bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 584: The Association of Psychosocial Risk Factors with Subclinical Atherosclerosis in South Asians
Authors: Shah Bijal , Shah Shriraj , Kandula Namratha , Kanaya Alka
Published: July 2021

Objective:
South Asians (individuals from India, Pakistan, Bangladesh, Nepal, and Sri Lanka) are at higher risk of cardiovascular disease (CVD) than other ethnic groups, however this increased risk cannot be explained by traditional risk factors. We investigated the association of psychosocial risk factors with carotid intima media thickness (cIMT), a measure of subclinical CVD, in a community-based cohort of South Asians living in the United States.

Methods:
A total of 906 individuals from the Mediators of Atherosclerosis in South Asians Living in America (MASALA) Study, aged 40-83, were included in this cross-sectional analysis. High resolution B-mode ultrasonography was used to measure right and left common cIMT (CCA) and internal cIMT (ICA). Linear regression analyses were done to test the associations of the following psychosocial variables: anger, anxiety, depressive symptoms, current and prior 6-month life stress, social support, and everyday hassles with CCA and ICA. In a multivariable model, results were adjusted for the following traditional CVD risk factors: age, sex, systolic blood pressure, hypertension medication use, education, physical activity, diabetes, BMI, smoking, and total/HDL cholesterol ratio. Interaction effects between sex and psychosocial variables were also tested.

Results:
In age- and sex- adjusted analyses, current life stress and life stress over the past 6 months were positively associated with CCA [mean difference per 1-SD increase (CI) was 0.014 (0.001-0.028; p=0.042) and 0.015 (0.001-0.029; p=0.031), respectively], but were no longer significant after adjusting for other CVD covariates. There was a significant sex interaction with anxiety (p=0.044). Among men, anxiety was positively associated with CCA [mean difference per 1-SD increase (CI) was 0.021 (0.001-0.041; p=0.04) in age-adjusted analyses, and 0.022 (0.002-0.042; p=0.031) in a fully adjusted model]. ICA was not associated with any psychosocial factor.

Conclusion:
Compared to results in other ethnic groups, there was no significant association between trait anger and cIMT in South Asians. Anxiety was associated with CCA independent of traditional CVD risk factors in men alone.
Abstract 590: Loss of Myeloid Cell Prostaglandin E Receptor 4 Does Not Alter Diabetes-Accelerated Atherosclerosis in a Murine Model of Type 1 Diabetes
Authors: Vallerie Sara N , Kramer Farah , Kanter Jenny E , Barnhart Shelley , Breyer Richard M , Andreasson Katrin I , Bornfeldt Karin E
Published: July 2021

Diabetes is associated with an increased risk of cardiovascular disease, largely due to increased atherosclerosis. Our studies have suggested myeloid cell prostaglandin E
2
(PGE
2
) production as a possible mediator of diabetes-accelerated atherosclerosis in a virally-induced mouse model of type 1 diabetes. Prostaglandin E Receptor 4 (EP4;
Ptger4
) is a major PGE
2
receptor in myeloid cells. We hypothesized that generation of a mouse model of myeloid cell-targeted EP4-deficiency would allow us to test the role of myeloid EP4 in diabetes-accelerated atherosclerosis.

Thus, we generated a

Ptger4
flox/flox
LysM-Cre
tg/tg

mouse model. Peritoneal macrophages isolated from these myeloid cell EP4-deficient (EP4
M-/-
) mice expressed <90%
Ptger4
mRNA compared to

LysM-Cre
tg/tg

controls (n=10; p<0.0001). To analyze the role of myeloid cell EP4 in diabetes-accelerated atherosclerosis, we transplanted bone marrow from EP4
M-/-
mice and littermate controls into lethally irradiated

Ldlr
-/-

RIP-LCMV mice (the model of type 1 diabetes) and, after 7 weeks of recovery, induced diabetes by viral infection and fed the mice a low-fat semi-purified diet for an additional 12 weeks. Diabetic EP4
M-/-
mice had similar blood glucose (568 ± 15 vs. 569 ± 15 mg/dl), blood cholesterol (531 ± 29 vs. 510 ± 37 mg/dl), and plasma triglycerides (249 ± 49 vs. 247 ± 44 mg/dl) as diabetic controls (n=15 all groups; mean ± SEM). At the endpoint, aortas were harvested for lesion area quantification. Diabetic EP4
M-/-
and diabetic wild type mice had similar lesion area (1.9% ± 0.2 vs. 1.7% ± 0.2), which were both increased (p < 0.01; n=9-15) as compared to their non-diabetic controls. Additionally, we analyzed the role of EP4 in inflammatory activation of myeloid cells ex vivo. EP4-deficiency had no significant effect on basal or lipopolysaccharide (LPS)-induced inflammatory gene expression in the absence of PGE
2
. Pretreatment of the cells with PGE
2
(10 nM) followed by LPS stimulation resulted in a significant reduction of
Tnfa
and
Il6
mRNA compared to LPS alone, and this anti-inflammatory effect of PGE
2
was completely blocked in EP4-deficient cells.

These results suggest that myeloid cell EP4 mediates anti-inflammatory actions of PGE
2
but that it is not involved in diabetes-accelerated atherosclerosis.
Abstract 600: Novel Assays to Determine in vivo Platelet Activation
Authors: Sosa Iberia R , Zagol-Ikapitte Irene , Bala Manju , Boutaud Olivier , Oates John
Published: July 2021

In vivo platelet activation is associated with several pathologic entities, including acute coronary syndrome, essential thrombocythemia, anti-phospholipid antibody syndrome, diabetes and metabolic syndrome. The need for more robust biomarkers with which to assess platelet activation in vivo in human diseases is well recognized. Our lab has developed two novel assays to study in vivo platelet activation and rate of turnover.

