bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of Cryo-Maze Procedure on Early and Intermediate Term Outcome in Mitral Valve Disease: Case Matched Study
Authors: Nakajima Hiroyuki , Kobayashi Junjiro , Bando Ko , Niwaya Kazuo , Tagusari Osamu , Sasako Yoshikado , Nakatani Takeshi , Kitamura Soichiro
Published: July 2021

Background

The maze procedure is an effective way to treat atrial fibrillation (AF) associated with mitral valve disease. In a last several years, cryoablation was substituted for atrial incision in many reports to simplify the maze procedure. However, there has been no comparative study to delineate the feasibility of the use of cryoablation.

Methods and Results

We compared the early and intermediate-term results of the maze procedure including pulmonary venous isolation from the left atrium using cryoablation (CM) with our conventional (Kosakai) maze procedure (KM) including encircling incision around the orifices of pulmonary veins. One hundred and 10 pairs of patients were matched in the age, left atrial dimension >70 mm, duration of AF >0 years, previous cardiac surgery, mechanical valve implantation and concomitant aortic valve procedures. CM required significantly shorter cardiopulmonary bypass time (186±56 minute versus 214±47 minute,
P
=0.001) and aortic cross-clamp time (134±43 minute versus 144±37 minute,
P
=0.03) than KM with less chest tube drainage (590±353 mL versus 745±618 mL,
P
=0.02) for 12 hours after operation. The sinus rhythm restoration rate in CM group (85.4%) was comparable with KM group (86.4%) at discharge. In the late results, the actuarial freedom from recurrence of sustained AF at 3 years in CM group (97.7%) was not significantly (
P
=0.11) different from that in KM group (90.4%). The actuarial freedom from stroke at 3 years in CM group was 99.0%.

Conclusion

The modification of the maze procedure including cryoablation for pulmonary venous isolation provided less aortic cross-clamp time and less amount of chest tube drainage with the comparable recovery and maintenance of sinus rhythm with KM. CM is a reliable and less invasive surgical option for the AF associated with mitral valve disease.
Long-Term Prognosis of Patients With Type A Aortic Intramural Hematoma
Authors: Kaji Shuichiro , Akasaka Takashi , Horibata Yoko , Nishigami Kazuhiro , Shono Hiroyuki , Katayama Minako , Yamamuro Atsushi , Morioka Shigefumi , Morita Ichiro , Tanemoto Kazuo , Honda Takashi , Yoshida Kiyoshi
Published: July 2021

Background

Recent studies have shown an favorable short-term prognosis of patients with type A acute aortic intramural hematoma (IMH). The difference of aortic pathology may have a different impact on clinical course compared with classic aortic dissection (AD). The purpose of this study was to elucidate clinical features and long-term prognosis of patients with type A IMH.

Methods and Results

Clinical data were compared retrospectively between 30 patients with acute type A IMH (IMH group) and 101 patients with acute type A AD (AD group) who were admitted to our institutions from 1988 to 1998. In AD group, 72 patients underwent surgical repair and 29 patients were treated medically. All patients in IMH group were treated initially with supportive medical therapy. Thirteen patients who demonstrated progression to AD or increase in size of hematoma underwent timed surgical repair except for 1 patient. The overall in-hospital mortality rate in IMH group was significantly lower than that in AD group (7% and 34%,
P
=0.004). Follow-up periods were 56±37 (IMH group) and 60±42 months (AD group), which revealed 1 and 6 late deaths, respectively. The actuarial survival rates in IMH group were all 90% at 1, 2, and 5 years, which were significantly higher than those in AD group (67%, 66%, and 62%, respectively;
P
=0.004).

Conclusions

Patients with type A IMH have better long-term prognosis than patients with AD.
An MRI Study of Neurological Injury Before and After Congenital Heart Surgery
Authors: Mahle William T. , Tavani Federica , Zimmerman Robert A. , Nicolson Susan C. , Galli Kristin K. , Gaynor J. William , Clancy Robert R. , Montenegro Lisa M. , Spray Thomas L. , Chiavacci Rosetta M. , Wernovsky Gil , Kurth C. Dean
Published: July 2021

Background

Neuorological deficits are observed in patients with congenital heart disease (CHD) before and after neonatal surgery, the etiology being multifactorial. To understand the impact of preoperative events and to characterize the evaluation of neurological injury, we performed serial magnetic resonance imaging (MRI) studies of the brain in a cohort of neonates undergoing open-heart surgery.

Methods and Results

Twenty-four term neonates with CHD were studied prospectively with brain MRI: before surgery, within 2 weeks of surgery, and several months after surgery. Preoperative MRI examinations showed periventricular leukomalacia (PVL) in 4 patients (16%) and infarct in 2 subjects (8%). MR spectroscopy was performed in 19 subjects preoperatively and revealed elevated brain lactate in 53%. An early postoperative MRI (n=21) identified new PVL in 48%, new infarct in 19%, and new parenchymal hemorrhage in 33%. New lesions or worsening of preoperative lesions occurred in 67% of subjects. No patient- or procedure-related factors for the development of early postoperative lesions were identified. A late postoperative MRI (n=17) demonstrated resolution of early lesions in 8 and mild cerebral atrophy in 2.

