bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 9796: The Presence of Post-bronchodilator Airflow Limitation Deteriorates Cardiac Prognosis in Patients With Chronic Heart Failure
Authors: Honda Yuki , Watanabe Tetsu , Netsu Shunsuke , Kinoshita Daisuke , Yokoyama Miyuki , Kadowaki Shinpei , Narumi Taro , Otaki Yoichiro , Nishiyama Satoshi , Takahashi Hiroki , Arimoto Takanori , Shishido Tetsuro , Miyashita Takehiko , Miyamoto Takuya , Kubota Isao
Published: April 2024

Background:
Chronic obstructive pulmonary disease has begun to gather attention as important comorbidity in patients with cardiovascular disease. However, it is undetermined whether airflow limitation is associated with cardiac prognosis of patients with chronic heart failure (CHF). The aim of the present study was to examine whether post-bronchodilator pulmonary function can predict cardiac prognosis in patients with CHF.

Methods and Results:
We performed post-bronchodilator spirometry in consecutive 198 patients with CHF. Airflow limitation is assessed by the ratio of post-bronchodilator forced expiratory volume in the first 1 second and forced vital capacity (FEV
1
/FVC), and by the ratio of FEV
1
and predicted FEV
1
(%FEV
1
). %FEV
1
but not FEV
1
/FVC was decreased with advancing New York Heart Association (NYHA) functional class. There were 45 cardiac events including 3 cardiac deaths and 42 re-hospitalizations for exacerbation of CHF during a median follow-up period of 446 days. Both FEV
1
/FVC and %FEV
1
were significantly lower in patients with cardiac events than in event-free patients (67.6 ± 12.5% v.s. 73.5 ± 9.4%, P <0.001; 66.6 ± 16.5% v.s. 80.6 ± 19.9%, P <0.0001, respectively). The receiver operating characteristic curve showed the area under the curve of FEV
1
/FVC and %FEV
1
for cardiac events were 0.667 and 0.701, respectively. Mean pulmonary arterial pressure and mean pulmonary arterial wedge pressure significantly correlated with %FEV
1
but not FEV
1
/FVC. Multivariate Cox proportional hazard analysis showed that %FEV
1
was an independent predictor of cardiac events after adjustment of possible confounders (hazard ratio per 1SD increase: 0.558; 95% confidence interval, 0.312-0.978). The patients were divided into tertiles of %FEV
1
. Kaplan-Meier analysis showed that patients in the lowest tertile had the highest event rate.

Conclusion:
Post-bronchodilator airflow limitation may deteriorate cardiac prognosis in patients with CHF.
Abstract 9798: The E3 lLgase Asb2 Regulates Cardiac Development Through Targeting Smad9 for Proteasomal Degradation
Authors: Min Kyung-Duk , Asakura Masanori , Ito Shin , Shirai Manabu , Yamazaki Satoru , Asanuma Hiroshi , Mochizuki Naoki , Kitakaze Masafumi
Published: April 2024

A growing body of evidence revealed that temporal regulation of transcriptional factors is crucially required for cardiac development. Although the induction of transcription factors such as Nkx2.5 and Tbx5 has been of particular interest, the role and mechanism of their timely down-regulation during cardiac development is not fully elucidated. We hypothesized that E3 ligase-dependent degradation of transcription factors plays crucial roles in cardiac development. To identify key E3 ligases regulating cardiac development, we induced three different populations of cardiomyocytes from murine embryonic stem cells treated with any of Noggin, Frizzled or vehicle. We analyzed the temporal changes in gene expressions of them and finally identified an E3 ligase, namely ankyrin repeat and socs box protein2 (Asb2). Both whole mount in situ hybridization of mouse embryos and subsequent RT-PCR revealed that the Asb2β transcript, an isoform of Asb2, is present predominantly in heart during the early embryonic stage. We found that Smad9, an intracellular transducer of the bone morphogenetic protein signals, interact with Asb2β. Biochemical analysis revealed that Asb2β specifically ubiquitinate Smad9, but not Smad1/5. Pulse chase analysis demonstrated that Smad9 was targeted for proteasomal degradation by Asb2β. Knockdown of zebrafish asb2 using morpholino caused significant thinning of the ventricular wall (3.6 ± 0.9 vs. 8.7 ± 1.0μm, p <0.01 ) and remarkable dilatation of the ventricular diameter (23.7 ± 1.1 vs. 11.3 ± 0.7μm, p<0.01 ) compared with wild type siblings. Importantly, simultaneous knockdown of smad9 rescued the impairment of cardiac development due to asb2 knockdown in zebrafish, whereas single knockdown of smad9 caused no abnormal phenotype. These results imply that the suppression of Smad9 is crucial for cardiac development. Also we confirmed that forced expressions of Smad9 in P19CL6 cells failed in cardiac differentiation while that of Asb2β did not affect their fate. We conclude that the accumulation of Smad9 critically impairs the cardiac development and the temporal degradation of Smad9 mediated by E3 ligase Asb2 is critically required for cardiognesis.
Abstract 98: The Assessment and Value of Bystander Cardio Pulmonary Resuscitation (by-CPR)
Authors: Hasselqvist-Ax Ingela , Herlitz Johan , Rosenqvist Mårten , Hollenberg Jacob , Nordberg Per , Ringh Mattias , Jonsson Martin , Axelsson Christer , Lindqvist Jonny , Svensson Leif
Published: April 2024

Background:
3 million people in Sweden are educated in CPR and the value of this has been questioned if this leads to increased By-CPR and survival.

Aim:
To describe different aspects and effect on survival after OHCA depending if bystander CPR (By-CPR) was performed or not, and if the bystander was Lay or Medical educated. Also to explore the effects from CPR training on times to CPR, alarm and on outcome, when a medical educated bystander perform CPR versus when a Lay person act.

Methods:
Patients in the Swedish Cardiac Arrest Registry receiving bystander CPR 1990-2011 were included and divided into:
No-ByCPR
, and
By-CPR
. By-CPR was further divided in
Lay-ByCPR
and
Med-ByCPR
when CPR was performed by professionals in terms of medical educated bystanders. Crew witnessed cases were excluded.

