bluuebunny/crossref_metadata_2025 huggingface dataset:
P4460microRNA-17-5p and microRNA-20a-5p downregulation by atorvastatin in Hepg2 cells: a new mechanism involved in the lipid-lowering therapy
Authors: Saavedra K , Leal K , Zapata D , Sagardia S , Ortega F , Zambrano T , Saavedra N , Salazar L A
Published: October 2019

Background

Hypercholesterolemia increases the risk of coronary artery disease and its pharmacological treatment has demonstrated, besides reducing cholesterol levels, a decrease in the incidence and mortality from coronary events. The treatment of hypercholesterolemia is mainly driven by using statins. However, the response to pharmacological therapy shows high inter-individual variability, resulting in a variable effect in both lipid lowering and risk reduction. Thus, a better understanding of lipid-lowering mechanism and response variability at molecular level is required. Previously, we demonstrated a deregulation of microRNA (miR) profile in HepG2 cells after atorvastatin treatment, including the downregulation of miR-17-5p and miR-20a-5p which potentially targets the LDL receptor gene (LDLR), suggesting that it might be involved in allowing the LDLR overexpression on the surface of hepatic cells to subsequently capture circulating LDL and to reach the expected lipid-lowering effect.

Purpose

To determine the role of miR-17-5p and miR-20a-5p on the regulation of LDLR gene expression in HepG2 cells.

Methods

Cells HepG2 were treated with atorvastatin 10μM for 24 hours. RNA extraction and enrichment of smallRNAs were performed. The gene expression of miR-17-5p, miR-20a-5p, miR-24-3p, miR-93-5p, miR-106a-5p and LDLR were evaluated. To evaluate the effect of miR-17-5p and miR-20a-5p on LDLR gene expression, both miRs were overexpressed or repressed by transfection of mimics or inhibitors respectively into HepG2 cells for 24, 48 and 72 Hours. The gene expression of LDLR was quantified by real time PCR using RPL27 gene as reference gene. The protein expression of LDLR and beta actin were evaluated using western blot and quantified using the ImageJ software.

Results

Our data showed that atorvastatin significantly repressed the expression of miR-17-5p (P<0.0001) and miR-20a-5p (P=0.0456) in HepG2 cells. In silico studies showed that miR-17-5p interact with the 3'-UTR region of the LDLR. Consistently, when miR-17-5p or miR-20a-5p were overexpressed by using mimics, we observed that gene and protein expression of LDLR decreased significantly (P<0.0001 and P<0.05 respectively). Consistently, when miR-17-5p or miR-20a-5p were repressed by the use inhibitors, we observed that the gene and protein expression of LDLR increases significantly (P<0.005).

Conclusions

In conclusion, we demonstrate that atorvastatin induces a significant down-regulation of the miR-17-5p and miR-20a-5p in HepG2 cells. The overexpression or repression regulate the gene and protein expression of LDLR.

Acknowledgement/Funding

FONDECYT N°3160567, FONDECYT N°1171765 and DIUFRO DI19-0094
P4475Vasodilation- and blood pressure normalization-independent cardioprotective effects of endogenous, physical activity-induced alpha calcitonin gene-related peptide in chronic hypertension
Authors: Skaria T , Mitchell K , Fischer J A , Born W , Gassmann M , Vogel J
Published: October 2019

Background

Alpha calcitonin gene-related peptide (αCGRP) is one of the strongest vasodilators and, as such, is cardioprotective in chronic hypertension when reducing the associated elevated blood pressure. However, we hypothesize that endogenous, physical activity-induced αCGRP has blood pressure independent cardioprotective effects in chronic hypertension.

Methods

Chronic hypertension was induced in WT and αCGRP−/− mice by one-kidney one-clip surgery. Chronic hypertensive WT and αCGRP−/− mice lived sedentarily or performed voluntary wheel running and were treated simultaneously with either vehicle, αCGRP or αCGRP receptor antagonist CGRP8–37. Cardiac function and tissue phenotype were evaluated echocardiographically and by ddPCR, Western blotting and histology, respectively.