Conclusions

Mild ischemic lesions, primarily in the form of PVL, occur in a number of neonates with CHD before surgery and >50% of patients postoperatively. Resolution of these lesions is common 4 to 6 months after surgery. Longer-term follow-up is needed to determine the significance of perioperative ischemic lesions on functional outcome.
Abstract 16: Amyloidogenic Modifications of Apolipoprotein A-I Promote a Strong Pro-inflammatory Response in Macrophages, but Formation of Amyloid Fibrils Abrogates the Pro-inflammatory Effect
Authors: Witkowski Andrzej , Chan Gary K , Li Nancy J , Lu Rui , Yokoyama Shinji , Cavigiolio Giorgio
Published: July 2021

Inflammation is central to atherosclerosis, as inactivation of inflammation pathways strongly reduces atherosclerosis progression. Particulate matter, such as cholesterol crystals and amyloid materials, promotes release of the potent pro-inflammatory cytokine IL-1β in macrophages. Recently, it has been demonstrated that soluble substances that are precursors of particulate matter, such as free cholesterol, oxidized LDL and amyloidogenic peptides (i.e. amyloid-β, IAPP), can also induce an inflammatory response.

In this study, we investigated the interplay between oxidation of apolipoprotein A-I (apoA-I), amyloid formation, and the inflammatory response of macrophages. We previously reported that oxidation of apoA-I methionines (MetO-ApoA-I) promotes protein aggregation and formation of amyloid fibrils when MetO-ApoA-I is incubated at pH 6.0. In contrast, at physiological pH, MetO-ApoA-I remains soluble and perfectly functional, as it promotes cholesterol efflux from macrophages with the same efficiency of intact-ApoA-I. However, upon incubation of mouse bone marrow derived macrophages with soluble pre-fibrillar MetO-ApoA-I, levels of pro-IL-1β synthesis were more than 2-fold higher than those induced by intact-ApoA-I. In contrast, amyloid fibrils produced by MetO-ApoA-I did not increase the levels of pro-IL-1β synthesis compared to intact-ApoA-I. Furthermore, the pro-inflammatory effect was not observed in macrophages derived from MyD88/TRIF knock-out mice, indicating that the response is membrane TLR receptors-dependent. In contrast, the >2-fold increase (MetO-ApoA-I vs. intact-apoA-I) in pro-IL-1β synthesis was maintained in macrophages derived from CD36 knock-out mice. This observation suggests that the signaling pathway is not exclusively dependent on the TLR2/TLR6/CD36 membrane complex. Thus, in atherosclerotic lesions, oxidized apoA-I species that are amyloidogenic, but otherwise functional, may induce a pro-inflammatory response in macrophages. Amyloid fibril formation in contrast, could reduce, rather than exacerbate, the inflammatory burden produced by these pro-inflammatory apoA-I species by sequestering them in the form of inert amyloids.
Abstract 249: Potential Tissue-specific Interactions Between Inflammation and Canonical Tgfβ Signaling in Marfan Syndrome
Authors: Black Rebecca L , Roos Carolyn M , Hagler Michael A , Thalji Nassir M , Zhang Bin , Verzosa Grace C , Miller Jordan D
Published: July 2021

Marfan syndrome is a connective tissue disorder frequently driven by mutations in the fibrillin-1 gene (Fbn1). This results in multiple aberrant cardiovascular phenotypes, including aortic aneurysm and mitral valve prolapse. While the molecular changes underlying aortic aneurysm formation have been extensively studied, the molecular underpinnings of mitral valve prolapse in this syndrome remain poorly understood. Therefore, we hypothesized that smad2/3 phosphorylation would be significantly increased in both aorta and mitral valve from Fbn1
+/1037G
mice with Marfan syndrome and associated with impaired anti-inflammatory signaling in both tissues. We used young (3 months) mice that were wild-type (Fbn1
+/+
) or fibrillin-1 mutant (Fbn1
+/1037G
) and fed a normal chow diet. qRT-PCR was used to measure mRNA levels in aortic arch and mitral valve tissue, and fluorescent immunohistochemistry to evaluate changes in canonical TGFβ signaling. Consistent with previous reports, TGF-β1 mRNA levels were increased in Fbn1
+/1037G
compared to wild-type mice in both aorta and mitral valve. Interestingly, while p-SMAD2/3 protein levels were increased in aorta from Fbn1
+/1037G
mice, we were surprised to find that p-SMAD2/3 protein levels were decreased in mitral valve from Fbn1
+/1037G
mice compared their wild-type littermates. Given the emerging role of inflammatory signaling in accelerated development of Marfan phenotypes, we sought to determine whether there were compensatory or maladaptive changes in IL10 (a known inhibitor of p-SMAD2/3). In aorta, IL10 mRNA levels were decreased in Fbn1
+/1037G
compared to Fbn1
+/+
mice, suggesting a maladaptive response. In contrast, IL10 levels in mitral valve tissue were significantly increased in Fbn1
+/1037G
mice compared to their wild-type littermates, suggesting a compensatory/protective response. Collectively, these data suggest that tissue-specific changes in IL10 levels may modulate p-SMAD2/3 signaling in aorta and mitral valve, which may be a key permissive step in the onset of Marfan-related phenotypes. Future work to experimentally determine the role of IL10 in the regulation of canonical and non-canonical TGFβ signaling and the penetrance of Marfan-associated phenotypes is warranted.
Abstract 300: Targeting IL-1β Protects From Aortic Aneurysms Induced by Disrupted TGFβ signaling in SMCs
Authors: Carnevale Daniela , Carnevale Raimondo , Da Ros Francesco , Cifelli Giuseppe , Casaburo Manuel , Iacobucci Roberta , Carnevale Lorenzo , Perrotta Marialuisa , Bressan Giorgio , Lembo Giuseppe , Lembo Giuseppe
Published: July 2021