Results:
In all 61 704 patients are included in the registry, and among them 30 188 bystander witnessed cases (49 %) were included in this survey. By-CPR have over the years continuously increased from 40% to 68% and 30 days survival increased from 3.8% 1990 to 10.7% 2011. Survival was 4.0% in No-ByCPR, 10.6% in By-CPR, 9.4% in Lay-ByCPR and 13.7% in Med-ByCPR.

Various aspects on delay to treatment were independently associated with survival to one month: Collapse-call for EMS (OR 0.70;95% CI 0.64-0.77); collapse-start of CPR (OR 0.72;95% CI 0.68-0.76); call for arrival of EMS (OR 0.41;95% CI 0.36-0.46). (Adjusted for age, gender, place and etiology)

Lay-ByCPR was significant better than No-ByCPR (OR 2.49) in all patients. Med-ByCPR had even better outcome compared to No-ByCPR (OR 2.84). When comparing Med-ByCPR vs. Lay-ByCPR bystanders, there were non- significant differences, OR 1.18 (CI:0.98-1.41).

Conclusion:
Increased By-CPR correlate to increased survival and can more than double survival rate compared to No-ByCPR.

Collapse to call, start of CPR, call-arrival EMS were independently associated with survival to one month. Lay-ByCPR were better than no ByCPR and as good as Med-ByCPR.
Abstract 9814: Nf-?B Inhibition Prevents Vascular Obliteration and Improves Immune Regulation in Severe Pulmonary Arterial Hypertension
Authors: Farkas Daniela , Alhussaini Aysar A , Kraskauskas Donatas , Kraskauskiene Vita , Nicolls Mark R , Voelkel Norbert F , Natarajan Ramesh , Farkas Laszlo
Published: April 2024

Nuclear factor-κB (NF-κB) and interleukin-6 (IL-6), a NF-κB downstream mediator, play a central role in inflammatory response and vascular cell growth. Inflammation and a dysregulated immune response are found in many forms of severe pulmonary arterial hypertension (PAH), but how the NF-κB pathway contributes to PAH development is unclear. The SU5416 and chronic hypoxia (Su/Hx) rat PAH model is, like severe human PAH, characterized by obliterative pulmonary vascular lesions and right ventricular failure. We hypothesized that activation of the classical NF-κB pathway in severe PAH promotes ongoing vascular lesion cell apoptosis and proliferation, as well as dysregulation of the immune system.

We aimed to determine the role of NF-κB in severe PAH induced by Su/Hx in rats.

PAH was induced by a single injection of SU5416 and exposure to chronic hypoxia. Su/Hx rats were treated from day 1-21 with the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) and/or anti-IL-6 antibody. After hemodynamic assessment at day 21, cytokine/chemokine expression, NF-κB activation, lymphocyte accumulation, as well as pulmonary arterial cell apoptosis and proliferation were evaluated by Western blot, Flow cytometry and immunohistochemistry.

The classical NF-κB pathway was activated in pulmonary arterial lesions SuHx rats. NF-κB inhibition with PDTC prevented the development of pulmonary arterial obliteration and in part PAH without reducing muscularization. However, the elevated lung levels of IL-6 were not reduced in PDTC-treated SuHx animals. Apoptosis of pulmonary artery wall cells and pulmonary arterial obliteration was prevented by PDTC or by PDTC+IL-6 inhibition and partially by IL-6 inhibition alone. Pulmonary arterial media wall thickness was not affected by any of these treatments. In Su/Hx rats, CD4
+
T cells were reduced and perivascular CD8
+
T lymphocytes and CD45RA
+
B lymphocytes were increased. NF-κB inhibition promoted immune regulation by increasing the number of perivascular CD4
+
T cells and reducing the number of perivascular CD8
+
T lymphocytes and CD45RA
+
B lymphocytes.

Inhibition of NF-κB may represent a therapeutic option for pulmonary arterial obliteration
via
reduced vessel wall cell apoptosis and improved immune regulation.
Abstract 9843: Proton Pump Inhibitors Inhibit DDAH and Processes Underlying Idiopathic Pulmonary Fibrosis
Authors: Ghebremariam Yohannes T , Ho Lawrence , Rosen Glenn D , Cooke John P
Published: April 2024

Rationale:
The cardiovascular enzyme dimethylarginine dimethylaminohydrolase (DDAH) has recently been implicated in the progression of idiopathic pulmonary fibrosis (IPF). By degrading asymmetric dimethylarginine (ADMA), an inhibitor of inducible nitric oxide (NO) synthase (iNOS), DDAH releases the brake on a pathway implicated in lung injury and fibrosis. In addition, DDAH promotes the pro-fibrotic activity of the TGFβ pathway.

Objectives:
We embarked on studies to discover DDAH inhibitors, and to assess the effect of such inhibitors on processes involved in IPF.

Methods:
We performed high throughput screening (HTS) of over 130,000 small molecules and discovered that the proton pump inhibitors (PPIs) modestly inhibit DDAH. We used cellular and molecular assays to study the effect of the PPIs on DDAH activity by measuring the concentration of ADMA. In addition, we assessed the effect of PPIs on collagen synthesis by IPF lung fibroblasts, and on the survival and proliferation of lung alveolar epithelial cells. Finally, a retrospective analysis of the Stanford University interstitial lung disease (ILD) database was performed to assess the effect of PPIs on transplant-free survival.

Results:
We found that the PPIs inhibit DDAH activity in biochemical assays, cell culture and in vivo. The resulting increase in ADMA level was mirrored by a reduction in NO production. In addition, the PPIs reduced the production of soluble collagen by primary IPF lung fibroblasts in response to TGFβ and regulated both proliferation and survival of lung alveolar epithelial cells. Retrospective review of the ILD database of 131 IPF patients (of who 85 were on PPIs for > 1 year) revealed a survival advantage (i.e. time to transplant or death when calculated from the time of diagnosis) of the patients on PPIs, including those without symptoms of Gastroesophageal disease (GERD); an indication for which the PPIs are primarily prescribed for, suggesting the involvement of a mechanism other than acid-suppression.