During platelet activation, malondialdehyde (MDA) is produced by the thromboxane synthase in amounts equimolar to thromboxane A2 and also non-enzymatically by lipid peroxidation resulting from the oxidative processes that accompany activation. MDA is a reactive dicarbonyl that reacts with amines, notably lysines on proteins, yielding covalent modifications of the proteins that then accumulate over the lifetime of the platelet. We developed an LC/MS/MS method for quantification of the most stable of three MDA adducts, the dilysyl-MDA crosslink, employing a [13C12] labeled internal standard. We found that activation of platelets with arachidonic acid leads to an increase in the levels of dilysyl-MDA crosslinks in platelets, which is inhibited by the thromboxane synthase inhibitor, ozagrel, by the cyclooxygenase inhibitor, aspirin, and by scavengers of reactive carbonyls, 3- methoxysalicylamine and Salicylamine.

High platelet turnover has been associated with increased risk for thrombosis and failure of antiplatelet agents. We propose a novel approach to studying platelet turnover by labeling platelets in vivo by oral administration of aspirin containing a deuterium labeled acetyl group (d3-aspirin). We can measure the clearance of d3-labeled platelets by using LC/MS/MS to measure the tryptic peptide (SLK) of COX-1 labeled with d3. This approach avoids exposure to radioactivity and the artifact resulting from manipulation of platelets labeled ex vivo.

The results of this study provide two novel assays with the potential to serve as markers of in vivo platelet activation and turnover, which may be useful in predicting thrombotic risk and efficacy of antiplatelet therapy in patients with medical conditions associated with platelet hyperactivity and high rate of platelet turnover.
Abstract 614: 1,25-dihydroxyvitamin D Enhances Vegf-stimulated Porcine Adipose-derived Mesenchymal Stem Cells Toward the Endothelial Phenotype Involving Wnt/β-catenin Pathway
Authors: Llamas Yovani , Almalki Sami , Agrawal Devendra K
Published: July 2021

Background:
Cell-based therapy using adipose-derived mesenchymal stem cells (AMSCs) is an attractive option for re-endothelialization post-angioplasty procedures. Vitamin D levels in circulating blood may regulate AMSC-based re-endothelialization of injured arteries. To our knowledge, the role of vitamin D and vascular endothelial growth factor (VEGF) in the differentiation of adipose-derived AMSCs into endothelial cells (ECs) has not been examined. In this study, we investigated the effect of vitamin D on VEGF-induced differentiation of MSCs into ECs.

Methods and Results:
MSCs isolated from porcine adipose tissue were CD11b-CD34-CD44+CD73+CD90+ and showed characteristics of MSCs. The MSCs were stimulated and differentiated into ECs with endothelial growth media (EGM+50ng/ml of VEGF) and EGM media containing 10nM of calcitriol (EGM+50ng/ml of VEGF +10nM calcitriol) for 10 days. The EC differentiation was assessed by mRNA expression by qPCR and protein expression by flow cytometry for endothelial cell markers. Calcitriol enhanced EGM+VEGF-induced differentiation of MSCs into ECs, as revealed by 2-fold increase in mRNA and 4-fold increase in protein expression of EC markers. Angiogenesis assay and acetylated low density lipoprotein (LDL) uptake assay were used to assess the endothelial functionality that showed significant increase in capillary tube sprouting, and an increase in LDL uptake by the differentiated cells in response to EGM +VEGF+ calcitriol. Examination of the findings from Wnt Pathway array revealed a 3-fold decrease in β-catenin and 3-fold increase in KREMEN1 protein in the cells treated with EGM + VEGF+calcitriol.

Conclusion:
Vitamin D significantly enhanced VEGF-induced differentiation of MSCs into endothelial cells. Thus, vitamin D status of the patients undergoing coronary intervention might regulate the development of thrombosis and intimal hyperplasia.
Abstract 626: Vascular Endothelial HSP60 and Von Willebrand Factor Induction Are Both Involved in Promoting Fatty-Streak Formation in ApoE Null Mice
Authors: Chen Tsung-Hsien , Chen Mei-Ru , Chen Tzu-Ying , Liu Shan-Wen , Hsu Ching-Han , Lin Kurt M
Published: July 2021

Objectives:
This study was designed to determine the murine atherosclerosis in ApoE null mice with inducible expression of human heat shock protein 60 (hHSP60) in vascular endothelium.

Background:
Autoimmunity to HSP60 may be involved in eliciting early atherosclerotic lesions. Most classical risk factors of atherosclerosis were previously shown in cell culture models to induce HSP60 expression in vascular ECs and in vivo particularly at regions predilected to lesions. However, it has not been demonstrated directly in an animal model whether HSP60 induction in ECs are capable of influencing lesion formation.

Methods:
We developed ApoE
-/-
::Cdh5-CreER
T2
::G-Lox-HSP60 triple Tg mouse model with tamoxifen-induced hHSP60 expression in ECs. Eight week-old triple TG mice were fed by tamoxifen citrate-contained chow for 2 weeks, followed by high fat chow (HF) for additional 4 and 8 weeks before sacrificed for oil red staining for fatty streaks and IHC staining.

Results:
In tamoxifen-fed triple Tg mouse, vascular EC expression of hHSP60 increased fatty-streak formation and increased the severity of lesions in comparison with uninduced triple Tg or wildtype ApoE mouse. In triple Tg mouse, we found tamoxifen strongly induced HSP60 expression in ECs of the lesions and to a lesser degree in ECs of veins and other arterial regions not predilected to lesions. Concomitant VWF induction at ECs and subendothelial regions was observed at areas with increased HSP60 expression.

Conclusions:
hHSP60 induction at vascular ECs accelerates fatty-steak formation in ApoE null mice that may involve increasing local VWF expression.
Abstract 631: Evaluation of Risk Factors for Cardiovascular Disease in Rheumatoid Arthritis
Authors: Rocha Vitor M , Pippa Maria Guadalupe B
Published: July 2021

Backgroung:
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease, that appear to be responsible for 50% of mortality for thrombotic events such as Myocardial Infarction (MI) and Ischemic Stroke (SI) in RA patients. Occur approximately a decade earlier in these patients compared with the normal population.