Aortic aneurysms represent a life-threatening condition because of the current lack of effective treatment, with therapeutic options limited to emergency surgery. Aneurysm formation is typically associated with extracellular matrix remodeling and persistent inflammation. Although the molecular mechanisms underlying aortic pathology remain largely unclear, TGFβ signaling is unquestionably implied and its downstream target Smad4 showed protective functions for maintenance of aortic walls’ integrity. Using mice with smooth muscle cells (SMCs) specific deletion of
Smad4
in the adult (
Smad4
-SMC
iko
), developing spontaneous aneurysms, we investigated the molecular mechanisms activated by dysregulation of TGFβ signaling. Structural disarrangement of ascending aorta media in
Smad4
-SMC
iko
mice was clearly appreciated early after Smad4 deletion as discrete breaks of elastic lamellae. Interestingly, the islands of damage evidenced in the aorta of
Smad4
-SMC
iko
were enriched of immune infiltrate, mainly composed by monocytes/macrophages, as indicated by flow cytometry and immunofluorescence. We then analyzed several pathways downstream to Smad4 inhibition, finding a selective activation of NF-kB/IL-1β pathway in SMCs. This danger signal released by SMCs later recruits innate immunity, hence arising inflammation. In order to test the relevance of this pathway in the formation of aneurysms induced by TGFβ dysregulation, we deleted
Smad4
in SMCs of mice with
Il1r1 null
background (
Smad4
-SMC
iko
;
Il1r1
-/-
). Serial ultrasonographic analyses revealed that ablation of IL1 receptor 1 protected mice with the SMCs deletion of
Smad4
from the progression of pathology and improved their overall survival. In the end, to test the translational potential of our findings, we neutralized IL-1β signaling with the clinically relevant murine version of the FDA-approved clinical drug canakinumab. During a time course of 16 weeks, while a weekly administration of control immunoglobulins did not change aneurysm progression in
Smad4
-SMC
iko
mice, treatment with anti-IL-1β antibody significantly hampered aneurysm formation in the aorta. These findings identify a mechanistic target for controlling aneurysms progression induced by disrupted TGFβ signaling.
Abstract 399: High Throughput Comprehensive Volumetric Approach for Determination of Particle Number and Composition of Lipoproteins in Normolipidemic and Dyslipidemic Populations
Authors: Kuklenyik Zsuzsanna , Barr John R , Pirkle James L ,   Cardiovascular Biomarkers Group
Published: July 2021

Lipoproteins (Lps) are large molecular assembles formed by lipid and apolipoprotein constituents. The physical metric of Lps as metabolically functional entities is particle concentration in serum or plasma (Lp-P). However, the metabolic functions of Lp particles is determined by their lipid/protein composition and structure. To be able to determine both Lp composition and Lp-P, a volumetric approach is required, as demonstrated by Segrest et al and other groups. In this work the volumetric approach was implemented but with applicability to population studies. The workflow included size based separation of Lps by asymmetric flow field-flow fractionation while collecting fractions with 1-1.5 nm increments in the range of 7-15 nm (HDL), 20-30 nm (LDL) and >30 nm Lps (40 fractions in total from 0.1 mL serum aliquots). The average particle size in each fraction was measured by dynamic light scattering. Three high throughput, parallel LC-MS/MS based methods were developed to quantify main non-polar lipids (FC, CE and TG), phospholipids (PC, SM, PE, PI and LPC), and apolipoproteins (apos A-I, A-II, A-IV, B, C-I, C-II, C-III and E). Quantification of particle size and all major Lp components was achieved with 4-15% CVs. Overall accuracy of the methods was demonstrated by ApoB-100/LDL-P molar ratios of 0.7-1.3 (vs. 1 expected) in the 22-26 nm maximum LDL size range. In the 7.5-13 nm size range, ApoA-I/HDL-P was 0.7-3.5 and ApoA-II/HDL-P of 0.5-2.5. Using the calculated Lp-P values, average individual analyte/Lp-P molar ratios were calculated in each fraction. The workflow was applied to 120 patient samples with wide range of Total-C and Total-TG levels. Multivariate response surface modeling was used to show significant correlations among individual lipid/Lp-P and apolipoprotein/Lp-P molar ratios. For example, with correction for particle size, the correlations of apoC-III/Lp-P and FC/Lp-P with SM/Lp-P, PC/Lp-P, TG/Lp-P and CE/Lp-P were determined, showing the effect of surface lipid and core lipid composition on apoC-III and FC binding to HDL and LDL particles, while also revealing significant cross effects among Lp components. By using <0.1 mL serum or plasma, the workflow is applicable to archived samples collected in large cohort studies.
Abstract 40: Platelet Fragmentation During the Hemostatic Response and its Prevention by a P2Y12 Antagonist
Authors: Tomaiuolo Maurizio , Matzko Chelsea N , Poventud-Fuentes Izmarie , Nettey Leonard , Herbig Brad A , Weisel John W , Diamond Scott L , Brass Lawrence F , Stalker Timothy J
Published: July 2021