Results

Blood pressure was similar among all hypertensive experimental groups. Endogenous αCGRP limited pathological cardiac remodeling and symptomatic heart failure already in sedentary, chronic hypertensive WT mice. In these mice, voluntary wheel running significantly improved cardiac tissue phenotype and function, that was abolished by CGRP8–37 treatment. In αCGRP−/− mice, αCGRP treatment, in contrast to voluntary wheel running, improved cardiac tissue phenotype and function. Specific inhibition of proliferation and myofibroblast differentiation of primary murine cardiac fibroblasts by αCGRP suggests involvement of these cells in αCGRP-mediated blunting of pathological cardiac remodeling.

Conclusion

Endogenous, physical activity-induced αCGRP has blood pressure independent cardioprotective effects and is crucial for maintaining cardiac function in chronic hypertension. Consequently, permanently inhibiting endogenous αCGRP signaling, as currently approved for migraine prophylaxis, could endanger hypertensive patients.

Acknowledgement/Funding

Swiss National Science Foundation, Novartis Foundation for Medical-biological Research
P4483Transforming growth factor-beta and arrhythmias in mitral valve prolapse patients
Authors: Malev E , Omelchenko M , Mitrofanova L , Vasina L , Pankova I , Gordeev M , Bondarenko B , Zemtsovsky E
Published: October 2019

Transforming growth factor-β (TGF-β) is a multifunctional cytokine with fibrogenic properties. Also increased TGF-β signaling contributes to the development of myxomatous changes of the mitral valve (MV). Recent data suggests that TGF-β may play a potentially important role in the heart arrhythmogenesis. Our aim was to evaluate the possible proarrhythmic effects of TGF-β in patients with mitral valve prolapse (MVP) and severe mitral regurgitation (MR) undergoing MV repair.

Methods

30 consecutive patients (mean age 53.1±9.4, 47% male) undergoing MV repair for severe MR due to MVP were enrolled in our observational, prospective, single-center study. Immunohistochemical characterization of mitral valve sections was performed with TGF-β1 and TGF-β2 primary antibodies. The levels of TGF-β1 and TGF-β2 in serum were determined by enzyme-linked immunosorbent assay Human Platinum ELISA.Transthoracic echocardiography and 24-hour Holter monitoring were performed pre- and postoperatively annually. Atrial fibrillation, PVCs and nonsustained ventricular tachycardia (VT) runs were reviewed.

Results

Resected MV leaflets showed the increase ofTGF-β1 and TGF-β2 positive cell count (33% and 38%, respectively). High level of TGF-β1 (>14.75 ng/ml) and/or TGF-β2 (>2.0 ng/ml) was detected in majority (77%) of patients and associated with thickening of posterior leaflet (r=0.67; p=0.016), residual valve prolapse (r=0.68; p=0.007) and recurrent MR (r=0.56; p=0.01), pre- and postoperative left atrial (p<0.001) and end-systolic LV diameter (p<0.001), and negatively with LV ejection fraction (p<0.001).

Atrial fibrillation was documented in 20% patients before repair. Postoperative AF occurred in 17% and associates with postoperative left atrial diameter (rs=0.60; p=0.008) and MR degree (rs=0.51; p=0.01). Total number of PVCs and non-sustained ventricular tachycardia runs dropped significantly in 1st (p=0.04, Wilcoxon matched pairs test) and 2nd (p=0.03), years of postoperative follow-up. Postoperative incidence of PVCs and VT associates strongly with postoperative end-diastolic LV diameter (rs=0.70; p=0.005), moderate negatively with LV ejection fraction (rs=−0.55; p=0.01).

TGF-β2 (but not TGF-β1) serum level were associated with postoperative incidence of atrial fibrillation (p<0.001), but not PVCs or VT. In univariate analysis, postoperative left atrial diameter (p=0.001), residual MR (p=0.003), myxomatous degeneration (p=0.008) and the serum level of TGF-β2 (p=0.001) were identified as risk factors of persistent atrial fibrillation after surgery.