Objectives:
To determine the risk of developing cardiovascular disease in patients with Rheumatoid Arthritis according to the classification criteria of the American College of Rheumatology.

Methods:
To assess the risk of cardiovascular diseases we studied 78 patients diagnosed with Rheumatoid Arthritis. For this we used the criteria of the risk score of Acute Coronary Disease in 10 years according to the Framingham Heart Study. A control group consisted of 21 patients with osteoarthritis and fibromyalgia was also assessed using the same criteria, where age, sex, systolic blood pressure values, total cholesterol, cholesterol HDL, presence of smoking and diagnosis of diabetes, were scored.

Results:
Patients with rheumatoid arthritis had a mean disease duration of 12.8 years (SD=7.4), age 58.6 years (SD=10.3) and the control group 59.3 years (SD=10,0). The old values of total cholesterol, HDL, blood pressure and being with Diabetes Mellitus showed positive correlations with the Cardiovascular Risk, and Blood Pressure in the index this correlation was stronger (r=+0.593) in Rheumatoid Arthritis and age (r=+0.702) in the control group. The Global Cardiovascular Risk in each group were considered low (7,8 points to Rematoid Artrhrits and 9,3 points to the control group).

Conclusion:
The results showed no increased risk of cardiovascular disease when compared to control group. Remember that control group fact be constituted by a larger number of diabetics, which likely impact these results.
Abstract 641: Hypotrophic Vascular Remodeling Associates With Vascular Calcification
in vivo
in Vitamin D
3
-stimulated Leptin-deficient
ob/ob
Mice
Authors: Carmo Luciana S , Almeida Youri E , Liberman Marcel
Published: July 2021

Vascular calcification may determine arterial flow imbalance through increasing vascular rigidity and Windkessel effect, frequently occurring in diabetes. Vascular remodeling, considered an adaptive response of the vessel to specific stimuli, may associate with calcification and participate in pathophysiology of cardiovascular disease. In order to further investigate the intersection between pathophysiology of vascular calcification and vascular remodeling, we hypothesized that leptin-deficient
ob/ob
mice, demonstrate increased vascular remodeling and vascular calcifying response to Vitamin D
3
in vivo
compared to C57BL/6 (C57) mice. We injected C57 and
ob/ob
mice with Vitamin D
3
8x10
4
IU (VitD) daily or saline 0.9% ip. (Cont) for 14 days and for 21 days. Results are showed as Mean±SEM. We considered statistically significant if p<.05 after ANOVA (Newman-Keuls). After 14d, o
b/ob
VitD aorta decreased aortic wall thickness (24.3±0.4μm)
versus
ob/ob
Cont (29.7±1.3μm),
vs.
C57VitD (34.4±0.6μm) and
vs.
C57Cont (39±1.3μm), p<.05 n=6. After 21d, we also showed that
ob/ob
VitD decreased aortic wall thickness (25.4±0.5μm)
vs.
ob/ob
Cont (29.7±1.3μm) and
vs.
C57Cont (39.0±1.3μm), p<.05 n=3. Moreover, o
b/ob
VitD decreased vessel wall area (VWA)= 79120±3957μm
2
vs.
ob/ob
Cont=85310±4593μm
2
and
vs.
C57Cont=96970±6719μm
2
after 14d (n=6) and also after 21d (
ob/ob
VitD=72090±3268μm
2
vs.
ob/ob
Cont=85310±4593μm
2
(n=3). On contrary, C57VitD did not change VWA. Coincidently,
ob/ob
VitD increased vascular calcification after 14d (total Ca
++
area burden=4548.2μm
2
, n=6) and after 21d (total Ca
++
area burden=2212.88 μm
2
, n=3) respectively. C57VitD and C57Cont did not calcify (n=6). Together with increased VWA loss and calcification,
ob/ob
VitD also showed augmented elastolysis and fibrosis. Nevertheless, hypotrophic remodeling did not determine any change in vascular lumen area (
ob/ob
VitD=208300±24810μm
2
;
ob/ob
Cont=207300±22740μm
2
, C57VitD=196800±22120μm
2
and C57Cont=225400±17960μm
2
) after 14d in this model. Vascular remodeling associated with calcification and other architectural changes of the vascular wall may bring important insights for investigating human cardiovascular disease in obese and insulin resistant background.
Abstract 647: Identification of Platelet Derived Growth Factors A, B, C and D Specific Role in Vascular Remodeling
Authors: Gonzalez Diez Maria , Razuvaev Anton , Hedin Ulf , Hamsten Anders
Published: July 2021

Restenosis is a major complication after coronary angioplasty and stenting. The major cause of restenosis is neointimal hyperplasia, which results from an excessive proliferative response of vascular smooth muscle cells (VSMC) to mechanical injury. Platelet derived growth factor (PDGF) family members (A, B, C, D) are known to be related to vascular remodeling. However whether this role is specific for each one or overlapping remains to be elucidated.

Aim:
To assess the specific role of PDGF family members (A, B, C, D) in vascular remodeling after injury.

Methods:
We used an established model of balloon injury in rat carotid artery. The endothelium of the intima is mechanically removed. The animals (n=10/group) were sacrificed at different time points after injury (0-2-20 hours, 2-5-15 days, 6-12 weeks). mRNA from carotid arteries were isolated for gene expression studies using microarray gene expression.