Previous studies using intravital microscopy have shown that hemostatic plugs formed in the mouse microvasculature have a characteristic architecture in which the extent of platelet activation reflects gradients in the distribution of platelet agonists radiating outwards from the injury site. In that setting, we found minimal overlap of thrombin and ADP signaling, with thrombin primarily responsible for robust platelet activation close to the injury site and P2Y
12
-mediated ADP signaling resulting in accumulation of minimally activated platelets. Here we have taken these studies a major step forward by integrating fluorescence with scanning electron microscopy. Hemostatic plugs produced by needle injury in mouse jugular veins were imaged
in situ
1 to 20 min after injury. The results show with unprecedented detail what could only be inferred previously, showing that platelet size, morphology and packing density vary remarkably depending on spatial localization within the hemostatic plug. The intraluminal and extravascular portions of the hemostatic mass presented distinct architectures. A large mass comprised almost exclusively of platelets was observed on the interior surface of the vein. Platelets closest to the injury edge had a highly activated morphology, including P-selectin surface expression, dense packing and platelet fragmentation, while those farther from the injury edge often remained discoid. In contrast, the extravascular portion of the hemostatic mass was rich in densely-packed, platelet-derived fragments intertwined with fibrin. Hemostatic plugs from mice treated with a P2Y
12
inhibitor were significantly smaller. The platelet activation gradient described above was less apparent and, notably, fragmentation of the platelets close to the injury edge was not observed with the inhibitor present. In conclusion, our findings indicate that 1) the development of a platelet activation gradient is a conserved feature of the hemostatic response across different vessels, 2) fragmentation of platelets closest to the injury site occurs very rapidly following injury, and 3) clinically relevant platelet signaling pathways play a role in regulating its formation.
Abstract 422: Protease-Activated Receptor 2 is Critical for the Formation and Progression of Atherosclerosis
Authors: Jones Shannon , Robbins Nathan , Saum Keith , Slone Samuel , Thompson Joel , Tranter Michael , Mackman Nigel , Owens A. Phillip
Published: July 2021

Objective:
Protease-activated receptor 2 (PAR-2)-dependent signaling results in augmented inflammation and has been implicated in the pathogenesis of several autoimmune conditions. While PAR-2 protein is present in coronary atherosclerotic lesions, the relevance of this finding has not been investigated in experimental models. The objective of this study was to determine the effects of PAR-2 on the development of atherosclerosis.

Methods and Results:
Relative expression of PAR-2 is increased in human coronary artery (21 fold) and mouse aortic arch (16 fold) atheromas versus control coronary and aortic arch arteries, respectively (P = 0.001). To determine the effect of PAR-2 deficiency on atherosclerosis, male low density lipoprotein receptor deficient (

Ldlr
-/-

) mice (8-12 weeks old) that were
Par-2

+/+

or
Par-2

-/-

were fed a fat and cholesterol-enriched diet for 12 (n = 10 each group) or 24 weeks (n = 5 each group). PAR-2 deficiency attenuated atherosclerosis in the aortic sinus and aortic root with no effects on total plasma cholesterol concentrations or lipoprotein distributions after 12 (P = 0.000433) and 24 (P = 0.037) weeks. These reductions were attributable to both hematopoietic and non-hematopoietic-derived PAR-2 from analysis of bone marrow experiments (n = 15 for each of 4 chimeric groups; P < 0.05). Mechanistic studies using ex vivo macrophages show that activation of PAR-2 results in augmented foam cell formation and apoptosis with treatment of oxidized low-density lipoprotein in conjunction with decreased expression of the nuclear receptor LXR-alpha and several cholesterol transporters. In addition, PAR-2 activation of ex-vivo cultured vascular smooth muscle cells (VSMCs) augments their transition to a macrophage-like state (after cholesterol treatment) via upregulation of human antigen R (HuR) and resultant stabilization of the transcription factor Krüppel-like factor 4 (KLF4).

Conclusion:
Our results indicate PAR-2 deficiency significantly attenuates the initiation (12 weeks) and reduces the progression (24 weeks) of atherosclerosis potentially via regulation of both lipid efflux from macrophages and the phenotypic modulation of VSMCs.
Abstract 452: Serine Carboxypeptidase 1 Mediates Vascular Remodeling by Increasing Inflammatory Cell Infiltration
Authors: Lee Ting-Hein , Miano Joseph
Published: July 2021

In pathological vascular remodeling, contractile vascular smooth muscle cells (VSMCs) switch their phenotype to highly proliferative and migratory states leading to neointimal formation. Inflammatory cell recruitment and infiltration, which is dependent on the increased expression of adhesion molecules on the endothelial cells, is a key event to initiate SMC phenotypic modulation in vascular remodeling. Serine carboxypeptidase 1 (scpep1), a novel protease containing the putative catalytic triad (Ser-Asp-His) common to all members of the serine protease family, has been proved to be involved in vascular remodeling by promoting SMC proliferation and migration in a catalytic triad-dependent manner. To determine whether Scpep1 modulates leukocyte adhesion and infiltration, a flow-induced model of vascular remodeling was conducted in wild-type (WT) or Scpep1 knockout (KO) mice. Scpep1-null mice show a decreased number of infiltrated leukocytes into the intima and media compared to WT mice. Further, mice devoid of Scpep1 show a dramatic reduction of vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) expression in vessels in comparison with that of WT mice. Consistent with our in vivo data, the expression levels of ICAM-1 and VCAM-1 on human umbilical vein endothelial cells (HUVECs) transfected with SiRNA against Scpep1 were significantly decreased after TNF-α treatment. Taken together, these data suggest that Scpep1 may increase leukocyte extravasation by increasing the expression of VCAM-1 and ICAM-1 adhesion molecules.
Abstract 557: Type 2 Diabetes is Associated With Impaired High-Density Lipoprotein Endothelial Protective Function
Authors: Vaisar Tomas , Couzens Erica , Hwang Arnold , Hoofnagle Andrew N , Barlow Carolyn E , DeFina Laura F , Kim Francis
Published: July 2021

Aim:
One of the hallmarks of diabetes is impaired endothelial function. High density lipoproteins (HDL) can exert protective effects on endothelium stimulating NO production and protecting from inflammation. Previous study suggested that HDL in obese people with diabetes and metabolic syndrome and markedly low HDL-C lost endothelial protective function. We aimed to test whether type 2 diabetes impairs HDL endothelium protective functions in people with otherwise normal lipid profile.