Conclusions:
Our data reveal a plausible biological explanation for the clinical benefit of the PPIs in IPF. The reported reduction in radiologic fibrosis score and significant survival advantage of IPF patients on PPIs may be due to modulation of the DDAH/NOS pathway.
Abstract 9852: T Lymphocyte Depletion Following Primary Percutaneous Coronary Intervention Predicts Infarct Size and Ischemia Reperfusion Injury
Authors: Boag Stephen , Shmeleva Evgeniya , Das Rajiv , Egred Mohaned , Zaman Azfar , Bagnall Alan , Owens Andrew , Keavney Bernard , Spyridopoulos Ioakim
Published: April 2024

Background:
We have previously demonstrated acute changes in lymphocyte numbers in peripheral blood following reperfusion with primary percutaneous coronary intervention (PPCI) for STEMI. The goal of this study was to investigate a potential role for T cells in ischemia reperfusion (I/R) injury.

Methods:
We analyzed blood from 22 STEMI patients undergoing PPCI. Blood was taken at the start of the procedure, and at 15, 30, 90 minutes, and 24 hours post reperfusion. In 5 patients with infarcts due to LAD occlusion, coronary sinus (CS) blood was also obtained 30-60min after reperfusion along with simultaneous aortic blood. 8-colour flow cytometric analysis was performed on the fresh blood to quantify lymphocyte populations. Cardiac MRI was performed at 1-7 days, and left ventricular ejection fraction, infarct size (measured by late gadolinium enhancement), microvascular obstruction (MVO), area at risk and salvage index quantified.

Results:
T-lymphocytes dropped between 0 and 90 minutes by a mean of 42% (0min mean 1767/μl, 90min 931/μl), CD4 T-helper cells by 31%, and CD8 cytotoxic T-cells by 55%. The change in total T-cells correlated with infarct size (r=-0.78, p<0.001), as did that of CD4 (r=-0.66, p<0.01) and CD8 T cells (r=-0.76, p<0.001).

The T cell drop between 0 and 90 minutes also correlated strongly with MVO (r=-0.72, p<0.01), as did the CD4 (r=-0.66, p<0.01) and CD8 T cell drop (r=-0.77, p<0.001). Myocardial salvage index correlated strongly with the change in T cells (r=0.85, p<0.001), CD4 T cells (r=0.76, p<0.01) and CD8 T cells (r=0.76, p<0.01) between 30 and 90 minutes.

Prior to reperfusion 6.4% of CD8 T cells were activated (CD69+), with progressive loss of CD69+ cells after 90 minutes (4.3%) and 24 hours (2.6%, 0min vs 24hr p<0.01). However, CS sampling showed an increase in CD69 expression between aortic and CS blood, suggesting activation of T cells as they pass through the myocardial vascular bed.

Conclusion:
Acute changes in T lymphocyte numbers following reperfusion after PPCI predict infarct size, MVO, and salvage index. The drop in these cells following reperfusion, and the dynamics of CD69 expression, suggest a potential role for CD69+ activated T cells in I/R injury. This requires further investigation and may represent a novel therapeutic target.
Abstract 9873: Inhibition of IL-1β Signaling Prevents Aneurysm Formation in a Novel Model of Thoracic Aortic Aneurysm
Authors: Johnston William F , Salmon Morgan , Su Gang , Stone Matthew L , Pope Nicolas H , Lu Guanyi , Upchurch Gilbert R , Ailawadi Gorav
Published: April 2024

Objective:
To determine the role of IL-1β signaling in a novel model of thoracic aortic aneurysms (TAAs).

Methods:
To develop a TAA model, 8-10 week old male C57Bl/6 wild type mice (WT) underwent thoracotomy with topical placement of an elastase soaked sponge (WT elastase) or saline soaked sponge (WT saline) for 5.5 minutes. Mice recovered and aortic dilation was measured in vivo at 3, 7, 14, 21 and 28 days (n=5 each). Next, to determine the contribution of IL-1β signaling in TAA formation, TAAs were induced in mice deficient of IL-1β (IL-1β KO) or IL-1 receptor (IL-1R KO) (n=10 each). Maximal aortic dilation was measured and thoracic aortas were harvested for histology and protein analysis. Last, WT mice pre-treated with either IL-1R antagonist anakinra (100mg/kg/day) or vehicle alone (n=8 per group) underwent the elastase TAA model to determine effects of pharmacologic IL-1R antagonism.

Results:
Application of an elastase soaked sponge to the thoracic aorta resulted in a progressive dilation over time with maximal aortic dilation of 99.6±24.7% at day 14 compared to 14.4±8.2% for WT saline control (p<0.0001). WT elastase aortas had increased elastin fragmentation, smooth muscle cell degradation, and infiltration by macrophages and neutrophils compared to saline aortas. Compared to positive WT controls, genetic deletion of IL-1β and IL-1R significantly decreased thoracic aortic dilation (WT control = 104.7±23.8% vs. IL-1β KO = 54.2±16.8% and IL-1R KO = 62.6±17.2%, p<0.05 for both). Both IL-1β KO and IL-1R KO aortas demonstrated preserved elastin and smooth muscle cell staining and decreased macrophage and neutrophil staining. Correspondingly, IL-1β and IL-1R KO aortas had significantly decreased inflammatory cytokines and MMP-9. Pretreatment of WT mice with anakinra inhibited TAA formation with reduction in maximal aortic dilation from 99.2±15.5% in the vehicle-treated mice to 73.3±24.9% in mice treated with anakinra (p<0.05).

Conclusions:
Topical application of elastase to the thoracic aorta reproducibly produces aortic dilation with molecular and histologic features that are consistent with TAA disease. Both genetic and pharmacologic inhibition of IL-1β signaling prevent TAA formation and may be a potential therapeutic target in human disease.
Abstract 9883: Impact of Low Transvalvular Gradient on Early and Late Outcomes After Aortic Valve Replacement for Aortic Stenosis
Authors: Kuwaki Kenji , Amano Atsushi , Inaba Hirotaka , Yamamoto Taira , Morita Terumasa , Dohi Shizuyuki , Shimada Akie , Kuroda Kishio
Published: April 2024

Background:
Few data are available concerning the results of aortic valve replacement (AVR) for low-gradient severe aortic stenosis (AS). Aim of this study was to assess the hypothesis that low-gradient is an independent predictor of early and late results after AVR.