Results:
PDGFs are differentially expressed in vascular remodeling (mRNA, A adj P val=3.28E-06, B adj P val=4.52E-8, C adj P val=5,91E-15, D adj P val=2,64E-18). Also the expression profile differs among them. We selected the genes highly correlated with each of the PDGFs (Spearman correlation, │rs >0.7│) and identified the most preeminent biological pathways associated to each one. PDGF-A positively correlates with program cell death. On the other hand, PDGF-B and C have some overlapping biological processes. There is positive correlation with blood vessel morphogenesis and angiogenesis (B), cell differentiation (B and C), DNA replication (B and C), antigen presentation and T-cell activation/differentiation (B and C). However, there is negative correlation with platelet activation (B) and cell adhesion (B and C). PDGF-D positively correlates with blood vessel morphogenesis and angiogenesis (like B) and cell differentiation (B, C), but is negatively correlated with T-cell activation/proliferation (opposite effect to B and C), apoptosis (opposite effect to A) and platelet activation (B).

Conclusion:
We identified specific biological processes for PDGF- A, B, C and D. Despite some overlapping, each one plays a specific role within vascular remodeling.
Abstract 664: Cerebrovascular Events in Patients Undergoing Endovascular Aortic Repair (EVAR) versus Open Aortic Repair (OAR) for Abdominal Aortic Aneurysm (AAA): A Pooled Meta-Analysis of 10,409 Patients
Authors: Ansari Ahmed S , Macedo Francisco Y , Hoang Vu , Contreras Johanna P , Birnbaum Yochai , Alam Mahboob
Published: July 2021

Background:
EVAR is still a relatively new modality for AAA repair and there are not many studies on the complications and risks associated with this procedure. In particular, there is a paucity of data in regards to the risks of Cerebrovascular Events (CVE). The purpose of the paper is to discuss the risks of CVE in patients who have undergone EVAR versus patients that have undergone OAR. We aimed to do a systematic review and meta-analysis of the CVE rates in patients undergoing EVAR versus OAR.

Methods:
Studies were included if they reported CVE outcomes comparing EVAR versus OAR in patients who underwent AAA repair. Of the 51 unique citations identi[[Unable to Display Character: ﬁ]]ed after the initial literature search and supplementary hand-searches, 10 studies comparing EVAR and OAR who underwent AAA repair met our inclusion criteria. Results were independently extracted by 2 reviewers. A random effects model was applied. The primary end was the incidence of stroke.

Results:
A total of 10 studies and 10,409 patients were included. Of the 10,409 patients, 2,659 patients underwent EVAR and 7,750 patients underwent OAR. The incidence of CVE in patients undergoing EVAR was 1.01% and the incidence of CVE in patients undergoing OAR was 1.03%. CVE (RR 0.83; CI 0.51-1.34; P=0.44; figure 1) were not statistically significant between patients undergoing EVAR vs OAR.

Conclusion:
This meta-analysis found that in patients undergoing EVAR versus patients going OAR, there was not a statistically significant difference and EVAR can be as safe as OAR regarding stroke related complications. These findings need to be confirmed with larger randomized control trials.
Abstract 676: Microrna-30 and Cthrc1: Translating Aging into Vascular Stiffness and Abdominal Aortic Aneurysm
Authors: Spin Joshua M , Zheng Wei H , Adam Matti , Raaz Uwe , Schellinger Isabel , Kayama Yoseke , Toyama Kensuke , Deng Alicia , Maegdefessel Lars , Tsao Philip S
Published: July 2021

Abdominal aortic aneurysm (AAA) is a major source of vascular morbidity and mortality, with increasing age representing one of the strongest risk factors. While increases in aortic extra-cellular matrix deposition may be protective, changes in vessel architecture with age result in heterogeneous stiffness and vascular calcification, which appear to pre-dispose to AAA development. MicroRNAs (miRs) are key regulators of vascular homeostasis and pathobiology.

Array profiling and qRT-PCR of aneurysmal aortic tissue in a murine AAA model (elastase-infused C57/B6) showed significant down-regulation of the miR-30 family, which is believed to have a role in vascular calcification. Increased age augmented this response, particularly for miR-30a, 30b and 30c. RNASeq profiling of a related AAA model (Ang-II in ApoE-/- KO) showed similar aortic down-regulation. Further, of differentially down-regulated miRs, miR-30 had the highest inverse correlation with mRNA gene targets. One predicted target - Cthrc1 (collagen triple helix repeat containing-1) - was the most consistently and significantly up-regulated gene across all time points in the AAA models. The protein resides within vascular smooth muscle cells (SMCs) and fibroblasts, responds to injury, and may regulate collagen expression and deposition. Immunofluorescence staining of AAA vs. normal aortas revealed increased expression of CTHRC1.

We further found that miR-30 family members bind to the CTHRC1 3’ UTR and regulate gene expression in vitro, and that antagomir suppression of miR-30 upregulates CTHRC1 in SMCs. We also demonstrated that signaling pathways known to increase in activity with aging within the aorta, and which are associated with vascular calcification and fibrosis (e.g. IL6-based inflammatory signaling, TGF-β signaling, and BMP-2 signaling) down-regulate miR-30 family expression in SMCs, and inversely up-regulate CTHRC1 expression. Forced overexpression of miR-30 in SMC in vitro down-regulates RUNX2, a key promoter of vascular stiffness and calcification. Taken together, these results suggest a significant role for miR-30 in pathways related to matrix deposition and calcification, regulating aortic pathobiology and age-related susceptibility to AAA.
Abstract 700: Accelerated Glycolysis in Adipose Tissue Macrophages Triggers Hif-1α in Obesity and Promotes Insulin Resistance.
Authors: Ramkhelawon Bhama , Ouimet Mireille , Simon Russell , Yan Bo , Spiro Westley , Moore Kathryn J
Published: July 2021

