bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 18624: Evidence from an Integrated Analysis Combining Genomics, Transcriptomics, and Lipidomics Implies a Causal Role of Inflammation for Low HDL-C
Authors: Laurila Pirkka-Pekka , Surakka Ida , Sarin Antti-Pekka , Tang Jing , Naukkarinen Jussi , Söderlund Sanni , Ehnholm Christian , Lehtimäki Terho , Eriksson Johan , Salomaa Veikko , Jula Antti , Raitakari Olli , Järvelin Marjo-Riitta , Palotie Aarno , Oresic Matej , Jauhiainen Matti , Taskinen Marja-Riitta , Ripatti Samuli 
Published: April 2024

Low HDL-C is a major risk factor for CVD. To elucidate potential novel pathways behind low HDL-C, we have employed 3 different omics: genomics, transcriptomics, and lipidomics.
We performed GWAS on 450 Finns with low or high HDL-C (90th percentiles). Out of 54 individuals, we obtained subcutaneous (SC) fat biopsies for transcriptome analysis, and isolated plasma HDL particles for lipidomics analysis with MS technology.
We first conducted gene network analysis for loci associated with low HDL-C observing that SNPs within 4 inflammatory pathways (e.g. antigen-presentation) were enriched among the low HDL-C associated genes (p=10^-5). Also, these inflammatory pathways were over-expressed in SC fat of low-HDL-subjects (p=10^-10). We then calculated genetic risk scores based on low HDL-C associating SNPs from these pathways, observing that high risk score resulted in both decreased HDL-C-levels and increased expression of these inflammatory pathways. Moreover, individual genes of these pathways (e.g. HLA-DRB1 [p=10^-7, TAP2 p=10^-6) exhibited cis-eQTLs, their expression inversely correlating with HDL-C.
Consistent with this, the inflammatory nature of the HDL particle of low HDL-C subjects was further highlighted by the elevation of proinflammatory ceramides and reduction of anti-oxidative plasmalogens in the lipidomic analysis, which was also genetic risk score dependent.
In a replication analysis of 5 Finnish population cohorts (n=11,211) the low HDL-C associated SNPs were not associated with HDL-C as quantitative trait, but only after using 75, 90, and 95 percentiles as low/high HDL-C criteria. Interestingly, the effect sizes of individual SNPs became stronger when more extreme phenotype criteria for low HDL-C were implemented (e.g. HLA-DRB1; OR for low HDL-C 75 % = 1.11, OR for 90 % = 1.38, OR for 95 % = 1.77).
Our findings imply that genetic variation influences inflammatory processes associated with low HDL-cholesterol on both expression and metabolite levels, suggesting more inflammatory and less vasoprotective role for HDL particles in low-HDL-subjects. Using the extreme phenotype approach, we also demonstrate the presence of ‘low HDL genes’ in addition to the population GWAS identified ‘HDL genes.’
Abstract 18668: The Clinical Impact of Post Procedural Peripheral Vascular Flow Reserve on Wound Healing Following Infrapopliteal Intervention in Patients with Critical Limb Ischemia
Authors: Fukunaga Masashi , Fujii Kenichi , Kawasaki Daizo , Miki Kojiro , Tamaru Hiroto , Imanaka Takahiro , Shibuya Masahiko , Masutani Motomaru , Ohyanagi Mitsumasa , Masuyama Tohru 
Published: April 2024