Conclusions

High level of TGF-β2 is associated with persistent atrial (but not ventricular) arrhythmias in MVP patients after mitral valve repair, possibly through 1) progression of valve myxomatous after reconstructive surgery (via recurrent MR and LA enlargement) and 2) previously shown alteration of the electrophysiological phenotype of cardiac myofibroblasts.
P4484Notch-dependent endothelial dysfunction in patients with aortic valve calcification
Authors: Kostina A S , Semenova D , Kiselev A , Urtyuga O , Shcherbinin T , Ibragimov A , Gordeev M , Uspenskiy V , Kostareva A , Malashicheva A
Published: October 2019

Background

Aortic valve calcification associated with either bicuspid or tricuspid aortic valve remains among the most dangerous cardiovascular diseases but cellular and molecular reasons of this pathology are not fully understood. It has been shown that NOTCH1 haploinsufficiency in endothelial cells derived from iPS and also inhibition of NOTCH1 in aortic valve endothelial cells gives rise to the activation of proosteogenic pathways. Endothelial cells regulate underlying interstitial cells and govern them to differentiation. Thus, elucidation of molecular mechanisms of endothelial dysfunction could shed light on valve calcification pathogenesis.

Purpose

To elucidate key genes responsible for valve endothelial dysfunction in aortic valve calcification.

Methods

Primary human aortic valve endothelial cells (VEC) were isolated from 45 patients (BAV, n=21; TAV, n=26) with calcific aortic valve disease and from 8 healthy donors. Expression of corresponding genes was estimated by qPCR.

Results

We checked expression of about 30 genes related to Notch/Wnt/Bmp pathways and shear stress response. Endothelial cells of patients with calcification had significantly lower mRNA levels of Notch component genes NOTCH2, NOTCH3, DLL4 and JAG1 as well as of Notch target genes HEY1, SNAIL and SLUG. Expression of Wnt-related genes such as DKK1, GREM1 and TCF4 was altered in VEC from calcified valves. Interestingly, mRNA level of ROBO4, recently suggested to be involved in endothelial dysfunctions, was significantly higher in VEC of patients with calcification. Moreover, endothelium from calcified valves had impaired expression of matrix gla protein (MGP), which is known to sequester calcium and inhibit soft tissue calcification in the vasculature and aortic valve.

Conclusions

Our data show that Notch pathway genes are downregulated in valve endothelial cells of the patients with aortic valve calcification. Our results suggest also implication of shear stress responsive genes and genes of endothelial performance in changing the properties of valve endothelial population of calcified valves and thus presumably to the pathogenesis of aortic valve calcification.

Acknowledgement/Funding

Russian Foundation For Basic Research 18-34-00277
P4487Inhibition of aortic valve calcification by SNF472 in vitro
Authors: Zabirnyk A , Bogdanova M , Ferrer M , Perez M , Kaljusto M , Stenslokken K , Salcedo C , Fiane A , Vaage J
Published: October 2019

Background

Calcific aortic valve disease is the 2nd most frequent cause of open heart surgery. The valve interstitial cells (VIC) are crucial for calcification. SNF472 (a derivative of phytic acid) is a calcification inhibitor currently in clinical development for the treatment of cardiovascular calcification (Phase 2 CaLIPSO trial, EudraCT 2016–002834–59). SNF472 has been shown to inhibit vascular calcification in several preclinical models.

Purpose

1. Establish a new model of calcification in cultured human VIC; 2. Investigate whether SNF472 would inhibit calcification in this model, and 3. Study if SNF472 might inhibit ongoing calcification processes.

Methods

Healthy and calcified aortic valves were obtained from heart transplant recipients and patients undergoing aortic valve replacement due to calcific valve disease, respectively. VIC were isolated and seeded in basic growth medium, osteogenic differentiation medium (Osteodiff) alone, and with addition of different concentrations of SNF472. The following series of studies were performed: 1. VIC from healthy and calcified valves were cultured for three weeks with Osteodiff; 2. VIC from calcified valves were cultured for 3 weeks in Osteodiff media with 0, 1, 3, 10, 30, or 100 μM SNF472; 3. VIC from calcified valves were cultured for 3 weeks in Osteodiff media in total, but after 1 or 2 weeks 30 or 100 μM SNF472 was added to the cultures (n=8). Calcification was visualized by Alzarin Red staining and quantified by spectrophotometry. Statistics analysis was performed nonparametric One-Way ANOVA (Friedman and Kruskal–Wallis tests) with Dunn's post-test.