During obesity, macrophages (Mø) accumulate in the visceral adipose tissue (VAT), giving rise to a state of chronic, low-grade inflammation that promotes insulin resistance and type 2 diabetes. We hypothesized that activation of HIF-1α in highly-metabolically active Mø sustains inflammation in obese VAT and promotes metabolic dysfunction. We show that hypoxic Mø, like M1-polarized Mø, shift their metabolism from oxidative phosphorylation to glycolysis, leading to the accumulation of HIF-1α-stabilizing intermediates. Extracellular flux analysis showed that treating Mø with the hypoxia mimetic CoCl2 or the saturated fatty acid palmitate reduced cellular oxygen consumption and increased the rate of extracellular acidification indicative of enhanced glycolysis. Metabolites known to accumulate during persistent glycolysis, such as succinate and lactic acid, activated HIF-1α in Mø and promoted inflammatory gene expression. To test the role of Mø HIF-1α in promoting VAT inflammation and metabolic dysfunction in obesity, we fed wild type or Mø-specific HIF-1α knock-out mice a high-fat diet (60% kcal fat) for 20 weeks. Notably, the ablation of HIF-1α in Mø reduced VAT inflammation as indicated by the reduced accumulation of F4/80+ cells and decreased expression of inflammatory cytokines (TNFα, IL-6, MCP-1). In addition, adipose tissue Mø isolated from Mø-HIF-1α knock-out mice showed increased expression of markers characteristic of M2 reparative Mø (Ym1, Fizz1, Aldh2) and reduced expression of M1 inflammatory Mø markers (Ccl2, Il1b), compared to Mø from WT mice. Furthermore, Mø-HIF-1α knock-out mice showed improved glucose homeostasis and insulin sensitivity, and reduced plasma insulin and free fatty acid levels compared to WT mice. Together, these data indicate that activation of HIF-1α in VAT Mø during obesity promotes tissue inflammation and insulin resistance.
Abstract 723: Agonist of Growth Hormone Releasing Hormone Enhances Angiogenic Therapy by Mesenchymal Stem Cells
Authors: Yu Hong , Ma Qunchao , Xia Xiangyang , Tao Quanwei , Lu Kai , Shen Jian , Block Norman , Webster Keith , Wang Jian’an , Schally Andrew V
Published: July 2021

Transplantation of bone marrow-derived mesenchymal stem cells (MSCs) represents a promising strategy for treating cardiovascular disease. However, the efficiency of such therapy is limited by poor cell survival and engraftment. Growth hormone-releasing hormone (GHRH) regulates growth and development through pleiotropic actions on multiple target cell and tissue types. Here we studied the effect of the GHRH agonist, JI-34, on MSC survival and angiogenic therapy in a mouse model of critical limb ischemia. Treatment of MSCs with JI-34 improved MSC viability and mobility and markedly enhanced endothelial tube formation in vitro. These effects were paralleled by increased phosphorylation and nuclear translocation of STAT3. In vivo, JI-34 pre-treatment enhanced the engraftment of MSCs into ischemic hindlimb muscles and augmented reperfusion and limb salvage compared with untreated MSCs. Significantly more vasculature and proliferating CD31+ and CD34+ cells were detected in ischemic muscles that received MSCs treated with JI-34. Our studies demonstrate a novel role for JI-34 to markedly improve therapeutic angiogenesis in hindlimb ischemia by increasing the viability and mobility of MSCs. These findings support additional studies to explore the full potential of GHRH agonists to augment cell therapy in the management of ischemia.
Isolated Left Anterior Descending Coronary Artery Disease
Authors: O’Keefe James H. , Kreamer Thomas R. , Jones Philip G. , Vacek James L. , Gorton Michael E. , Muehlebach Gregory F. , Rutherford Barry D. , McCallister Ben D.
Published: July 2021

Background
—Single-vessel coronary artery disease is usually treated with PTCA; however, this approach when applied to the left anterior descending coronary artery (LAD) is hampered by high restenosis rates, often approaching 50%. Coronary stenting (STENT) and left internal mammary artery bypass grafting of the LAD (LIMA-LAD) are other options that have been successfully used for single-vessel LAD disease. The optimal mode of revascularization for patients with isolated single-vessel LAD disease is unclear. The purpose of the present study was to examine PTCA versus STENT versus LIMA-LAD with respect to short- and intermediate-term outcomes.

Methods and Results
—This was an observational retrospective cohort study comparing in-hospital and intermediate-term outcomes and functional class among patients with isolated single-vessel LAD disease revascularization. Consecutive eligible patients were grouped according to their initial revascularization procedure and systematically followed up. A total of 704 patients qualified for the study: 469 in the PTCA group, 137 in the STENT group, and 98 in the LIMA-LAD group. Follow-up data were complete for 97% of patients and averaged 27±13 months. In-hospital mortality for the PTCA, STENT, and LIMA-LAD groups was 1.1%, 0%, and 0% (
P
=0.51), respectively. Median hospital stays after the procedure for the respective treatment groups were 1, 1, and 5 days (
P
<0.001), and occurrences of in-hospital myocardial infarction were 0.9%, 1.5%, and 1.0% (
P
=NS). Repeat revascularization procedures were performed in 30%, 24%, and 5% of the PTCA, STENT, and LIMA-LAD groups (
P
=<0.001 for LIMA-LAD versus other groups,
P
=0.11 for PTCA versus STENT). Actuarial 2-year mortality was 3.9%, 2.6%, and 1% in the PTCA, STENT, and LIMA-LAD groups (
P
=0.33).

Conclusions
—Revascularization for isolated LAD disease using PTCA, STENT, or LIMA-LAD results in low in-hospital adverse event rates and good long-term results. Repeat procedures are required less often after LIMA-LAD than after either PTCA or STENT. Long-term mortality was not statistically different, but the trend was for the lowest mortality with LIMA-LAD, a somewhat higher mortality with STENT, and the highest mortality with PTCA.
Comparative Histopathology of Radial Artery Versus Internal Thoracic Artery and Risk Factors for Development of Intimal Hyperplasia and Atherosclerosis
Authors: Ruengsakulrach Permyos , Sinclair Roger , Komeda Masashi , Raman Jai , Gordon Ian , Buxton Brian
Published: July 2021

Background
—In this study, we examined the comparative histopathology, morphometry, and risk factors for the development of intimal hyperplasia and atherosclerosis in the radial artery (RA) and the internal thoracic artery (ITA).