Background: The impaired coronary blood flow reserve after coronary intervention has been related to microvascular impairment leading to increased morbidity and mortality. We evaluated whether this finding can be generalised to patients with critical limb ischemia (CLI) undergoing endovascular treatment (EVT) for infrapopliteal arterial disease.
Methods: Eleven limbs (Rutherford 4 and 5) from 10 patients of CLI with angiographic evidence of infrapopliteal arterial disease underwent measurement of peripheral vascular flow reserve (VFR). A pressure/temperature sensor-tipped guidewire was positioned in the proximal popliteal artery at 5cm distal to the guiding catheter. With 3 mL of saline at room temperature used as an indicator, by hand-injection, thermodilution curves in the infrapopliteal artery were obtained both at baseline and at intra-arterial papaverine-induced maximum hyperemia (30mg). VFR was calculated from the ratio of inverse mean transit times at hyperemia and baseline. The VFR measurements were performed both before and after EVTs. Wound healing was defined as the progressive reduction in wound surface area from the beginning of the study.
Results: The procedure success rate was 100%, and VFR was measured in all patients without any complication. Wound healing was achieved in 6 limbs after EVT (healing group) and not achieved in 5 (non-healing group). The average pre- and post-VFR was 4.1±2.6 and 5.8±4.2 respectively. There was no significant difference in pre-VFR values between healing and non-healing group (4.3±3.2 versus 3.7±2.0). However, post-VFR values was significantly higher in the healing group than in the non-healing group (6.3±4.1 versus 3.3±1.8, p<0.05). VFR values in non-healing group decreased or remained unchanged in all patients mainly due to increase in resting blood flow.
Conclusions: VFR values immediately after EVT for infrapopliteal arterial disease remained unchanged in patients with poor wound healing mainly due to increase in resting blood flow. This finding suggests that a therapeutic effect can not be obtained if the arteriolar bed is damaged after EVT. This easily assessable VFR is useful in clinical risk stratification for patients with CLI immediately after EVT in the catheterization laboratory.
Abstract 18679: Stand Alone Cox-Maze Procedure for Patients with Non Paroxysmal Atrial Fibrillation- A Single Center Experience
Authors: Ad Niv , Henry Linda , Hunt Sharon , Freihling Ted , Wish Marc , Holmes Sari 
Published: April 2024

Background: Catheter ablation for atrial fibrillation (AF) performed percutaneousely or using minimally invasive (MI) off bypass surgical techniques is shown to be limited in patients with non-paroxysmal AF (non PAF). The Cox-Maze procedure (CM) on bypass is effective in non-PAF patients, but concerns about associated morbidity were raised. The study purpose assesses the safety and efficacy of a stand alone on pump CM procedure in patients with non-PAF.
Methods: Since 2005, 690 patients had surgical ablation at our institution: 175 (25%) referred for stand alone CM procedure; 138 (20%) undergoing a stand alone procedure for non-PAF . All patients are followed prospectively thru our AF registry. Rhythm verified by EKG and 24-hour holter using the Heart Rhythm Society definition of failure. Health-related quality of life (HRQL, SF-12) and AF symptoms assessed preoperatively/12 months post procedure.
Results: Mean age of: 56.9±8.7 years; 60% had at least 1 prior cardioversion and 42% had a catheter ablation; other descriptives and major perioperative morbidities table. The return to sinus rhythm at 6, 12 and 24 months and off antiarrythmic drugs respectively are: 93%/83%; 93%/85%; 90%/79%. In a multivariate analysis, duration of AF predicted rhythm 12 months after surgery, with 20% greater odds of AF at 12 months for each year increase in duration (OR=1.20, CI: 1.03-1.40) after adjustment for other risk factors. By 2 years, only 20% of patients remained on Coumadin with only1 embolic stroke in 44±26 patient months. HRQL significantly improved (p<0.001) and symptoms significantly decreased (p=0.003) by 12 months. By Kaplan-Meier analysis - 97.6% cumulative survival (CI: 95-100%) at 2 years.
Conclusion: On pump stand alone CM procedure can be performed with comparable morbidity to catheter ablation. Long term success in non-PAF patients with large left atria is promising. Our experience suggests development of educational strategies to overcome an initial learning curve.
Abstract 18692: High Flavanol Dark Chocolate Reduces NT-proBNP in Patients with Chronic Heart Failure
Authors: de Palma Rodney , Sotto Imelda , Khan Noorafza Q , Wood Elizabeth G , Butler Jane , Johnston Atholl , Rothman Martin T , Corder Roger 
Published: April 2024

Background:
Endothelial dysfunction in patients with heart failure (HF) has been linked to a worse prognosis. High flavanol cocoa products improve endothelial function, but it has yet to be established whether such changes are sufficient to confer medical benefit. We investigated whether high flavanol dark chocolate (HFDC) reduces the severity of HF by measuring changes in amino-terminal pro-B type natriuretic peptide (NT-proBNP).