Results

Calcification was found to be 30% stronger in cultures of VIC from calcified valves as compared to cultured VIC from healthy valves (p=0.03). SNF472 successfully inhibited VIC calcification in a dose-dependent manner. SNF472 concentrations of 1, and 3 μM inhibited calcification by 7% (not significant) and 66% (p=0.08) respectively. Concentrations of 10, 30, and 100 μM completely inhibited calcification. 30 and 100 μM of SNF472 added after 1 week reduced ongoing calcification by 84% (p<0.01) and 100% (p<0.01) respectively. When given after 2 weeks of ongoing calcification non-significant inhibition was still observed (21 and 30%, respectively).

Conclusions

VIC from calcified valves have a more pro-calcification phenotype than VIC from healthy valves. SNF472 is able to inhibit the development VIC calcification in vitro. By early intervention SNF472 is also able to stop the progression of ongoing calcification. SNF472 shows to be a promising therapy to treat heart valve calcification.

Acknowledgement/Funding

EC FP7 (GA 609020), Balearic Islands Government grant (ES01/TCAI/41_2017), FEDER 2014-2020, Laboratoris Sanifit, Palma, Spain; University of Oslo
P4489Morphological changes in the EGDE-treated bioprosthetic heart valves
Authors: Ovcharenko E , Klyshnikov K Y U , Glushkova T , Rogulina N , Barbarash L S
Published: October 2019

Background

Prosthetic heart valves fabricated from pericardium preserved in EGDE (ethylene glycol diglycidyl ether) may be a promising option for patients with valvular heart disease.

Purpose

To assess morphological changes in the failed PeriCor and UniLine bioprostheses and to determine the underlying mechanisms contributing to their dysfunction.

Methods

17 patients with EGDE-treated mitral bioprosthetic valves (PeriCor group, n=11, UniLine group= 6). undergoing repeat mitral valve replacement were included in the study. The median age of patients at the time of the primary replacement was 59 (54; 64) and 57 (55, 65) years, respectively. All cases of calcifications, spontaneous perforations, leaflet tears and ruptures, pannus growth, bioprosthetic leaflet fusion were assessed using microscopy and micro-computed tomography. The contribution of degenerative changes leading to the failure of bioprostheses was estimated with the Chi-square test.

Results

Pannus growth was observed in 53.8% of all explanted bioprostheses. Its overgrowth was abundant covering the leaflets and the stent struts and resulted in decreased effective orifice area and subsequent stenosis. Bioprosthetic leaflet fusion was observed only in the PeriCor group and accounts for 70%. Of them, 93% of cases of leaflet fusion was accompanied by the ruptures in the opposite commissural zones and subsequent leaflet perforations. The signs of calcification were reported in 57.6% of cases. Of them, 50% of cases had calcified stent frame tissue covering and 35% - pannus. Interestingly, calcification was not the main cause leading to the valve failure in 53.3% of cases.

Conclusion

Modes of bioprosthetic valve dysfunction include primary tissue degeneration, calcification and pannus growth. Primary tissue degeneration, pannus growth and commissural fusions account for a larger percentage in the modes of dysfunctions for EGDE-treated xenoaortic bioprostheses rather than calcification. Our findings suggest that preservation methods play one of the key roles in the dysfunction pattern.
P4491Noninvasive evaluation of force distribution in mitral annuloplasty rings: do rigid annuloplasty rings increase stress?
Authors: Ovcharenko E , Klyshnikov K Y U , Kokov A , Glushkova T , Barbarash L S
Published: October 2019

Purpose

To evaluate forces distribution, local stresses and deformation of mitral annuloplasty rings in response to annuloplasty.

Methods

Seguin (St. Jude Medical), Physio I (Edwards LifeScience), Memo 3D (Sorin) and Future SG (Medtronic) MAR of size 30 mm were included in the study. The study group included 4 males patients aged 52–68 years who underwent isolated mitral valve annuloplasty for ischemic mitral regurgitation. All surgeries were performed by the same experienced operator according to the standardized protocol. The mechanical properties of the similar set of MAR were evaluated under uniaxial compression by 15% in the longitudinal and transverse directions on the Testing Machines Z5.0 (Zwick/Roell). Biomechanics was assessed with MSCT. The MAR frame models at the initial state and at the ventricular ejection and atrial systole phases were obtained from DICOM-data using computer tomography Sensation Somatom 64 (Siemens). The models were compared using the innovative numerical algorithm in MatLab (Mathworks) by forming pairs for “systole – diastole”, “initial state – diastole” for all four types of MAR. We compared the mobility of the implanted devices and changes in the physiological saddle shape geometry of the mitral annulus in response to annuloplasty. We performed the quantitative analysis of the movement of each point of the reconstructed model between two states with the subsequent calculation of the required forces based on the finite element analysis.

