derived CD34 (CLBS10) in pts with LV dysfunction (LVEF ≤48% by MRI) ≥4 days post-STEMI. All pts underwent mini BM harvest and were randomized 1:1 to intracoronary infusion of CD34 (minimum dose 10M±20% cells) or placebo (cell diluent). Primary safety endpoints included AEs, SAEs and MACE (CV mortality, HF hospitalization, reinfarction, revascularization). Secondary endpoints included LVEF change from baseline. Regression analyses were performed to assess the influence of BM CD34 content on outcomes.

Results:
161 patients were randomized and received intracoronary infusion (Jan 2013-Dec 2014). Mean age was 57±10 and 82% were men. Mean follow-up time was 18 mo, and safety data are accruing. BM CD34 content was not associated with differences in baseline characteristics with the exception of diabetes prevalence being higher in those with higher BM CD34 count (p=0.03). In controls, regression analyses showed no association of BM CD34 content with rates of MACE (p=0.2), SAEs (p=0.4), or change in LVEF (p=0.9). However, in CD34 treated pts, there was a dose-dependent improvement in LV function (p=0.045) and dose-dependent trends in MACE and SAE reduction compared to controls. As previously reported SPECT perfusion improved to a similar degree in control and treated pts.

Conclusions:
These data suggest that intracoronary infusion of CD34 cells, rather than BM CD34 cell content, is responsible for the benefit observed in the CD34 treatment group. The finding of a dose-response relationship is an important advance for defining the CD34 as an active agent for tissue repair. Future studies will further define CD34 dosimetry.
Abstract 12880: Malnutrition Assessed by Geriatric Nutritional Risk Index Provides the Long-term Prognostic Information in Patients Admitted for Acute Decompensated Heart Failure, Regardless of Reduced or Preserved Left Ventricular Ejection Fraction; A Comparison With Prognostic Nutritional Index and CONUT Score
Authors: Yamada Takahisa , Morita Takashi , Furukawa Yoshio , Tamaki Shunsuke , Iwasaki Yusuke , Kawasaki Masato , Kikuchi Atsushi , Kondo Takumi , Ishimi Masashi , Hakui Hideyuki , Ozaki Tatsuhisa , Satoh Yoshihiro , Seo Masahiro , Ikeda Iyo , Fukuhara Eiji , Fukunami Masatake
Published: July 2021

Backgrounds:
Malnutrition is associated with increased mortality risk in patients (pts) with acute decompensated heart failure(ADHF). Nutritional status is assessed by several indices, such as Geriatric Nutritional Risk Index (GNRI), Prognostic Nutritional Index (PNI), and Controlling Nutritional Status (CONUT) score. However, there is no information available on the comparison of prognostic significance of these indices in ADHF pts, relating to reduced or preserved left ventricular ejection fraction (HFrEF or HFpEF).

Methods and Results:
We studied 303 consecutive pts admitted for ADHF and discharged alive (HFrEF(LVEF<50%);n=163, HFpEF(LVEF≥50%);n=140). Nutritional status was evaluated at the discharge by GNRI calculated as follows: 14.89 • serum albumin (g/dl) + 41.7 • BMI/22, PNI calculated as follows: 10 • serum albumin (g/dl) + 0.005 • total lymphocyte count (/ml) and CONUT score calculated by serum albumin, total cholesterol levels and lymphocyte count. During a follow-up period of 5.0±4.3 yrs, 75 pts had cardiovascular death (CVD). At multivariate Cox analysis, GNRI (p<0.0001) was significantly associated with CVD, independently of systolic blood pressure, serum sodium level and eGFR, although PNI and CONUT score showed a significant association with CVD at univariate analysis. ROC analysis revealed that GNRI of 88 was a fair discriminator for CVD (AUC 0.70(95%CI 0.63-0.77), p<0.0001). In group with HFrEF, CVD was significantly more frequently observed in pts with than without low GNRI <88 (48% vs 25%, p<0.0001, adjusted HR 3.5[1.8-6.6]). Furthermore, in group with HFpEF, pts with low GNRI had the significantly increased risk, compared to those with high GNRI>88 (36% vs 10%, p<0.0001, adjusted HR 3.8[1.4-10.2]).

Conclusion:
Malnutrition assessed by Geriatric Nutritional Index provides more valuable long-term prognostic information than PNI and CONUT score in pts admitted for ADHF, regardless of HFrEF or HFpEF.
Abstract 12908: Effects of Metabolic Syndrome on In-Stent Restenosis After PCI: Obesity Paradox and Sex-Associated Differences
Authors: Sakamoto Kenji , Komura Naohiro , Tsujita Kenichi , Yamanaga Kenshi , Tabata Noriaki , Akasaka Tomonori , Miyazaki Takashi , Yamamoto Eiichiro , Kojima Sunao , Kaikita Koichi , Nakamura Sunao , Hokimoto Seiji , Ogawa Hisao
Published: July 2021

Background:
The impact of metabolic syndrome (MetS) on the efficacy of PCI remains controversial.

Hypothesis:
This controversy may be due in part to a positive influence of obesity (the “obesity paradox”) among the factors included in the definition of MetS. Fat distribution also varies by sex, possibly confounding the impact of obesity.

Methods:
To elucidate the possible effects of obesity in MetS patients on in-stent restenosis (ISR) or target lesion revascularization (TLR), 546 patients treated with coronary stents (BMS or DES) were stratified according to the presence of MetS with or without obesity, using NCEP-ATP III guidelines. Waist circumference or BMI (in patients without waist circumference data) was used for diagnosis of obesity. Follow-up angiography was scheduled 8 to 9 months after PCI to obtain ISR, which was defined as %diameter stenosis (%DS)>50%.