Methods:
We retrospectively analyzed a series of 340 consecutive AS patients (area≦1.0cm
2
) who underwent AVR from 2002 to 2012. Low-gradient AS was defined by the mean transvalvular gradient <40mmHg (n=68, 20%). The outcome measures included hospital mortality, major postoperative complication, prolonged length of hospital stay, and late survival.

Results:
Hospital mortality was 3.2% (n=11) (low-gradient 8.8%; high-gradient 1.8%; p=0.01). Low-gradient AS was an independent predictor for hospital mortality (odds ratio [OR] 6.0, 95% confidence interval [CI]: 1.6 to 21.2, p=0.006), but did not predict any postoperative major complication. NYHA class III/IV was another independent predictor of hospital mortality (OR 19.3, 95%CI: 2.4 to 155.1, p=0.005). In the patients with low-gradient AS who were in NYHA class III/IV (n=25), hospital mortality was significantly higher (24%) compared to those in NYHA class II (n=43, hospital mortality 0%). Multivariable predictors of late mortality (excluding hospital death) included NYHA class III/IV (OR 9.6, 95%CI: 1.2 to 76.7, p=0.03) and creatinine >2mg/dl (OR 6.9, 95%CI: 2.1 to 22.8, p=0.002). Low-gradient was no longer a risk of late mortality in operative survivors. The survival rate at 7 years after AVR was 84±10% in low-gradient and 95±2% in high-gradient patients (p=0.42). We also calculated propensity score for low-gradient status (C-statistic: 0.71), and 37 low-gradient were matched to 41 high-gradient patients. No statistically significance was observed in late survival between propensity matched low and high-gradient patients (83% vs 95% at 7 years, p=0.86).

Conclusions:
Low-gradient AS was an independent predictor of increased hospital mortality, but did not predict late mortality in operative survivors. Surgical risk was very high in low-gradient patients with advanced NYHA class. However, AVR could be performed safely if low-gradient AS patients were in NYHA class II, and good long-term survival was seen in operative survivors.
Abstract 9905: Nitrative Modification of Caveolin-3 and Subsequent Dissociation From AdipoR1 Occurs in Failing Heart and Contributes to Adiponectin Resistance
Authors: Lau Wayne Bond , Wang Yajing , Yi Wei , Sun Yang , Wang Xiaoliang , Yuan Yuexing , Lopez Bernard , Christopher Theodore , Gao Erhe , Koch Walter , Ma Xin
Published: April 2024

Cardiac response to adiponectin (APN), a cardioprotective molecule, is significantly reduced during heart failure (HF), due to unknown underlying mechanisms. We recently reported Caveolin-3 (Cav3) plays an essential role in APN signaling by holding AdipoR1 in close proximity with its downstream signaling molecules. The current study investigated whether Cav3/AdipoR1 expression and/or their interaction are altered in the failing heart, thereby contributing to APN resistance and HF progression. Adult male mice were subjected to MI. Molecular, biochemical, and functional assays were performed 2 weeks post-MI, a time point during which significant APN resistance develops. Expression (mRNA and protein) of Cav3, AdipoR1, and known intracellular APN signaling molecules remained unchanged. However, Cav3/AdipoR1 complex formation significantly decreased. Among multiple post-translational modifications observed in the failing heart, Cav3 nitrative modification was the most significant (3.57±0.4-fold, P<0.01). In vivo treatment with a peroxynitrite (ONOO
-
) decomposition catalyst reduced Cav3 nitration and restored Cav3/AdipoR1 association. In vitro exposure of adult cardiomyocytes (CM) to SIN-1 (an ONOO
-
donor) or authentic chemical ONOO
-
caused significant Cav3 nitration, reduced Cav3/AdipoR1 association, and blocked APN-induced AMPK phosphorylation (P<0.01). APN treatment significantly attenuated Ang-II induced neonatal CM hypertrophy (P<0.01). However, the anti-hypertrophic effect of APN was virtually abolished by knockout of either Cav3 or AdipoR1, or SIN-1 pre-treatment in CM. Finally, in neonatal CM isolated from Cav3KO mice transfected with WT Cav3 vector, SIN-1 caused significant Cav3 nitration, Cav3/AdipoR1 dissociation, and blocked APN-induced AMPK activation. In contrast, in neonatal CM isolated from Cav3KO mice transfected with mutated Cav3 (in which all 5 tyrosine residues were substituted by phenylalanine) vector, no Cav3 nitration was observed after SIN-1 exposure; Cav3/AdipoR1 association was maintained, and APN-induced AMPK activation was preserved. These results demonstrate Cav3 tyrosine residue modification during HF progression causes Cav3/AdipoR1 dissociation, blocking APN cardioprotection.
Abstract 9906: Aldosterone Targets Raptor to Promote Pulmonary Smooth Muscle Cell Proliferation and Modulate Pulmonary Arterial Hypertension
Authors: Aghamohammadzadeh Reza , Loscalzo Joseph , Leopold Jane A , Maron Bradley A
Published: April 2024