Results

Future CG MAR has the greatest longitudinal and transverse stiffness (18.1N and 4.8N, respectively), whereas Memo 3D demonstrates the lowest values (2.3N and 1.5N). The rest two models show intermediate values of 4.2 - 11.3 N to 2.0 - 4.3N. The comparative analysis of MAR before and after implantation shows that Physio demonstrates the most pronounced deviations from normal physiological shape with significant annular compression along the intercommissural diameter by 1.36 mm resulted in a rounded annulus shape. None significant geometrical deformity among the other prosthetic rings. MEMO 3D demonstrates an average deformation by 0.18 mm across all zones, Seguin - 0.42 mm, Future CG - 0.34 mm. The force distribution analysis demonstrated the least forces of MEMO 3D, whereas the largest ones (up to 1.5N) are shown by Future SG, leading to the induction of locally elevated stress in surrounding tissues, potentially triggering the development of paravalvular fistulae.

Conclusion

Preliminary results demonstrate that the use of flexible rings with initially mobile structure allows preserving the native mitral annulus mobility after annuloplasty and reducing the stress (forces) acting on the surrounding tissues. The presented non-invasive method for estimating the stress of mitral annulus is crucial for advanced clinical practice as it allows further studying of the underlying pathologic mechanisms of developing paravalvular fistulae.
P4499Development of a hydrogel-based pre-vascularized 3D cardiac patch displaying capillary network
Authors: Kitasato L , Atlas Y , Joanne P , Germain S , Agbulut O , Muller L
Published: October 2019

Purpose

Stem cell-based attempts at regenerating chronically failing heart have not met the clinical outcomes expected by experimental studies. The efficacy of cell transplant is largely dependent on the engraftment rate, which requires cells to receive an adequate blood supply. To address this issue, we propose to develop a composite tissue engineering construct made of biocompatible pre-vascularized fibrin hydrogel. The objectives of this study are to determine co-culture conditions and to optimize fabrication of fibrin hydrogels supporting generation of capillaries and cardiomyocyte activity at the same time.

Materials and methods

Rat primary cardiomyocytes were co-seeded with human umbilical vein endothelial cells (HUVECs) in fibrin hydrogels. Cultures were performed in 96 well plates. Cells were cultured in a mixture of medium conditioned with human dermal fibroblasts and of cardiomyocyte medium (1:1) for 8 days. To improve co-culture of the two cell types, insulin (1 μg/mL) and/or VEGF (5 ng/mL) were added 24 hours after the initial day of culture and maintained for 24 hours. The cells treated with VEGF were also treated 5 days after initial seeding with insulin and VEGF (insulin at 1 μg/mL and VEGF at 1 or 5 ng/mL). After culture, cardiomyocytes were immuno-stained for Troponin T or Connexin-43, endothelial cells for CD31, basement membrane for collagen IV. From spinning disk images, cardiomyocyte volume, contraction and total length/ branches of capillaries were measured.

Results

: We first determine the best conditions allowing the generation of active cardiomyocytes and the formation of a network of mature capillaries into fibrin hydrogels. We showed that cardiomyocytes volume and contraction were not influenced by the addition of VEGF or insulin. For cells treated with VEGF for 24 hours, total length and total branches of capillaries were significantly increased over other conditions without supplements (control), or with insulin alone or with VEGF. We also observed lumen formation and basement membrane deposition.

Conclusions

These results may provide a new model of vascularized human heart tissue for in vitro studies, displaying cardiomyocyte contractility together with lumenized capillary formation. Furthermore, our data may help overcome current obstacles toward the success of cardiac cell therapy for damaged myocardium. In such approach, endothelial capillaries will serve as structural and trophic support through inosculation with the host cardiac vasculature after epicardial graft. As a perspective of this work, and in order to improve the cardiomyocyte alignment and the development of capillaries, we will design specific PDMS mold to allow the formation of a micro-tissue. Application of human cardiac cells and implantation in in vivo model is expected.