Methods and Results
—Paired specimens of RAs and ITAs, obtained from 150 patients who underwent CABG, were evaluated with histopathology; 110 pairs of arteries were suitable for morphometric analysis. The severity of disease was evaluated on the basis of percentage of luminal narrowing, intimal thickness index, and intima-to-media ratio. Risk factors were determined with stepwise linear regression. Intimal hyperplasia was seen in 141 RAs (94%) and 103 ITAs (69%) (
P
<0.001). Atherosclerosis was seen in 5% of RAs and 0.7% of ITAs (
P
=0.04). Medial calcification was found only in RAs (20 of 150, 13.3%) (
P
<0.001). Morphometric analysis showed that compared with ITAs, RAs had a significantly higher intimal area, medial area, percentage of luminal narrowing, intimal thickness index, and intima-to-media ratio (all
P
<0.001) Factors found to be significant (
P
<0.05) predictors of the 3 severity indices of intimal hyperplasia, including atherosclerosis, in RAs were peripheral vascular disease, smoking, age, and diabetes. Risk factors for intimal hyperplasia in ITAs were age and smoking.

Conclusions
—The RA is more likely to have atherosclerosis, intimal hyperplasia, and medial calcification than the ITA. Morphometric analysis indices showed marked differences between the RA and the ITA. Care should be taken when selecting the RA as a conduit in CABG, particularly in patients who are elderly, diabetic, smoke, or have peripheral vascular disease.
Intravenous Arginine-Vasopressin in Children With Vasodilatory Shock After Cardiac Surgery
Authors: Rosenzweig Erika Berman , Starc Thomas J. , Chen Jonathan M. , Cullinane Suzanne , Timchak Donna M. , Gersony Welton M. , Landry Donald W. , Galantowicz Mark E.
Published: July 2021

Background
—Recent investigations at our institution have studied a variety of vasodilatory shock states that are characterized by vasopressin deficiency and pressor hypersensitivity to the exogenous hormone. Our experience in adults prompted the use of arginine-vasopressin (AVP) in a similar group of critically ill children.

Methods and Results
—This report describes our early experience (from February 1997 through April 1998) in 11 profoundly ill infants and children (5 male, 6 female) ages 3 days to 15 years (median, 35 days) treated with AVP for hypotension after cardiac surgery which was refractory to standard cardiopressors. Although underlying heart disease was present (congenital heart defects in 10 and dilated cardiomyopathy in 1), only 2 patients had severely depressed cardiac function as demonstrated by 2D echocardiogram before administration of AVP. All patients were intubated and receiving multiple catecholamine pressors and inotropes, including dobutamine (n=10), epinephrine (n=8), milrinone (n=7), and dopamine (n=4) before receiving AVP. Five patients received AVP intraoperatively immediately after cardiopulmonary bypass, 5 in the intensive care unit within 12 hours of surgery, and 1 on postoperative day 2 for hypotension associated with sepsis. The dose of AVP was adjusted for patient size and ranged from 0.0003 to 0.002 U · kg
−1
· min
−1
. During the first hour of treatment with AVP, systolic blood pressure rose from 65±14 to 87±17 mm Hg (
P
<0.0001; n=11), and epinephrine administration was decreased in 5 of 8 patients and increased in 1. Plasma AVP levels before treatment were available in 3 patients and demonstrated AVP depletion (median, 4.4 pg/mL; n=3). All 9 children with vasodilatory shock survived their intensive care unit stay. The 2 patients who received AVP in the setting of poor cardiac function died, despite transient improvement in blood pressure.

Conclusions
—Infants and children with low blood pressure and adequate cardiac function after cardiac surgery respond to the pressor action of exogenous AVP. AVP deficiency may contribute to this hypotensive condition.
Cardiac Arrest in Infants After Congenital Heart Surgery
Authors: Rhodes John F. , Blaufox Andrew D. , Seiden Howard S. , Asnes Jeremy D. , Gross Ronda P. , Rhodes Julianna P. , Griepp Randall B. , Rossi Anthony F.
Published: July 2021

Background
—The survival rate to discharge after a cardiac arrest in a patient in the pediatric intensive care unit is reported to be as low as 7%. The survival rates and markers for survival strictly regarding infants with cardiac arrest after congenital heart surgery are unknown.

Methods and Results
—Infants in our pediatric cardiac intensive care unit database were identified who had a postoperative cardiac arrest between January 1994 and June 1998. Parameters from the perioperative, prearrest, and resuscitation periods were analyzed for these patients. Comparisons were made between survivors and nonsurvivors. Of 575 infants who underwent congenital heart surgery, 34 (6%) sustained a documented cardiac arrest; of these, 14 (41%) survived to discharge. Perioperative parameters, ventricular physiology, and primary rhythm at the time of arrest did not influence outcome. Prearrest blood pressure was lower in nonsurvivors than in survivors (
P
<0.001). A high level of inotropic support prearrest was associated with death (
P
=0.06). Survivors had a shorter duration of resuscitation (
P
<0.001) and higher minimal arterial pH (
P
<0.02) and received a smaller total dose of medication during the resuscitation. Although survivors had an overall shorter duration of resuscitation, 5 of 22 patients (23%) survived to discharge despite resuscitation of >30 minutes.

Conclusions
—The outcome of cardiac arrest in infants after congenital heart surgery was better than that for pediatric intensive care unit populations as a whole. Univentricular physiology did not increase the risk of death after cardiac arrest. Infants with more hemodynamic compromise before the arrest as demonstrated with lower mean arterial blood pressure and higher inotropic support were less likely to survive. The use of predetermined resuscitation end points in this subpopulation may not be justified.
Prediction of Progression or Regression of Type A Aortic Intramural Hematoma by Computed Tomography
Authors: Kaji Shuichiro , Nishigami Kazuhiro , Akasaka Takashi , Hozumi Takeshi , Takagi Tsutomu , Kawamoto Takahiro , Okura Hiroyuki , Shono Hiroyuki , Horibata Yoko , Honda Takashi , Yoshida Kiyoshi
Published: July 2021

Background
—It has been reported that early surgery should be required for patients with type A aortic intramural hematoma (IMH) because it tends to develop classic aortic dissection or rupture. However, the anatomic features of type A IMH that develops dissection or rupture are unknown. The purpose of this study was to investigate the predictors of progression or regression of type A IMH by computed tomography (CT).