Methods:
Patients with HF and a history of ischemic heart disease (n = 32), stable on optimal medication according to standard guidelines, were randomized to consume 50 g per day of either HFDC or low flavanol dark chocolate (LFDC) for 4 weeks, and then crossed over to consume the alternative dark chocolate for a further 4 week. The flavanol contents of the HFDC and LFDC were 1094 and 95 mg/50 g. NT-proBNP, blood pressure, and aortic pulse waveform derived from radial artery applanation tonometry were assessed at baseline, after each 4-week treatment phase, and at follow-up 4 weeks after completion of chocolate consumption.

Results:
24 subjects completed the study. After 4 weeks consumption of HFDC, NT-proBNP was significantly lower compared to baseline (P = 0.016), LFDC (P = 0.019) and at follow-up (P = 0.004). After HFDC, diastolic blood pressure (DBP) was decreased compared to LFDC (mean decrease ± SD; -7 ± 10 mmHg, P = 0.003 and compared to baseline measurements (-4 ± 9 mmHg, P = 0.047). Figure 1 shows a comparison of mean changes in DBP and NT-proBNP after HFDC compared to baseline, LFDC and follow-up values. Mean decrease in NT-proBNP was >30% in 12 patients.

Conclusions:
Reductions in NT-proBNP and blood pressure after HFDC are consistent with a decrease in vascular resistance resulting in reduced left ventricular afterload. Post treatment reductions of NT-proBNP >30% have previously been associated with improved outcome in patients with HF. Hence, long-term benefits of high flavanol interventions in HF merit further investigation.
Abstract 18734: KLF4 Regulates Aortic Aneurysm Morphology and Deletion Attenuates Aortic Aneurysm Formation
Authors: Salmon Morgan , Johnston William F , Su Gang , Upchurch Gilbert R , Owens Gary K , Ailawadi Gorav 
Published: April 2024

Objective: Kruppel-like Factor 4 (KLF4) is known to play a role in inducing phenotypic modulation of smooth muscle cells (SMC) following ischemia reperfusion injury and in atherosclerosis; however, its role in aortic aneurysms (AA) remains unknown. The study objective was to evaluate the role of genetic deletion of KLF4 on development of experimental AAs.
Methods: 8-12 week male (n=12) KLF4 flx/wt ERT tamoxifen Cre+ mice (“KLF4 conditional het KO mice”) and KLF4 flx/wt ERT tamoxifen Cre- (WT) mice underwent elastase perfusion following tamoxifen injection. In separate experiments, 8-12 week male (n=13) KLF4 flx/flx Smooth muscle myosin heavy chain (Myh11) Cre+(“SMC specific conditional KLF4 KO mice”), and KLF4 wt/wt SM-MHC Cre+ (“Myh11 Cre WT”) underwent elastase perfusion following tamoxifen administration. At 14 days, maximal aortic dilation was measured with video micrometry. Aortic samples were evaluated with histology for α-actin, macrophages, neutrophils, T lymphocytes and elastin.
Results: Maximal aortic dilation was significantly reduced in KLF4 conditional het KO mice compared to WT controls (42.9 ± 7.3% versus 78.9 ± 12.6%, p<0.039). In addition, these mice had reduced macrophage and neutrophil infiltration with greater elastin preservation and α-actin expression. SMC specific conditional KLF4 KO mice also showed a significant reduction in aortic dilation following elastase perfusion as compared to Myh11 Cre+ WT controls (53.4 ± 7.76% versus 93.8 ± 16.2%, p<0.028). These mice also had reduced macrophage and neutrophil staining and increased elastin preservation and α-actin expression.
Conclusions: KLF4 plays a critical role in promoting AA formation, since heterozygous KLF4 KO mice showed reduced aneurysm formation. At least part of this effect is due to loss of KLF4 in SMC since SMC specific conditional KLF4 KO mice also showed reduced AA formation as well as decreased immune cell recruitment and greater preservation of elastin and SMCs. Taken together, results identify KLF4 as a novel therapeutic target for treatment of aneurysms.
Abstract 18830: Increase in Platelet Reactivity After Red Blood Cell Transfusion in Coronary and Non-coronary Patients: Results from the Transfusion-2 Study
Authors: Silvain Johanne , Abtan Jeremie , Martin Rejane , Kerneis Mathieu , O'Connor Stephen A , Brugier Delphine , Barthelemy Olivier , Beygui Farzin , Collet Jean-Philippe , Montalescot Gilles 
Published: April 2024