Acknowledgement/Funding

ESC research grant, Fondation de l'avenir, Societe Francaise de Cardiologie, Institut Servier
P4500Cellular senescence of endothelial cells impairs angiogenesis by altering energy metabolism through p53-tigar axis
Authors: Urata R , Ikeda K , Nakagawa T , Hoshino A , Honda S , Yagi N , Emoto N , Matoba S
Published: October 2019

Background

Ischemic disease is prevalent in elderly population due to impaired angiogenesis. Endothelial cell (EC) generates energy largely via glycolysis, which is further activated when angiogenesis actively occurs. PFK-1 is one of the most important regulatory enzymes for glycolysis, which is activated by PFKFB3. On the other hand, TIGAR inhibits PFK-1 under the control of p53. Crucial roles of PFKFB3 in EC functions under physiological and pathological conditions have been reported; however, a role of TIGAR in EC angiogenic functions remains to be elucidated. Furthermore, it remains unknown whether and how cellular senescence affect the energy metabolism in EC.

Purpose

The purpose of this study is to investigate molecular mechanisms underlying EC dysfunction associated with ageing, especially by focusing on endothelial energy metabolism.

Method and result

Senescent EC showed reduced glucose consumption assessed by [U-13C]-glucose tracer assay in association with increased expression of p53 and TIGAR. Angiogenic capacity assessed by tube-formation assay was reduced in senescent EC. Of note, either silencing of TIGAR by siRNA or lentivirus-mediated overexpression of PFKFB3 improved angiogenic capacity in senescent EC. These results collectively suggest that senescence impairs glycolysis in EC by activating p53-TIGAR axis, which leads to senescence-associated endothelial dysfunction. To analyze an impact of EC senescence in angiogenesis in vivo, we generated EC-specific progeroid mice in which dominant negative form of telomere repeat-binding factor 2 (TRF2) was overexpressed in EC under the control of the TIE2 promoter. After confirming EC-specific senescence in these endothelial progeroid mice, we generated hind-limb ischemia model. Recovery of blood flow assessed by laser doppler velocimeter was significantly impaired in endothelial progeroid mice, indicating that EC senescence is directly and causally implicated in age-related angiogenic dysfunction. Of note, genetic inactivation of TIGAR completely rescued the impaired ischemia-induced neovessel formation in EC-specific progeroid mice.

Conclusion

Using unique endothelial progeroid mice, we revealed that EC senescence is a bona fide risk for ischemic disease, largely by reducing glycolysis in EC through p53-TIGAR axis. Our data suggest that endothelial energy metabolism is an attracting therapeutic target for the prevention and/or treatment of ischemic diseases, especially in elderly population.
P4505VECTOR-HF: The first human experience with the V-LAP, a wireless left atrial pressure monitoring system for patients with heart failure
Authors: Sievert H , Di Mario C , Perl L , Meerkin D , Abraham W T
Published: October 2019

Background/Introduction

Invasive pressure-guided therapy has been shown to improve outcomes in patients with heart failure (HF). Thus far, only right-sided pressure sensors have shown clinical efficacy and safety. The Vectorious Medical Technologies V-LAP™ is a novel battery-less and wireless left-sided pressure monitoring system, directly assessing left-atrial pressure (LAP) in an ambulatory setting. In pre-clinical studies, it was shown to enable accurate and safe measurement of LAP. We hereby describe the first human experience with the device.

Methods

The V-LAP left atrial monitoring systEm for patients with Chronic sysTOlic and diastolic congestive heart failuRe first-in-human (VECTOR) study is a prospective, multicenter, single arm, open-label clinical trial to assess the safety, performance and usability of the V-LAP system in patients with heart failure. The V-LAP™ wireless sensor is implanted using a trans-septal access, under angiographic and echocardiographic guidance. The system includes an external unit, which both powers the implant and collects data via radio frequency communication upon activation, designed to be operated on a daily basis. We hereby describe the first cases, implanted in the CardioVascular Center, in Frankfurt, Germany.