Methods:
In a case-control study (n=40 per group) nested in the Cooper Center Longitudinal Study, we isolated HDL and measured its ability to stimulate activity of endothelial nitric oxide synthase (eNOS; phosphorylation of Ser1177) in endothelial cells and the ability of HDL to suppress inflammatory response of endothelial cells (NFkB activation). Additionally, we also measured by LCMS levels of sphingosine-1-phosphate (S1P) and plasma P-selectin by ELISA.

Results:
The HDL in people with type 2 diabetes lost almost 40% of its ability to stimulate eNOS activity (P<0.001) and 20% of its ability to suppress inflammation in endothelial cells (
P
<0.001) compared to non-diabetic controls despite similar BMI and lipid profile (HDL-C, LDL-C, TC, TG).The ability of HDL to stimulate eNOS activity was negatively associated with plasma levels of P-selectin, an established marker of endothelial dysfunction (r=–0.32,
P
<0.001). Furthermore, sphingosine-1-phosphate (S1P) levels were decreased in plasma of people with diabetes (
P
=0.017) and correlated strongly with HDL-mediated eNOS activation.

Conclusions:
Collectively, our data suggest that HDL in individuals with type 2 diabetes loses its ability to maintain proper endothelial function independent of HDL-C, perhaps due to loss of S1P, and may contribute to development of diabetic complications.
Abstract 592: Constitutive CD40-Signaling in Dendritic Cells Limits Atherosclerosis by Provoking Inflammatory Bowel Disease and Ensuing Cholesterol Malabsorption
Authors: Kusters Pascal J , Seijkens Tom T , Winkels Holger , Gijbels Marion J , Weber Christian , Gerdes Norbert , Lutgens Esther
Published: July 2021

The co-stimulatory molecule CD40 is a major driver of atherosclerosis. It is expressed on a wide variety of cell types including mature dendritic cells (DCs) and required for optimal T cell activation and expansion. It remains undetermined if and how CD40 on DCs impacts the pathogenesis of atherosclerosis. Here we examined the effects of constitutively active CD40 in DCs on atherosclerosis, using low-density lipoprotein-deficient

(Ldlr
-/-

) bone-marrow chimeras that express an engineered latent membrane protein 1 (LMP)/CD40 fusion protein conferring constitutive CD40 signaling under control of the CD11c promoter (
DC-CD40ca
). As expected,

DC-CD40ca/Ldlr
-/-

chimeras showed increased antigen presenting capacity on DCs and increased T cell numbers. However, they developed extensive neutrophilia compared to
wt
/

ldlr
-/-

chimeras. Despite overt T cell expansion and neutrophilia we observed a reduction in cDC frequency and a dramatic reduction in atherosclerosis (

CD40wt/ldlr
-/-

22076±3763 μm
2
vs.

DC-CD40ca/ldlr
-/-

2511±1256 μm
2
). Further analyses revealed that cholesterol and triglyceride levels decreased by 37% and 60%, respectively, in

DC-CD40ca/Ldlr
-/-

chimeras. Moreover,

DC-CD40ca/Ldlr
-/-

chimeras developed inflammatory bowel disease characterized by massive transmural influx of leukocytes and lymphocytes, resulting in villous degeneration and lipid malabsorption. Constitutive activation of CD40 in DCs results in inflammation of the gastrointestinal tract, thereby impairing lipid uptake, which consequently results in attenuated atherosclerosis.
Abstract 594: Matrix Gla Protein Associates With Coronary Artery Calcification and Increases in Subacute Myocardial Infarction Together With Inflammatory Activation by Tumor Growth Factor-β1
Authors: Pesaro Antonio Eduardo , Serrano Carlos Vicente , Katz Marcelo , Pereira Carolina , Mangueira Cristovao L , de Carvalho Ana Eduarda Z , Salmazi Karina L , Nomura Cesar H , Franken Marcelo , Liberman Marcel
Published: July 2021

Osteogenic Proteins (OP) and atherosclerotic inflammation modulate vascular calcification. Patients with acute myocardial infarction (MI) demonstrate higher inflammation and develop accelerated coronary artery calcification (CAC), compared to stable coronary artery disease patients. We aimed to: (a) test the association of OP and inflammatory proteins with CAC in individuals assessed for primary cardiovascular prevention; (b) evaluate these biomarkers in acute and subacute phases post-MI. We prospectively enrolled 170 patients, divided in 3 groups: (1) primary prevention patients who underwent ambulatory coronary computed tomography with a CAC score ≥ 100, n=100; (2) primary prevention patients with a CAC score=zero, n=30; (3) post-MI patients, n=40, during acute (3±1 days post-MI) and subacute (46±17 days post-MI) phases. Serum OP (osteoprotegerin, RANKL, fetuin-A and Matrix Gla protein [MGP]) and serum inflammatory proteins (C-reactive protein, oxidized LDL, tumoral necrosis factor-α and tumor growth factor [TGF]-β1) were measured by ELISA. Associations of plasma OP and inflammatory proteins levels with CAC were adjusted by age, sex and use of statins. In the post-MI group, all biomarkers were compared both in acute vs. subacute phases and in acute phase vs. CAC zero group. Compared to CAC zero, patients with CAC score ≥ 100 were older, predominantly men and had higher rates of hypertension and diabetes. After adjusted analysis, only MGP was associated with a CAC score ≥ 100 (OR 1.48 [95% CI 1.01-2.16; per 100ng/ml increase; p=0.047). Serum MGP and TGF-β1 were higher in subacute phase compared to acute phase post-MI (median [25-75 percentile], 342 vs. 279ng/ml respectively; p=0.01 and 711 vs. 492pg/ml; p=0.03). All biomarkers were similar in acute phase post-MI vs. CAC zero. In conclusion, serum MGP was associated with higher CAC in primary cardiovascular prevention patients. After MI, both serum MGP and TGF-β1 levels increased in the subacute phase. Our findings unveiled a potential role for MGP as a biomarker of CAC in primary cardiovascular prevention. Additionally, this clinical study unfolds further mechanistic hypothesis of how increased TGF-β1 and MGP may modulate vascular inflammation and CAC progression in subacute MI patients.
Abstract 597: Effect of Electronic Cigarettes on Cardiovascular Health
Authors: Malovichko Marina V , Agarwal Abhinav , Winner Millicent , Smith Michel , Sithu Srinivas , Gordon Terry , Bhatnagar Aruni , Conklin Daniel , Chen Lung-Chi , Srivastava Sanjay
Published: July 2021