In pulmonary arterial hypertension (PAH), elevated levels of aldosterone (ALDO) induce pulmonary smooth muscle cell (PSMC) proliferation and hypertrophy of distal arterioles. Raptor, part of the mammalian target of rapamycin (mTOR) complex 1, modulates PSMC growth; however, the role of ALDO-raptor signaling in PAH is not known. We hypothesized that stimulation of raptor by ALDO increases PSMC proliferation to promote vascular dysfunction in PAH. To test our hypothesis, human PSMCs were treated with vehicle control (V) or ALDO (10
-7
mol/l) for 15, 30, or 60 min. Compared to V-treated cells, ALDO for 60 min increased protein levels of P-mTOR(Ser2448) (26.1 ± 12.8 vs. 61.4 ± 17.8 units, p<0.05) and P-raptor(Ser792) (19.4 ± 7.1 vs. 32.1 ± 2.2 units, p<0.05) without affecting total mTOR/raptor levels. We next explored the effect of ALDO on Akt, which is an upstream mediator of raptor activation. ALDO increased the P-Akt(Ser473)/Akt ratio at 15 and 30 min by 56% (P<0.02) and 80% (P<0.02), respectively. ALDO also induced a time-dependent (0, 15, 30, 60 min) increase in levels of the raptor target P-p70S6k (Thr389) (56.8 ± 3.1 vs. 75.6 ± 3.6 vs. 79.0 ± 2.8 vs. 84.6 ± 4.8 units, P<0.01), and increased cell proliferation by 29% (P<0.02) as assessed by the tetrazolium assay. Next, we investigated the effect of ALDO-raptor signaling on vascular remodeling in PAH
in vivo
. Compared to controls, immunohistochemistry of pulmonary arterioles from rats with monocrotaline (MCT)-PAH demonstrated increased P-p70S6k(Thr389) (114 ± 16 vs. 188 ± 25 units, P<0.02). In turn, inhibition of ALDO with eplerenone (10 μM) decreased P-p70S6k levels in ALDO-treated cells
in vitro
(33.6 ± 1.9 vs. 27.5 ± 2.2 units, P<0.03), and spironolactone (25 mg/kg/d) decreased P-p70S6k levels in pulmonary arterioles of MCT-PAH rats
in vivo
(188 ± 25 vs. 96 ± 27 units, P<0.02). Attenuation of P-p70S6k expression in MCT-PAH by spironolactone was associated with a decrease in indexed pulmonary vascular resistance (35.9 ± 3.2 vs. 21.5 ± 3.2 mmHg*min*g/ml, P<0.05) and the number of muscularized arterioles by 54% (P<0.05). These data demonstrate that Akt/raptor/p70S6k activation by ALDO promotes PSMC proliferation, and may represent a novel mechanism by which to account for pulmonary vascular remodeling in PAH.
Abstract 9914: Cardiomyocyte-specific Overexpression of GTP Cyclohydrolase 1 Improves Cardiac Function in Streptozotocin-induced Diabetic Cardiomyopathy
Authors: Ge Zhi-Dong , Baumgardt Shelley L , Paterson Mark , Liu Yanan , Qiao Shigang , Warltier David C , Kersten Judy R
Published: April 2024

Background:
Emerging evidence suggests that GTP cyclohydrolase 1 (GTPCH) is critical for activity of nitric oxide synthase and sarcoplasmic reticulum Ca
2+
ATPase and myocardial relaxation in normal myocardium. We hypothesized that increased expression of GTPCH ameliorates cardiac dysfunction in streptozotocin (STZ)-induced diabetic cardiomyopathy.

Methods:
Transgenic mice with cardiomyocyte-specific overexpression of human GTPCH gene (GTPCH-Tg) and their wild-type littermates were injected with 50 mg/kg/day STZ (i.p.) for 5 consecutive days to induce diabetes or vehicle as control. Structure and function of the left ventricle were evaluated using echocardiography and in Langendorff-perfused hearts. Western blotting was used to measure expression of GTPCH and p38 mitogen-activated protein kinase (p38 MAPK). Cardiac biopterins were determined by HPLC.

Results:
Blood glucose concentrations were significantly increased in both GTPCH-Tg and wild-type mice 2 to 12 weeks after STZ injection. There were no significant differences in cardiac structure and function between vehicle-treated GTPCH-Tg and wild-type groups throughout the experiment. Twelve weeks after the injection, STZ-induced diabetes resulted in significant decreases in fractional shortening, the mitral E/A ratio, and ±dP/dt in wild-type mice (fractional shortening: 23±3% vs. 40±3% in vehicle; E/A: 1.36±0.10 vs. 1.87±0.12 in vehicle, n=10, P<0.05) but not GTPCH-Tg mice. The ratio of GTPCH/GAPDH was lower in STZ-treated wild-type than vehicle-treated wild-type mice (0.05±0.01 vs. 0.24±0.05 in vehicle, n=4, P<0.05). In contrast, the ratio of phosphorylated p38 MAPK/total p38 MAPK was significantly higher in STZ-treated wild-type than vehicle-treated wild-type mice. These negative effects of STZ-induced diabetes were abolished by GTPCH overexpression. Cardiac tetrahydrobiopterin levels were dramatically higher in GTPCH-Tg than wild-type mice in both vehicle- and STZ-treated groups.

Conclusions:
Decreased GTPCH contributes to cardiac dysfunction in STZ-induced diabetic cardiomyopathy. Cardiac overexpression of GTPCH improves cardiac function in diabetic cardiomyopathy by decreasing activation of p38 MAPK and increasing cardiac tetrahydrobioptein levels.
Abstract 9937: Comparison of Aortic Root Dimensions using Multi Slice Computer Tomography and 2D Transthoracic Echocardiography. CARDIA Study
Authors: Yeboah Joseph , Teixido Gisela , Jacobs David , Terry James G , Lima Joao A , Ge Yaorong , Lovato Jame , Sidney Stephen , Goff David , Carr Jeff
Published: April 2024

Introduction:
Multislice computer tomography (MSCT) is the gold standard for measuring aortic root dimensions; however, in clinical practice 2D transthoracic echocardiography (2DTE) is commonly used to diagnose and monitor aortic root diseases. Limited data exist on the accuracy of the 2DTE approach. We assessed the agreement between MSCT and 2DTE dimensions of the aortic root in middle-aged adults free of clinical aortic diseases who were part of the ongoing Coronary Artery Risk Development in Young Adults (CARDIA) Study.

Methods:
2DTE and MSCT were used to measure the aortic root dimensions in 1197 CARDIA participants. The MSCT aortic root dimension was measured on non-contrast enhanced images using 0.5-0.6mm slices reformatted to provide true cross sections perpendicular to the vessel centerline, 3 D Slicer® (planimetered: [ROI pixel count multiplied by unit pixel area]) while the 2DTE aortic root diameter was measured by leading-edge to leading-edge approach [MM mode, Parasternal long axis with aorta and left atrium in view] and the area obtained using π r2. Correlation coefficient and Bland Altman plots were used to assess the agreement between the 2 approaches.