BACKGROUND: Red blood cell (RBC) transfusion increases platelet activation and aggregation in vitro in healthy volunteers. This provides a possible mechanism for the increase in recurrent ischemic events and mortality reported after RBC transfusion in acute coronary syndrome (ACS) patients. The aim of the study was to replicate these findings in coronary and non-coronary patients exposed to RBC transfusion.
METHODS: Platelet reactivity was measured before and 12 hours after RBC transfusion using light transmission aggregometry with four different agonists and Vasodilatator-Stimulated Phosphoprotein Platelet Reactivity Index (VASP-PRI) by flow cytometry. Consecutive and unselected patients were considered. Relative changes in maximum platelet aggregation (MPA) and in residual platelet aggregation assessed 6 minutes after initiation were considered as well as VASP-PRI.
RESULTS: Our study population consisted of 53 patients (45% of coronary patients) of whom 25 were on dual antiplatelet therapy (DAPT) (20 with clopidogrel and 5 with prasugrel) and 11 on aspirin alone. Transfusion led to a significant increase in MPA irrespective of the agonists used: 8.8% with ADP (52.1 ± 3.1 vs. 56.7 ± 2.8 p=0.03) and 12.5% with TRAP (46.8 ± 22 vs. 53.7 ± 24, p=0.02). A similar trend was observed with arachidonic acid and with the VASP PRI index (13.0 ± 23 vs. 16.5 ± 25, p = 0.2 and 46.3 ± 31 vs. 50.2 ± 27, p=0.3 respectively), although the difference was not significant. The impact of transfusion was more pronounced in patients exposed to DAPT (coronary patients) although P2Y12 Inhibitors provided lower levels of baseline platelet aggregation (Relative changes of +13.8%, p=0.02 with ADP, +24.5%, p=0.01 with TRAP, and +10%, p = 0.6 for the VASP-PRI).
CONCLUSION: Red blood cell transfusion increase platelet reactivity in patients. This effect is more pronounced among patients treated with P2Y12 inhibitors and may account for the detrimental effect of RBC in the context of ACS.
Abstract 19337: Cathepsin L is Required to Modulate Cardiac Hypertrophy through Activation of the Autophagy-Lysosomal Dependent Protein Processing Pathway
Authors: Moon Mark , Sun Mei , Ouzounian Maral , Li Guohua , Liu Youan , Gramolini Anthony , Liu Peter P 
Published: April 2024