Methods and Results
—Twenty-two consecutive patients with type A IMH were studied by serial CT images. Aortic diameter and aortic wall thickness of the ascending aorta were estimated in CT images at 3 levels on admission and at follow-up (mean 37 days). We defined patients who showed increased maximum aortic wall thickness in the follow-up CT (n=9) or died of rupture (n=1) as the progression group (n=10). The other 12 patients, who all showed decreased maximum wall thickness, were categorized as the regression group. In the progression group, the maximum aortic diameter in the initial CT was significantly greater than that in the regression group (55±6 vs 47±3 mm,
P
=0.001). A Cox regression analysis revealed that the maximum aortic diameter was the strongest predictor for progression of type A IMH. We considered the optimal cutoff value to be 50 mm for the maximum aortic diameter to predict progression (positive predictive value 83%, negative predictive value 100%).

Conclusions
—Maximum aortic diameter estimated by the initial CT images is predictive for progression of type A IMH.
Stent-Supported Reconstruction of the Aortoiliac Bifurcation With the Kissing Balloon Technique
Authors: Scheinert Dierk , Schröder Malte , Balzer Jörn O. , Steinkamp Hermann , Biamino Giancarlo
Published: July 2021

Background
—Bilateral iliac artery obstructions involving the aortic bifurcation or high-grade stenosis of the abdominal aorta are not usually considered an indication for percutaneous treatment. The purpose of the present study was to evaluate the initial and long-term results of primary stent implantation for reconstruction of the aortic bifurcation.

Methods and Results
—In 48 patients with obstructions of the aortoiliac segment, primary stent implantation was performed with the “kissing balloon technique.” Preinterventional angiography showed bilateral stenoses (>85%) of the proximal common iliac arteries in 25 patients, unilateral occlusions and contralateral stenosis in 22 patients, and bilateral occlusion in 1 patient. In 7 cases, stents were placed for the treatment of high-grade infrarenal aortic stenoses. After excimer laser–assisted recanalization of the common iliac artery obstructions, the aortic bifurcation was reconstructed with the bilateral simultaneous implantation of Palmaz stents (diameter, 7 to 8 mm). Stents used for the treatment of aortic stenoses (Palmaz, n=6; Gianturco, n=1) had a diameter ranging from 20 to 25 mm. In all patients, stents were placed successfully (residual stenosis <30%) and without complications. A clinical improvement of +2 to +3 according to American Heart Association criteria was observed in 41 and 7 patients, respectively. Follow-up was performed clinically (standardized treadmill testing and color-coded Doppler ultrasound) and angiographically. The primary angiographic patency rate (24-month follow-up) was 86.8%. In 3 patients, angiography revealed significant restenoses, which were successfully treated with percutaneous transluminal angioplasty.

Conclusions
—Primary stent implantation with the kissing balloon technique is safe and effective for the treatment of aortoiliac obstructions involving the aortic bifurcation and represents a true endovascular alternative to surgery.
Enhanced Nitric Oxide–Mediated Vascular Relaxation in Radial Artery Compared With Internal Mammary Artery or Saphenous Vein
Authors: Shapira Oz M. , Xu Aiming , Aldea Gabriel S. , Vita Joseph A. , Shemin Richard J. , Keaney John F.
Published: July 2021

Background
—The superior long-term patency of internal mammary artery coronary bypass grafts compared with venous grafts has been attributed in part to increased endothelium-derived nitric oxide (·NO) production. Interest in the radial artery as an alternative bypass conduit has recently been revived; however, its biological characteristics remain incompletely defined. The purpose of this study was to compare the ·NO-mediated vasomotor properties of the radial artery to those of the internal mammary artery and saphenous vein.

Methods and Results
—Matched segments of radial artery, internal mammary artery, and saphenous vein (n=24 patients) were examined by use of organ-chamber methodology. Endothelium-dependent and -independent vasomotor responses were assessed by dose-response curves to acetylcholine,
N
G
-nitro-
l
-arginine methyl ester (L-NAME), 8-bromo-cyclic 3′,5′-guanosine monophosphate (8-bromo-cGMP), and nitroglycerin. Maximum ·NO-mediated radial artery relaxation in response to acetylcholine (86±10%) was significantly greater than internal mammary artery (56±9%) or saphenous vein (11±5%, both
P
<0.0001). Similarly, acetylcholine-stimulated cGMP accumulation in radial artery (9.1±1.7 pmol/mg protein) was also greater than internal mammary artery (6.2±0.3 pmol/mg protein) or saphenous vein (1.4±0.2 pmol/mg protein, both
P
<0.05). Estimated basal endothelial ·NO production, assayed as the percent maximum contraction in response to L-NAME, was greater in radial artery (39±5%) than internal mammary artery (23±6%) or saphenous vein (5±2%, both
P
<0.05). Maximum relaxation of all vessels to nitroglycerin was similar, although the sensitivity of radial artery to nitroglycerin was greater (EC
50
=33±7 nmol/L) than the internal mammary artery (203±32 nmol/L) or saphenous vein (97±12 nmol/L, both
P
<0.05). Vascular cGMP in response to 0.1 μmol/L nitroglycerin was significantly higher in the radial artery (8.3±1.4 pmol/mg protein) compared with the internal mammary artery (3.5±1.3 pmol/mg protein) or saphenous vein (1.4±0.3 pmol/mg protein, both
P
<0.0001). Relaxation to 8-bromo-cGMP was identical for all 3 conduits.