Results:
Mean age 49.9 ±3.6 yrs, BMI 30.5 ±7.1 kg/m2, LDL-C 110.3 ±33.5 mg/dL, HDL-C 57.3 ±17.4 mg/dL, 52.9% blacks, 45.6% males, 11.1% diabetics, 39.3% former/current smokers and 35.4% had hypertension. Prevalence of aortic root dilation (>4cm) was 1.7% by MSCT and 2.1% by 2DTE. The mean aortic root diameter and area by 2DTE and 3 D slicer® were 3.07 ±0.42 cm and 3.02± 0.33 cm; 8.3± 1.7 cm2 and 7.5 ±2.1 cm2 respectively. The aortic root diameters/ areas by the 2 approaches had a Pearson correlation coefficient of 0.67. In the Bland Altman analysis the bias and limits of agreement for aortic root diameter and area were -0.15 and -0.80 to 0.48 cm; -0.57 and -3.8 to 2.7cm2 respectively. The sensitivity, specificity, PPV and NPV of 2DTE for diagnosing aortic root dilation were 0.43 (0.22 to 0.66), 0.98 (0.976 to 0.991), 0.33 (0.17 to 0.54) and 0.99 (0.982 to 0.995) respectively.

Conclusions:
The accuracy of 2DTE for aortic root dimensions shows moderate agreement with the MSCT suggesting that there will often be disagreement between these 2 approaches which would have significant clinical and cost implications.
Abstract 9949: Prognostic Value of Longitudinal Strain of Right Ventricle in Patients With Stable Coronary Artery Disease
Authors: Chang Wei-Ting , Tsai Wei-Chuan , Liu Yen-Wen , Lee Cheng-Han , Liu Ping-Yen , Chen Ju-Yi , Li Yi-Heng , Tsai Liang-Miin
Published: April 2024

Background:
Regional strain by speckle tracking echocardiography is an emerging technique and can be used for assessment of right ventricle (RV). The aims of this study were to validate the prognostic value of RV strain as a new index of RV systolic function in patients with stable coronary artery disease.

Methods and Results:
We recruited 142 patients receiving elective coronary angiography for suspected coronary artery disease (mean age 64 ± 11 years, 113 men). RV lateral wall strain was measured by using speckle tracking echocardiography from apical 4 chamber view. The median follow-up duration for the entire patient population was 23.07 ± 6.58 months. During the follow-up, 21 patients died and 39 patients reached major adverse cardiovascular events. After excluding non-cardiovascular death, patients who died (18, 12.6%) had lower left ventricular ejection fraction (53.61±12.29 vs. 61.13± 14.27 %, p
=
0.03 or greater impairment of RV lateral wall strain (-12.29 ±3.26 vs. -17.42± 5.12%, p
=
0.01) compared with survivors. Besides, patients who developed arrhythmia had higher rate of right coronary artery involvement (82.9 vs 51.5 %, p
=
0.001) or impaired RV lateral wall strain (-12.29 ±3.26 vs. -17.42 ±5.14 %, p
=
0.001). Using -18% as a cutoff point for RV strain, patients with strain ≤ -18 % had superior outcome compared to patients with an RV lateral wall strain > -18 % (log-rank X
2
, 9.04 and 6.94 for cardiovascular mortality and arrhythmia events respectively, p
=
0.003 for both). After multivariate regression analysis, RV lateral wall strain was an independent prognostic factor for both cardiovascular mortality (hazard ratio 9.24; 95% confidence interval 1.2-71.2; p
=
0.03) and arrhythmia (hazard ratio 2.44; 95% confidence interval 1.03-5.8; p
=
0.04) (Fig).

Conclusions:
RV lateral wall strain by speckle-tracking echocardiography is significantly related to long-term cardiovascular outcome and newly developed arrhythmia of patients with stable coronary artery disease.
Abstract 10014: The Impact of Fractional Excretion of Potassium, a Possible Marker of Renin-angiotensin-aldosterone Activation or Low Output, on the Survival Rate of Heart Failure Patients Treated With Tolvaptan
Authors: Hiasa Ken-ichi , Fujino Takeo , Sakamoto Takafumi , Ide Tomomi , Higo Taiki
Published: April 2024

Introduction:
Although hyponatremia is known to negatively impact on survival in heart failure, sodium (Na) sparing aquaresis by tolvaptan (TLV) failed to demonstrate survival benefit.

Hypothesis:
We hypothesized TLV may reduce GFR or activate renin-angiotensin-aldosterone (RAAS) system via augmentation of intravascular free water clearance, therefore, these compensational mechanism may exacerbate the prognosis in heart failure.

Methods:
A retrospective cohort design was used to assess 82 patients treated with TLV. We analyzed intravascular free water clearance, serum Na change, and fractional excretion of potassium (FEK), which correlates RAAS activation or GFR reduction.

Results:
Positive intravascular free water clearance significantly correlated with increases in serum Na. TLV tended to increase FEK in all groups. However, there was significant deference in the increase rate of FEK between short-term administration group and other groups, especially in poor prognostic groups as follows: the necessity of surgical intervention or renal replacement therapy (ex. ventricular asssist device, valve replacement or hemodialysis) or death, 5.5 vs 5.7%, 25.3 vs 35.3%, 28.9 vs 106.2%, respectively.

Conclusions:
Long-term administration of TLV reduces intravascular free water, sodium excretion, urine volume and GFR and in turn activates RAAS. FEK can be a useful biomarker for detection of RAAS activation/ GFR reduction in patients treated with TLV.
Abstract 10031: Small Aortic Root Size Has Prognostic Implications Both for Women and Men With Asymptomatic Aortic Stenosis
Authors: Bahlmann Edda , Cramariuc Dana , Minners Jan , Lønnebakken Mai Tone , Ray Simon , Gohlke-Baerwolf Christa , Nienaber Christoph A , Jander Nicolaus , Chambers John B , Kuck Karl Heinz , Gerdts Eva
Published: April 2024

Background:
Sex-specific analysis of small aortic root has not been reported in asymptomatic aortic stenosis (AS) patients.

Methods:
We used echocardiographic and outcome data from 1560 patients with asymptomatic initially mild-moderate AS enrolled in the Simvastatin and Ezetimibe in Aortic Stenosis study. A small aortic root was defined as an inner diameter at the aortic sinotubular junction < 1.5cm/m in women and < 1.6cm/m in men.