Background_Autophagy is critical in the maintenance of cellular protein quality control involved in the cell growth, survival and death. Cathepsin L (CTSL) is a key member of the lysosomal protease family that is expressed in the murine and human heart, and may play an important role in dynamic protein control. We hypothesized that CTSL is important in regulating protein processing in the heart, particularly under pathological stress.
Methods and Results_Phenylephrine-induced cardiac hypertrophy in vitro was significantly more pronounced in CTSL deficient neonatal cardiomyocytes compared to controls. This was accompanied by a significantly increased accumulation of autophagosomes, increased levels of ubiquitin-conjugated protein, impaired protein degradation and increased cell death. These phenomena were rescued with Ctsl1 replacement via adeno-associated virus mediated gene transfer. In the in vivo murine model of aortic banding (AB), CTSL deficiency (Ctsl-/-) markedly exacerbated cardiac hypertrophy, worsened cardiac function, and increased mortality. Ctsl-/- AB mice demonstrated significantly decreased lysosomal activity, and increased sarcomere-associated protein aggregation. Homeostasis of the endoplasmic reticulum was also altered with increased Bip and GRP94 proteins in Ctsl-/- AB mice, accompanied by increased ubiquitin-proteasome system activity and higher levels of ubiquitinated proteins in response to AB. These changes ultimately led to a decrease in cellular ATP production, enhanced oxidative stress, and increased cellular apoptosis.
Conclusions_Lysosomal CTSL is a key contributor to modulate the cardiac response to hypertrophic stress through regulation of protein processing and quality control.
Abstract 19381: Imatinib Mesylate Modifies Induced Pathological Hypertrophy by Altering Myocyte Calcium
Authors: Barr Larry , Kubo Haji , Gao Hui , Makarewich Catherine , Berretta Remus , Force Thomas , Houser Steven R 
Published: April 2024

Background —

Imatinib mesylate (IM) is a small molecule inhibitor of the fusion protein Bcr-Abl, which causes chronic myelogenous leukemia. There is some concern that IM can induce cardiac dysfunction in cancer patients. A previous study showed that chronic treatment of adult mice with IM for 3-4 weeks leads to deterioration in contractile function and LV mass decrease. We investigated the effects of IM on neonatal rat ventricular myocytes (NRVMs). The hypothesis is that calcium regulatory mechanisms are altered to induce pathological hypertrophy.

Methods and Results —

NRVMs were treated with a clinical dosage (2 µM) of IM. Western analysis showed a significant increase in phospholamban phosphorylation at T-17, signifying activation of CaMKII. The rate of decay of the systolic Ca
2+
transient was increased, consistent with an increase in rate of Ca
2+
resequestration into the SR. Coulter counter analysis was used to determine cell size and showed that average NRVM volume increased significantly (Con-102 pl; IM-133 pl. p<0.05). Myocyte surface area also increased with IM treatment (Con-6277 μm
2
; imatinib-10259 μm
2
p<0.05). Western analysis showed significant increases in ANP abundance, a pathological hypertrophy marker, after IM administration. NRVMs were infected with AdNFATc3-GFP and NFAT nuclear translocation was analyzed as nuclear/cytoplasmic GFP. Nuclear translocation was significantly increased with IM treatment. The calcineurin inhibitor FK506 inhibited IM induced NFAT nuclear translocation (Con-0.8162 ± 0.032; imatinib-2.233 ± 0.13; imatinib+FK506-0.6277 ± 0.037. p<0.05).

Conclusions —

These data show that clinical doses of IM activate pathological hypertrophy signaling pathways by enhancing SR function. This could be a mechanism for adverse cardiac effects of IM.
Abstract 19637: Superiority of Calcium Sensitizer Over Beta-Adrenoceptor Agonist for Treatment of Myocardial Dysfunction after Deep Hypothermic Circulatory Arrest. Role of Calcium Desensitization
Authors: Rungatscher Alessio , Hallstroem Seth , Giacomazzi Alice , Linardi Daniele , Tessari Maddalena , Menon Tiziano , Mazzucco Alessandro , Faggian Giuseppe 
Published: April 2024