Electronic cigarettes (E-cig) are battery operated devices used for the delivery of aerosolized nicotine. Unlike conventional cigarettes, E-cig do not contain tar and several other chemicals abundant in conventional cigarettes, and have therefore become extremely popular over the last decade. However, little is known about the health effects of E-cig. To examine the effect of E-cig on cardiovascular health we exposed 8-week old C57BL/6 (C57; maintained on normal chow) and apoE-KO mice (maintained on Western diet) to filtered air or E-cig (36 mg/ml nicotine aerosolized in glycerol/propylene glycol, 50/50, v/v) for 12 weeks (3 h/day; 7 days a week). Total suspended particle (TSP) mass concentration (124 ± 14 mg/M
3
) particle size (0.67 μM) and total carbon (33.1 %TSP) were kept constant. Cotinine was undetectable in the plasma of air exposed mice, but the plasma cotinine levels were 11.7±1.2 and 38.7±3.6 ng/ml in E-cig exposed C57 and apoE-KO mice respectively. Exposure to E-cig did not affect the body weight of C-57 or apoE-KO mice. Complete blood count showed that total leukocyte levels were decreased by 28 percent (P<0.05) in E-Cig exposed mice as compared with air exposed mice. However, flow cytometric analyses of immune cells showed that levels of CD4+ T-cells, CD8+ T-cells, B-Cells and monocytes in E-cig exposed mice were comparable with air exposed. E-cig had no effect on circulating endothelial progenitor cells, insulin resistance, platelet monocyte aggregates and plasma lipoproteins and cytokines in C57 mice. Similarly, plasma cholesterol (E-cig 1088±61 vs air 1102±61 mg/dL) and triglyceride (E-cig 95±9 vs air 77±5 mg/dL) levels of E-cig exposed apoE-KO mice were comparable with air exposed controls. However, the aortic lesion area of E-cig exposed apoE-KO mice was 1.2 fold higher than the air exposed mice (P<0.05). Collectively, these data suggest that electronic cigarettes moderately increase aortic atherosclerosis without affecting plasma lipids, insulin resistance, systemic inflammation and platelet activation.
Abstract 11741: Severe Aortic Stenosis With Normal Left Ventricular Ejection Fraction, Normal Flow and Low Gradients. Another Paradox or Only Moderate Stenosis?
Authors: Alexandru Dragos ,   Simcha Pollack, Florentina Petillo, Ana Anagnostopoulos, Nathaniel Reichek, Eddy Barasch
Published: July 2021

Background:
Among the 4 hemodynamic subsets of severe AS with preserved EF, based on LV stroke volume index (SVi) and mean pressure gradients, normal flow with a low gradient (NF/LG) has been attributed to measurement errors, small body size or inconsistencies in guideline criteria and associated with a favorable prognosis. We hypothesized that AV weight (AVW) in NF/LG AS, would be lower than that in other hemodynamic groups.

Methods:
Between 2010-13, 403 consecutive patients (pts) undergoing AV replacement (AVR) for severe isolated AS, (mean age 76.8 (9.3) yrs, 56% men, AVA index 0.36 (0.10 cm2)/m2, EF = 61.3 ± 4.6%, 11% bicuspid valves, mean follow-up 18 ± 9 months), underwent intraoperative TEE and had the AV weighed after excision (AVW = 2.4 ± 0.9 g), and excised valves were collected in formaldehyde, dried and weighed. All echo variables were measured off-line by a single observer on a dedicated reading station (Agfa). Medical records were reviewed to extract clinical data and all-cause mortality determined from the Social Security Death Index. Analysis of covariance (ANCOVA), Chi-square test, and Cox proportional hazards regression models were used as appropriate.

Results:
(for unadjusted comparisons see table.) In models adjusted for age, gender BSA, EF and annular area, AVW and AVW index remained lower in NF/LG than that in the high gradient groups (p<.01 for both). Although the number of deaths was small, no significant difference in all-cause mortality or time from AVR to death was found among the 4 groups (p=0.27 and p=0.28, respectively). AVR improved survival to a similar degree regardless of hemodynamic phenotype.