Results:
A small aortic root was found in 17.4% patients at baseline and independently associated with higher pulse pressure/stroke volume index and aortic root wall thickness, higher pressure recovery, lower LV mass index and female sex in multivariate logistic regression analysis (all p<0.05). In sex-specific multivariate Cox regression analysis, adjusting for the known prognosticators age, hypertension and AS severity and for randomized study treatment, having a small aortic root predicted a 66% higher rate of ischemic cardiovascular events and a 2-fold higher rate of non-haemorrhagic stroke and cardiovascular death (all p<0.05) in men and a 2-fold higher rate of CABG in women (Table). Presence of small aortic root did not influence total mortality or aortic valve replacement in either gender.

Conclusion:
In asymptomatic AS patients without known cardiovascular disease or diabetes, having a small aortic root was associated with increased rate of cardiovascular events in both women and men.

Table. Small aortic root as predictor of different cardiovascular events in multivariate analyses in women and men [HR (95%CI)].
Abstract 10115: The Diagnostic Value of Global and Territorial Longitudinal Strain at Rest for the Detection of Coronary Artery Disease in Patients Without Type 2 Diabetes Mellitus
Authors: Zuo Houjuan , Yang Xiuting , Wang Dao Wen , Wang Hong
Published: April 2024

Background:
Global longitudinal strain (GLS) at rest aids the detection of coronary artery disease (CAD). However, myocardial strains are affected by both ischemia and diabetes mellitus (DM), and previous studies that evaluated the performance of GLS for detecting ischemia always included a certain DM patients in the study population. Thus, we sought to investigate in patients with no DM the power of GLS for detecting three-vessel CAD, and whether territorial longitudinal strain (TLS) could help identifying individual coronary artery stenosis

Methods and results:
We retrospectively studied 211 consecutive patients with suspected CAD and normal left ventricular (LV) ejection fraction. The patients with DM were excluded. All patients underwent echocardiography and subsequently coronary angiography. LV global and segmental peak systolic longitudinal strain (PSLS) parameters were quantified by two-dimensional speckle tracking echocardiography (2D STE). Territorial PSLSs were calculated based on the perfusion territories of the 3-epicardial coronary arteries in a 17-segment LV model. Critical CAD was defined as luminal diameter stenosis ≥ 70% in ≥ 1 epicardial coronary artery. Totally 145 patients had critical CAD on coronary angiography. Significant differences were observed in all strain parameters between patients with and without CAD. The AUC for GLS in the detection of three-vessel CAD was 0.875 at a cutoff value of -19.05% with sensitivity 78.1% and specificity 72.7%, which increased to 0.926 after excluding apical segments (cutoff value -18.66%; sensitivity 84.4% and specificity 81.8%). The TLS values were significantly lower in regions supplied by stenotic compared with non-stenotic coronary arteries. It has better power to identify LCX and LAD stenosis than RCA stenosis. An area under the curve (AUC) for the TLS to identify critical LCX, LAD and RCA stenosis, in order of diagnostic accuracy, is 0.818 for LCX, 0.764 for LAD and lastly 0.723 for RCA.

Conclusions:
In patients with no DM and suspected CAD, GLS is an excellent predictor of three-vessel CAD with high accuracy. A higher cut point than that reported before was obtained and should be used. TLS could identify which coronary artery is stenotic with fair sensitivity and specificity.
Abstract 10250: Associations of Adiponectin and Leptin With Measures of Cardiac Structure and Function Among African Americans: The Jackson Heart Study
Authors: Horbal Steven R , Dibaba Daniel , Musani Solomon K , Hall Michael E , Liu Jiankang , Taylor Herman A , Fox Ervin R , Bidulescu Aurelian
Published: April 2024

Introduction:
Adipokines are associated with measure of cardiac remodeling. Studies assessing the effects of adipokines among those with and without common risk factors such as hypertension, obesity and type 2 diabetes are sparse. Thus, the objective of our investigation was to assess the association of adiponectin and leptin with measures of myocardial structure and function among African Americans--a group with a high prevalence of cardiovascular risk factors.

Methods:
The study sample included 4,866 African American participants from the Jackson Heart Study. Multivariable adjusted linear models were used to determine the association of adiponectin and leptin with echocardiographic measures of myocardial structure and function including left ventricular (LV) mass index, and E/A ratio. Stratified analyses were conducted among participants with and without hypertension, obesity and type 2 diabetes.

Results:
In participants who were not obese, LV mass index was directly associated with adiponectin and inversely associated with leptin [β = 0.52, β = - 2.03, respectively]. A direct association of adiponectin and an inverse association of leptin with E/A ratio was observed among those who were not obese [β = - 0.02, β = - 0.02, respectively]. A direct association of adiponectin and an inverse association of leptin with E/A ratio were observed regardless of hypertensive status or Type II diabetes status [Overall: β = 0.02, β = - 0.02, respectively].

Conclusion:
In a large African American population, opposite associations of adiponectin and leptin were observed with measures of myocardial structure and function that varied based on presence or absence of common cardiovascular risk factors.
Abstract 10252: Lipoprotein (a) in Familial Hypercholesterolemia With Proprotein Convertase Subtilisin Kexin Type 9 Gain-of-function Mutations
Authors: Tada Hayato , Kawashiri Masa-aki , Yoshida Taiji , Teramoto Ryota , Nohara Atsushi , Inazu Akihiro , Mabuchi Hiroshi , Yamagishi Masakazu
Published: April 2024

Background:
Lipoprotein (a) [Lp(a)] is an established residual risk factor for cardiovascular disease. In contrast to statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to reduce Lp(a) by as much as 30%, but the mechanism remains unclear. Currently, no data exists regarding direct comparisons of serum Lp(a) levels between patients with familial hypercholesterolemia (FH) caused either by LDL receptor (LDLR) or PCSK9 mutations, which could reveal the role of PCSK9 in human Lp(a) metabolism.