Results:
Mean age of the subjects was 70.5±9.8 years, and 32.1% were female. By standard criteria, 286 patients (52.4%) were diagnosed as MetS, and 320 patients (58.6%) met criteria for obesity. Among MetS patients, 61 patients (21.3% of MetS patients) were categorized as non-obesity. At 8 to 9 months follow-up, % DS, ISR rates, and TLR rates had trends to be higher in MetS than no-MetS (ISR; 26.6% in MetS, 20.0% in non-MetS, p=0.085). These parameters showed no difference between obesity and non-obesity (ISR; 23.8% in obesity, 23.0% in non- obesity, p=0.918, TLR; 14.1% in obesity, 15.0% in non-obesity, p=0.805). In patients with MetS (Figure), however, the ratio of %DS and ISR were significantly greater in the absence of obesity in female patients, whereas no difference was observed in male patients. In multivariate analysis, non-obesity was an independent predictor for ISR or TLR in female patients with MetS.

Conclusions:
Overall, obesity was not related to ISR or TLR after PCI. In female MetS patients, however, comorbidity of obesity appeared to be paradoxically protective.
Abstract 13133: Cardiovascular Abnormalities and Their Adverse Influence on Mortality in Patients With Intracranial Hemorrhage: A Meta-Analysis
Authors: Vallabhajosyula Saraschandra , Mahfood Haddad Toufik , Kabach Amjad , Kanmanthareddy Arun , Morrow Lee E , Esterbrooks Dennis J
Published: July 2021

Introduction:
Intracranial hemorrhage (ICH) is associated with high mortality rate of 30-52% despite current advances in management. New cardiovascular abnormalities (CA), such as EKG or cardiac biomarker abnormalities ensue in ICH and are postulated to be due to hypothalamic injury and catecholamine surge. These CA are thought to portend a poor prognosis.

Methods:
We evaluated clinical studies reporting CA in ICH and assessing their effect on mortality. Studies without a control group, pediatric, and non-English literature were excluded. We extracted data on demographics, comorbidities and mortality [in-hospital (IHM), 30 day (30M) and 90 day (90M)]. CA data included EKG changes (bradycardia, atrial fibrillation, bundle branch blocks, QTc prolongation, ST-segment depression, and ST-segment elevation), biomarker elevation (troponin-T (TnT), CK-MB and BNP), and wall motion abnormalities (WMA). Unadjusted and adjusted rates for CA and pooled risk ratio (RR) with 95% CI were calculated using Mantel-Haenszel random effects model for mortality.

Results:
We reviewed 453 studies, of which 26 met our inclusion criteria. Heterogeneity varied from moderate to severe depending on the outcome chosen. Of a total 5580 patients, 2796 (50.1%) had sub-arachnoid hemorrhage (SAH), 1633 ICH (29.3%) and 1151 (20.6%) both. The incidence of CA is presented in Table 1. Of these 26 studies, 19 evaluated the influence of new CA on mortality. IHM was noted in 175/566 (30.9%) and 491/2496 (19.7%) patients with and without CA, respectively. In addition, 30M and 90M were noted in 18/38 (47.4%) vs. 14/136 (10.3%) and 90/175 (51.4%) vs. 247/1139 (21.7%) patients with and without CA, respectively. CA was associated with worse IHM (RR 2.03, 95% CI 1.58-2.62, p<0.001), 30M (RR 3.18, 95% CI 1.86-5.42, p<0.001) and 90M (RR 2.11, 95% CI 1.44-3.08, p<0.001) in patients with ICH compared to those who did not have CA.

Conclusion:
CA are common in patients with ICH and are associated with worse IHM, 30M and 90M.
Abstract 13168: Food Quality Score and the Risk of Coronary Heart Disease
Authors: Fung Teresa , Pan An , Hou Tao , Mozzafarian Dariush , Bhupathiraju Shilpa , Willett Walter , Hu Frank
Published: July 2021

Introduction:
We have previously derived a food based diet quality score associated with weight change. In this analysis, we prospectively assessed the association between this score and risk of coronary heart disease (CHD).

Methods:
We followed 74,667 women in the Nurse’ Health Study (baseline age 35-55 y), 28,977 men in the Health Professionals Follow-up Study (baseline age 50-72), and 92,513 women in the Nurses’ Health Study 2 (baseline age 25-42) without a history of cardiovascular disease for up to 26 years between 1984 and 2011. Diet was assessed up to 7 times using repeated food frequency questionnaires. We computed the Food Quality Score (FQS) for each individual. A higher FQS score represents a healthier diet. The association between the FQS and CHD risk was assessed using Cox proportional hazard model controlling for potential confounders. We also compared the strength of association of FQS with other diet quality scores.

Results:
We ascertained 6497 incident CHD events, including 4594 nonfatal myocardial infarct (MI) and 2055 fatal cases. Comparing top to bottom deciles, the pooled RR was 0.66 (95% CI=0.58-0.74, p trend<0.001) for total CHD, 0.63 (0.54-0.73, p trend<0.001) for non-fatal MI, and 0.73 (0.59-0.90, p trend=0.001) for fatal MI. The association for CHD was significant in lean (BMI<25) and overweight (BMI>=25) individuals, those with or without a family history of MI, and physical activity above or below the median. When comparing the FQS with other diet quality scores that have previously been associated to lower CHD risk, one standard deviation increase in the FQS was not significantly different from the Alternate Mediterranean Diet score, the Alternate Healthy Eating Index-2010 or the Dietary Approaches to Stop Hypertension score in its association with CHD risk.

Conclusion:
A higher FQS was associated with lower CHD risk. The FQS was comparable to food and nutrient based diet quality score that have previously been associated with lower CVD risk and indicates a potential to develop a simple food only diet quality for public health applications of assessing diet quality.