BACKGROUND: Rewarming from deep hypothermic circutatory arrest (DHCA) produced a calcium desensitization by cTnI phosphorylation that results in myocardial dysfunction. This study was aimed to investigate the acute overall hemodynamic and metabolic effects of epinephrine and levosimendan on myocardial function after rewarming from deep hypothermia.
METHODS AND RESULTS Forty male Wistar rats (400-500 g) underwent cardiopulmonary bypass and were cooled to a core temperature of 13°C to 15°C within 30 minutes. After 15 minutes of DHCA, they were randomly assigned to treatment with levosimendan (0.1 μg/kg/min) (n=15) or epinephrine (0.1 μg/kg/min) (n =15) or saline as control (n =10). The rewarming lasted 60 minutes. Systolic and diastolic function was evaluated at different preloads with a conductance catheter. Levosimendan produced a significantly better recovery of the slope of the left ventricular end-systolic pressure volume relationship (Ees) and preload recruitable stroke work (PRSW) than ephinephrine (as percentage of baseline respectively 85+9 vs 51+11, p=0.003 and 78+5 vs 48+8, p=0.005). Levosimendan and not ephinephrine compared to control reduced left ventricular stiffness expressed by end-diastolic pressure volume relationship (EDPVR) and improved ventricular relaxation described by Tau. Levosimendan preserved high-energy phosphates content and energy charge and reduced lactate plasma concentration. Ephinephrine (E) determined a significant cTnI phosphorylation during normothermia (N) and enhanced cTnI phosphorylation after DHCA (H/R). On the contrary levosimendan (L) prevent cTnI phosphorylation that was not different from normothermic control (Fig. 1).
CONCLUSIONS: Levosimendan is more effective than epinephrine for treatment of myocardial dysfunction after DHCA. Ephinephrine has a detrimental effect on calcium desensitization that has a key role in myocardial dysfunction after rewarming from DHCA.
Abstract 19681: Endothelial PGC-1alpha Mediates Vascular Dysfunction in Diabetes
Authors: Sawada Naoki , Jiang Aihua , Takizawa Fumihiko , Croce Kevin , Manika Andre , Tesmenitsky Yevgenia , Kang Kyu-Tae , Bischoff Joyce , Kalwa Hermann , Michel Thomas , Kamei Yasutomi , Benjamin Laura , Sata Masataka , Ogawa Yoshihiro , Arany Zolt 
Published: April 2024

[Background] Endothelial dysfunction and aberrant angiogenesis is a hallmark of diabetes. How metabolic perturbations deteriorate endothelial function, however, still remains elusive. The transcriptional coactivator PPARgamma-coactivator-1alpha (PGC-1alpha) is a powerful regulator of metabolism in numerous cell types and is involved in the development of diabetes, but its role in endothelial cells remains poorly understood.
[Objective] We hypothesized that PGC-1alpha may mediate endothelial dysfunction and aberrant neovascularization associated with diabetes.
[Methods and Results] PGC-1alpha mRNA was upregulated by two to fivefold in cultured endothelial cells (ECs) following high glucose stimulation as well as in the ECs isolated from distinct diabetic mouse models (streptozocin-induced type I DM, high fat diet (HFD) feeding, and ob/ob mice). Forced expression of PGC-1alpha abolished VEGF and S1P-induced EC migration, and diminished the capacity of EPCs to undergo vasculogenesis. Conversely, pro-angiogenic factors like VEGF, sphingosine 1-phosphate (S1P) and NO rapidly downregulated PGC-1alpha in ECs, suggesting a role for PGC-1alpha in angiogenic signaling. Consistently, deletion of PGC-1alpha caused pronounced EC migration to a level comparable to that provoked by VEGF. Mechanistically, the angiostatic effect of PGC-1alpha was mediated through inhibition of Rac1 and Akt/eNOS pathway. Transgenic overexpression of PGC-1alpha in ECs in vivo recapitulated multiple diabetic phenotypes, including aberrant reendothelialization in response to carotid injury, wound healing, and blood flow recovery in response to hindlimb ischemia. Conversely, deletion of PGC-1alpha in ECs rescued wound healing dysfunction in type I and II diabetic animals, and restored blood flow recovery in type I diabetic animals with hindlimb ischemia.
[Conclusion] Our data identify EC PGC-1alpha as a critical negative regulator of endothelial function and angiogenesis. Upregulation of PGC-1alpha by hyperglycemia renders ECs unable to properly undergo angiogenesis, and thus constitutes a critical mechanism underlying vascular dysfunction in diabetes.