Methods and Results:
Forty-two mutation-determined heterozygous FH patients with a PCSK9 gain-of-function mutation (FH-PCSK9, mean age=52, mean LDL-C=235 mg/dl), 198 mutation-determined heterozygous FH patients with a LDLR mutation (FH-LDLR, mean age=44, mean LDL-C=217 mg/dl), and 4,015 controls (CONTROL, mean age=56, mean LDL-C=109 mg/dl) were evaluated. We assessed their Lp(a), TC, triglyceride, HDL-C, LDL-C, use of statins, presence of hypertension, diabetes, chronic kidney disease, smoking, body mass index (BMI) and coronary artery disease. Multiple regression analysis showed that HDL-C, the use of statins, the presence of hypertension, smoking, BMI, and Lp(a) were independently associated with the presence of coronary artery disease overall. The serum level of Lp(a) in FH-LDLR was significantly higher than that of the CONTROL (median Lp(a)=11.8 mg/dl [IQR:6.5-29.4] vs 21.9 mg/dl [IQR:10.0-34.2], respectively, p=2х10-7). However, there was no significant difference between the serum level of Lp(a) in FH-LDLR and that of FH-PCSK9 (median Lp(a)=21.9 mg/dl [IQR:10.0-34.2] vs 21.1 mg/dl [IQR:11.7-34.9], respectively).

Conclusion:
These data suggest that Lp(a) is mainly catabolized via the LDL receptor. A significant paradox between statins and PCSK9 inhibitors in terms of Lp(a) catabolism remains.
Abstract 10277: Effect of CoQ10 on Contractile Reserve of Hibernating Swine Myocardium Following Bypass Surgery
Authors: Hocum Stone Laura , Duffy Cayla , Butterick Tammy A , Holley Christopher , Crampton Melanie , Ward Herbert B , Swingen Corey , Kelly Rosemary F , McFalls Edward O
Published: April 2024

Background:
We have previously shown that the recovery of regional function and maximal oxygen consumption in a pig model of hibernating myocardium is incomplete at 4 weeks following bypass surgery (CABG). Because clinical studies suggest a beneficial effect of chronic administration of Coenzyme Q10 (CoQ10) in ischemic heart disease, we tested the benefit of this supplement on contractile reserve, using MRI.

Methods:
Twelve pigs underwent placement of a constrictor around the LAD artery and had reduced function by MRI at 12 weeks. They then underwent off-pump byass using a left internal mammary artery graft and were allowed to recover. Pigs were given daily dietary supplements of either CoQ10 (10 mg/kg/day) or placebo and restudied with MRI at 4 weeks post-CABG. Images were acquired prior to and following CABG with a 3.0-T scanner (Achieva, Philips Medical Systems, Andover MA, USA), with a 4-element phased array coil on the chest and EKG gating. Regional circumferential strain (EC) measures were determined at baseline and at the time of the final study post-CABG, during an infusion of low dose dobutamine. Immediately post-stress, blood samples were obtained for analysis of troponins.

Results:
One animal did not survive and comparisons are made between the Placebo (N=6) and CoQ10 (N=5) groups. At 12 weeks following instrumentation and just prior to CABG, strain in the LAD region of all animals was lower than the remote regions at rest (-14.27±0.65 versus -15.13±0.69 P<0.05). At 4 weeks post-CABG, baseline strain in placebo and CoQ10 groups was -12.4±1.2 and -13.7±0.8 respectively (NS). In addition to no differences in basal function, there were no intergroup differences in either contractile reserve in the LAD region, as measured by circumferential strain, or cardiac troponin levels post-stress (Figure). In summary, in this model of chronic myocardial ischemia, daily supplementation with CoQ10 did not improve basal function or contractile reserve at 4 weeks following CABG.
Abstract 10291: Predictive Values of N-Terminal Pro-B-Type Natriuretic Peptide and Cardiac Troponin I for Myocardial Fibrosis in Hypertrophic Obstructive Cardiomyopathy
Authors: Zhang Changlin , Liu Rong , Yuan Jiansong , Cui Jingang , Hu Fenghuan , Yang Weixian , Zhang Yan , Chen Youzhou , Qiao Shubin
Published: April 2024

Background:
Myocardial fibrosis, as a hallmark of hypertrophic cardiomyopathy (HCM), can be detected by late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR). The combination of high-sensitivity cardiac troponin T (hs-cTnT) and B-type natriuretic peptide (BNP) has been suggested useful in detecting myocardial fibrosis in patients with non-obstructive HCM. However, the values of those biomarkers to predict myocardial fibrosis in hypertrophic obstructive cardiomyopathy (HOCM) remain unclear.

Hypothesis:
We assessed the hypothesis that circulating levels of N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) and cardiac troponin I (cTnI) may predict LGE in patients with HOCM.

Methods:
Patients with HOCM (n=163; age=47.2 ± 10.8, [range 20 to 71] years; 38.7% females) underwent peripheral venous sampling to determine concentrations of NT-proBNP and cTnI. Contrast-enhanced CMR was performed to identify and quantify myocardial fibrosis. We evaluated the relation between LGE and levels of NT-pro BNP and cTnI.

Results:
LGE was detected in 120 of 163 patients (73.6%), and involved 31.6 ± 14.5% of left ventricle (range 2.9% to 73.5%). All participants had left ventricular outflow tract obstruction (LVOT gradient at rest, 78.7 ± 32.5 mmHg). Patients with LGE had significantly higher levels of NT-proBNP and cTnI than those without LGE (1386.2 [904.6 - 2340.8] vs. 866.6 [707.2 - 1875.2] pmol/L, P=0.003; 0.024 [0.010 - 0.049] vs. 0.010 [0.005 - 0.021] ng/ml, P<0.001, respectively). The extent of LGE was positively correlated with log cTnI (r=0.371, P<0.001) and log NT-proBNP (r=0.211, P=0.007). On multivariable analysis, log cTnI and log NT-proBNP were independent predictors of the presence of LGE (OR=3.916, P=0.010; OR=16.6, P=0.014, respectively). According to receiver operating characteristic curve analysis, combined measurements of NT-proBNP level ≥867.0 pmol/L and/or cTnI ≥0.025ng/ml indicated good diagnostic performance for the presence of LGE, with specificity of 92% or sensitivity of 90%.

Conclusions:
Both NT-proBNP and cTnI are useful for identifying myocardial fibrosis, respectively. Combined measurements of these biomarkers further improve their values in detecting myocardial fibrosis in patients with HOCM.