Conclusions:
1. Compared with high gradient groups, pts with normal flow-low gradient have a lower AVW and AVW/aortic annulus area, a lower severity of stenosis and less LV remodeling. 2. These findings support the recent recommendation to categorize these pts as having only moderate AS.
Abstract 12364: Circulating Cardiac and Inflammatory Biomarkers to Predict Post-Operative Atrial Fibrillation in the OPERA Trial
Authors: Masson Serge , Wu Jason H , Barlera Simona , Bani Laura , Marchioli Roberto , Macchia Alejandro , Vago Tarcisio , Puskas John D , Favaloro Roberto René , Hershson Alejandro Rubén , Sinatra Riccardo , Melina Giovanni , Nicolosi Liliana , Dreas Lorella , VanderWoude John , Tognoni Gianni , Mozaffarian Darisuh , Latini Roberto ,   on behalf of the Investigators of the OPERA Study
Published: July 2021

Objectives:
Post-operative atrial fibrillation (POAF) is a common complication after cardiac surgery and predicts increased morbidity and mortality. Identification of patients at high risk of POAF with the help of circulating biomarkers may enable early preventive treatment but data are limited, especially in contemporary surgical patients.

Methods:
Plasma concentrations of N-terminal probrain natriuretic peptide (NT-proBNP), high sensitivity cardiac troponin T (hs-cTnT) and C-reactive protein (hsCRP) were measured at enrollment, on the morning of cardiac surgery, at end-surgery, and 2 days post-surgery in 562 patients undergoing cardiac surgery, randomized to perioperative supplementation with oral fish oil or placebo in the international clinical trial Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation trial (OPERA). The primary endpoint was incident POAF lasting ≥ 30 seconds, centrally adjudicated and confirmed electrocardiographically.

Results:
Higher levels of NT-proBNP and hs-cTnT before surgery were associated with older age, renal or cardiac dysfunction and higher EuroSCORE, while hsCRP correlated positively with BMI. NT-proBNP (2172 [1238-3758] ng/L) and hsCRP (118 [75-165] mg/L) peaked on post-operative day 2, while hs-cTnT peaked at the end of surgery (373 [188-660] ng/L). Fish oil supplementation did not alter the time course of the cardiac or inflammatory biomarkers. Concentrations of the 3 biomarkers, on the morning of surgery, or changes in their level between morning of surgery and post-surgery, were not significantly associated with POAF after adjustment for clinical and surgical characteristics.

Conclusions:
Among patients undergoing cardiac surgery, cardiac markers are related to clinical and surgical characteristics, have different perioperative time courses but do not help in predicting the risk of POAF.
Abstract 017: Friends Make Children Less Sedentary but Neighborhoods Make Them More Active
Authors: Barnett Tracie , Henderson Melanie ,   QUALITY Rsch Team
Published: July 2021

Background and Purpose:
Sedentary behavior (SB) and physical inactivity are distinct constructs for which separate research and intervention paradigms may be warranted. To this end, we compared individual- and neighborhood-level risk factors of each among youth at risk of obesity.

Methods:
Data are from QUALITY, a cohort study of the natural history of obesity in Quebec, Canada. Baseline data were obtained in 2005-2008 when children were aged 8-10y (n=512 families). Activity level was measured using accelerometers at age 8-10y and again 2 years later at age 10-12y. At each time point, children were categorized as inactive if they did <60 min/day of moderate to vigorous physical activity (PA) and as excessively sedentary if they recorded <100 counts/min for
>
50% of the day. Children were required to have worn the device for at least 4 days and for at least 10 hours/day. Child-level factors included sex, sleep duration, and weekly frequency seeing friends; neighborhood-level factors included density of fast food outlets, convenience stores, and parks; school proximity, street connectivity, land use mix, disorder, social and material deprivation, and parental perceived safety. Separate logistic regression models were estimated for each of inactivity and excessive SB. We tested models using the identical set of baseline risk factors at both time points. Analyses were restricted to 413 children with complete data at age 8-10y, and to 283 children with complete data at age 10-12y. Models controlled for child’s obesity status, father and mother’s obesity status, and parental education.

Results:
At both time points, girls were 75% to 85% more likely to be inactive than boys, but were equally likely to be excessively sedentary as were boys. Also at both time points, each additional weekly outing with friends reduced the likelihood of being sedentary by 20%, but did not reduce the likelihood of being inactive. Only area-level disorder was associated with being excessively sedentary, and only in 10-12y olds; in contrast, several factors increased the likelihood of being inactive, including area deprivation at age 8-10y (OR: 1.7; 1.0-3.0) and perceived lack of safety at age 10-12y (OR: 2.8: 1.1-6.3). Moreover, the likelihood of being inactive decreased by 24% for each quintile increase in land use mix. Although obesity status in children was strongly associated with outcomes in all models, other determinants were unaffected by its inclusion in the models.

Conclusions:
Our findings suggest that physical inactivity and sedentary behavior are driven by largely distinct paradigms. Each of these may be impacted through increases in light PA. Although interventions need to target all spheres of influence, reducing physical inactivity may be more effectively mediated by features of the built environment, while leveraging social and peer groups may be more effective to reduce sedentary behaviors.
Abstract 025: Cross-sectional Relations of Serum Cortisol and Cognitive and Structural Brain Measures in Young Adults: The Framingham Heart Study
Authors: Echouffo Tcheugui Justin B , Conner Sarah , Himali Jayandra J , Maillard Pauline Maillard , DeCarli Charles S , Beiser Alexa S , Vasan Ramachandran S , Seshadri Sudha
Published: July 2021

Introduction:
Chronic stress and related changes in serum cortisol have adverse effects on brain structure and cognition in animal models. However, evidence from population-based studies is scant. We assessed the association of early morning serum cortisol with cognition and brain structural integrity in middle-aged adults without dementia.

Hypotheses:
High or low levels of serum cortisol are associated with lower cognitive performance and brain volumes.