Conclusions
—These data indicate that ·NO-dependent relaxation of radial artery is greater than that of internal mammary artery or saphenous vein. This difference is related to endothelial production of ·NO and/or vessel sensitivity to ·NO. Such favorable physiological characteristics of radial artery could conceivably contribute to improved long-term patency of this conduit compared with saphenous vein.
Serotonin-Induced Coronary Contraction Increases After Blood Cardioplegia-Reperfusion
Authors: Métais Caroline , Li Jiany , Li Jian , Simons Michael , Sellke Frank W.
Published: July 2021

Background
—Coronary contraction has been implicated in causing suboptimal myocardial function after coronary bypass surgery. Addition of blood to cardioplegic solutions has been shown to improve endothelial function after cardioplegia. In this study, the effects of blood cardioplegia and brief reperfusion on vascular reactivity in patients with coronary artery disease and the expression (mRNA and protein) of enzymes involved in vasomotor regulation were examined.

Methods and Results
—The atrial appendages of patients undergoing coronary artery surgery were harvested before cardiopulmonary bypass (control, n=8) and after bypass from a nonischemic tissue atrial segment exposed to cold, hyperkalemic blood cardioplegia (mean, 60 minutes) and a brief period (10 minutes) of reperfusion (CP-Rep, n=8). Responses of atrial arterioles were studied in vitro with video-microscopy. Reverse-transcriptase polymerase chain reaction and Western blotting were used to examine the expressions and protein content, respectively, of enzymes involved in vasomotor regulation. Serotonin caused a minimal dilation under baseline conditions but after CP-Rep elicited a potent contractile response that was inhibited in the presence of the selective inducible cyclooxygenase (COX-2) inhibitor NS398. Substance P caused an endothelium-dependent relaxation of atrial arterioles through release of nitric oxide, and ADP caused relaxation mediated through release of prostaglandins. After CP-Rep, relaxation to substance P was impaired, whereas endothelium-independent relaxation to nitroprusside and response to ADP were unchanged. Expression and protein level of COX-2 were significantly increased after CP-Rep. In contrast, expression of inducible (nitric oxide synthase-2) or constitutive endothelial (nitric oxide synthase-3) nitric oxide synthase, prostacyclin synthase, and constitutive cyclooxygenase (COX-1) were not altered after CP-Rep.

Conclusions
—CP-Rep increases serotonin-induced contraction of human microvessels caused by the release of products of COX-2 and the impaired release of nitric oxide. These findings have implications regarding altered coronary microvascular regulation and the cause of coronary spasm after cardiac surgery.
Patient Outcome and Valve Performance Following a Second Aortic Valve Homograft Replacement
Authors: Hasnat K. , Birks E. J. , Liddicoat J. , Hon J. K. F. , Edwards S. , Glennon S. , Yacoub M. H.
Published: July 2021

Background
—Homograft valves offer many advantages; however, there is concern about their use in second aortic valve replacement because of the complexity of the procedure and the possibility of accelerated degeneration.

Methods and Results
—One hundred and forty-four patients underwent a second aortic homograft replacement between 1973 and 1997 (mean follow-up 6.5±5 years, range 1 to 20 years). Eighty-three were male, and 61 were female, aged 17 to 77 years, mean 49.0 years. All patients had undergone previous aortic valve replacement with a homograft. The indication for reoperation was aortic regurgitation in 75 patients (52.1%), aortic stenosis in 28 (19.4%), and mixed aortic valve disease in 41 (28.5%). Root replacement was performed in 54 patients (38%) and subcoronary in 90 (62.5%). Early mortality was 3.4%. The actuarial survival rate was 93% and 82% at 5 and 10 years, respectively. Freedom from tissue degeneration was 96% and 80% at 5 and 10 years, respectively, and freedom from reoperation was 97% and 82% at 5 and 10 years, respectively.

Conclusions
—This study shows that a second aortic valve homograft replacement results in good early and long-term survival. Accelerated degeneration does not occur. Left ventricular performance is improved, and earlier surgery could further improve outcome, indicating that an aortic homograft is a safe, durable option for patients requiring a second aortic valve replacement.
Predictors of the Long-Term Outcome After Combined Aortic and Mitral Valve Surgery
Authors: Turina Juraj , Stark Thomas , Seifert Burkhardt , Turina Marko
Published: July 2021

Background
—The influence of preoperative clinical, hemodynamic, and surgical procedures on long-term prognosis after combined aortic and mitral valve surgery is not well known.

Methods and Results
—One hundred seventy patients (mean age, 50.5 years; 102 men and 68 women) who underwent surgery for chronic combined aortic and mitral valvular disease between 1975 and 1989 were followed up for an average of 10.6 years. Additional repair of tricuspid valve was performed in 29 patients (17%), and aortocoronary bypass graft surgery was performed in 7 patients (4.1%). The perioperative mortality rate was 4%, and 10- and 20-year survival rates were 61% and 33%. Only 12 of 94 deaths (11%) were non–cardiac related. At 10 and 20 years, 57% and 21% of patients were free of reoperation, respectively. The main predictors of late survival in univariate analysis were age at surgery (
P
=0.0002), preoperative left ventricular ejection fraction (
P
=0.002), cardiac index (
P
=0.007), tricuspid surgery (
P
=0.03), pulmonary vascular resistance (
P
=0.03), NYHA class (
P
=0.04), and additional aortocoronary bypass graft surgery (
P
=0.04). Duration of symptoms, gender, cause of valvular disease, and type of prosthesis were not predictive of postoperative outcome. In multivariate stepwise Cox analysis, ejection fraction (
P
=0.0008), age at surgery (
P
=0.0011), and tricuspid surgery (
P
=0.007) were independent predictors of late survival.

Conclusions
—In combined aortic and mitral valve disease, preoperative myocardial function is the main predictor of long-term survival. Low operative mortality rates and good late outcome make valve replacement mandatory before deterioration of myocardial function occurs. Additional tricuspid valve disease requiring surgery significantly decreases the late survival rate.