Methods:
We evaluated dementia-free Framingham Study (Generation 3) participants (mean age 48.5 years; 46.8% men), who underwent cognitive testing of memory, abstract reasoning, visual perception, attention, and executive function (n= 2231), and brain MRI (n=2018) to assess total white matter, lobar gray matter, and white matter hyperintensity volumes and fractional anisotropy (FA) measures. We used linear or logistic (cortisol categorized in tertiles, middle tertile as the reference) regression to assess the relations of cortisol with cognition, MRI volumes and voxel-based microstructural white matter integrity and gray matter density, adjusting for age, sex, APOE and vascular risk factors.

Results:
Higher cortisol (highest tertile vs. middle tertile) was associated with worse memory and visual perception, as well as lower total cerebral brain, occipital and frontal lobar gray matter volumes (Table
)
. Higher cortisol was associated with multiple areas of microstructural changes on voxel-based analyses (gray matter density and FA). The association of cortisol with total cerebral brain volume varied by sex (
Pinteraction
=0.048
,
highest cortisol tertile inversely associated with cerebral brain volume in women [
P=
0.001] but not in men [
P
=0.717]). There was no effect modification by the apoE4 genotype of the relations of cortisol and cognition or imaging traits.

Conclusions:
Higher serum cortisol was associated with lower brain volumes and impaired memory in asymptomatic young adults in their forties; women may be particularly susceptible to this influence.
Abstract 034: Tracking Lifestyle Behaviors, Healthcare Access, and Healthcare Quality for Cardiometabolic Diseases at the State-Level From 1990-2016
Authors: Reitsma Marissa B , Barber Ryan M , Roth Gregory A , Afshin Ashkan
Published: July 2021

Introduction:
While a range of population-level and clinical interventions have been implemented to improve cardiometabolic (CM) health in the US, little is known about their different effects at the state-level.

Objective:
To develop a novel index to evaluate the performance of the healthcare system and population-level interventions to improve CM health at the state-level from 1990 to 2016.

Methods:
To evaluate healthcare access and quality, we estimated risk-standardized age-standardized mortality rates for six CM diseases that are amenable to healthcare. Risk-standardization removed geographic variation in all risk factors not directly amenable to medical intervention. To evaluate the effect of population-level interventions, we estimated the risk-weighted exposure to lifestyle risk factors including smoking, alcohol, diet, body mass index, and physical activity. We averaged the healthcare index with the risk factor index to create a single composite index. Data sources included mortality and risk factor estimates from the Global Burden of Disease 2016 Study.

Results:
Between 1990 and 2016, healthcare access and quality for CM diseases significantly improved in 38 states. These increases were mainly driven by significant improvements nationwide in healthcare for ischemic heart disease, ischemic stroke, and rheumatic heart disease. Notably, healthcare for diabetes significantly worsened in 16 states. There were no significant changes in the lifestyle risk factor index since 1990. Stability was driven by diverging trends, with smoking and diet quality significantly improving and BMI significantly worsening in all states. Importantly, the gap between the best and worst performing states across all indices increased between 1990 and 2016, indicating greater health disparities.

Conclusions:
This study has quantified the separate and combined effects of healthcare access, quality, and risk factors on CM health, with implications on priority setting for both population-level and clinical interventions.
Abstract 047: Sedentary Behavior Increases Risk for Cardiovascular Disease in Older Women: The Objective Physical Activity and Cardiovascular Health (OPACH) Study
Authors: Bellettiere John , LaMonte Michael J , Rillamas-Sun Eileen , Kerr Jacqueline , Evenson Kelly R , Lee I-Min , Di Chongzhi , Buchner David , Hovell Melbourne F , LaCroix Andrea Z
Published: July 2021

Background:
Evidence on sedentary behavior and cardiovascular disease (CVD) is largely based on self-reported sedentary time. Furthermore, how sedentary time is accumulated (in longer vs. shorter bouts) may be related to CVD risk but has not been tested.

Methods:
Women (n=5638, mean age=79±7) with no history of myocardial infarction or stroke wore accelerometers for 4-7 days and were followed for up to 4 years for incident CVD. Hazard ratios (HR) and 95% confidence intervals (CIs) for CVD and coronary heart disease (CHD) events were estimated across quartiles of sedentary time
and
mean sedentary bout duration using Cox proportional hazard models adjusting for covariates. Separate models evaluated associations after adding moderate-to-vigorous physical activity (MVPA) and possible mediators: body mass index, diabetes, hypertension, systolic blood pressure, fasting glucose, HDL-cholesterol, and triglycerides. We then tested whether mean bout duration was associated with increased risk for CVD and CHD among women with above median sedentary time (≥10hr/day).

Results:
Covariate-adjusted HRs for CVD and CHD increased across quartiles of both sedentary time and mean bout duration (Table). All CHD associations remained significant but attenuated after adjustment for possible mediators. After adjustment for MVPA, highest vs. lowest quartile HRs (CI) for CHD were 1.6 (0.7-3.4; p-trend = .08) for sedentary time and 1.8 (0.9-3.5; p-trend = .047) for mean bout duration. Among women with high sedentary time, the HRs (CI) comparing the 75
th
vs. 25
th
percentile of mean bout duration were 1.05 (0.95-1.15) for CVD and 1.16 (1.01-1.34) for CHD.

Conclusions:
Both sedentary time and mean bout duration showed independent, dose-response associations with increased risk of CVD and CHD events in older women. Among women with high sedentary time, longer mean bout duration was associated with higher CHD risk. Taken together, this provides evidence that both total sedentary time and the way it is accumulated are predictive of incident CHD.