Results

At this point in time, there have been two successful implantations of the V-LAP™, performed in two NYHA Class III patients. Both were admitted repeatedly for exacerbations of HF, and demonstrated elevated NT-ProBNP levels. They were therefore considered appropriate candidates for the monitoring system, to enable optimal medical therapy. The procedure was performed in a trans-femoral, trans-septal fashion, under mild sedation, with a successful implantation of a V-LAP™, and calibration for pressure measurement. There were no complications, data showed accurate LAP reading (Figure 1).

Conclusions

In the first-in-human cases, the implantation of the novel wireless left atrial pressure sensor V-LAP™ was feasible, safe, and showed good accuracy and precision. We now await both short and long-term efficacy and safety outcomes of the device, with the hopes of optimizing care according to ambulatory LAP data for patients with HF.

Acknowledgement/Funding

Vectorious Medical Technologies
P4515The aging heart failure patient: frailty and cognitive impairment more common than you would expect - baseline data of the heart-brain clinic
Authors: Kleipool E E F , Handoko M L , Van Rossum A C , Hornstra J M , Peters M J L , Liem S S , Muller M
Published: October 2019

Background

Heart failure (HF) is a cardiovascular disease that is increasing by epidemic proportions, largely due to an aging society and therapeutic advances in disease management. Because heart failure is largely a cardiogeriatric syndrome, age-related syndromes such as frailty and cognitive impairment are common in heart failure patients.

Purpose

To assess the prevalence and determinants of frailty and cognitive impairment in a HF population ≥60 years of age.

Methods

Data from n=236 patients with HF (77±9 years; 43% female) visiting the heart-brain clinic in Amsterdam in 2018–2019. HF severity was evaluated by NT-proBNP and NYHA-classification. Frailty was assessed using Fried's frailty criteria, cognition using the Montreal cognitive assessment (MoCa). Logistic regression analyses were performed to evaluate which variables were associated with frailty and cognitive impairment.

Results

Median (IQR) NT-proBNP was 2000 (876–3469) pmol/L, 38% of patients had NYHA III-IV. 51% of patients were pre-frail and 28% frail. 77% of the patients were (mildly) cognitive impaired. Age, NYHA-classification III-IV, NT-proBNP>2000 pmol/L and use of ≥10 drugs were associated with frailty; HR (95% CI): 2.0 (1.4–3.0) per 10 years, 3.4 (1.9–6.2), 1.8 (1.0–3.2) and 1.8 (1.4–3.3) respectively. Age was associated with cognitive impairment; HR (95% CI) 2.2 (1.4–3.6) per 10 years.

Figure 1

Conclusion(s)

Frailty affects almost a third of the patients with HF and is more prevalent in older patients and those with more severe HF. Screening for frailty and cognitive impairment should be part of the standard workup in older HF patients as frail and/or cognitively impaired HF patients are less likely to adhere to their HF treatment and more likely to be (re)admitted to hospital for HF.
P4532PR interval prolongation, still a marker of worse outcome in patients treated with cardiac resynchronization therapy
Authors: Van Stipdonk A M W , Dural M , Salden F , Ter Horst I A H , Crijns H J G M , Prinzen F W , Meine M , Maass A H , Vernooy K
Published: October 2019

Background

Patients without left bundle branch block (non-LBBB) generally derive little benefit from CRT. Recently, CRT has been suggested to be beneficial in patients with prolonged PR interval. However in the general HF population, the presence of prolonged PR interval is associated with worse outcome.

Purpose

To evaluate the association of a prolonged PR interval with clinical outcome in CRT-treated LBBB and non-LBBB patients.

Methods

Pre-implantation 12-lead ECGs from 1.245 consecutive CRT patients without atrial fibrillation from 3 implanting centres in the Netherlands were evaluated for the presence of LBBB QRS morphology and PR interval prolongation (≥230ms). The primary endpoint was the combination of left ventricular assist device implantation, cardiac transplantation and all-cause mortality.

Results

Patients with LBBB (n=620) showed a significantly shorter mean PR interval than non-LBBB patients (n=625) (187ms vs 198ms, p<0.001). Prolonged PR interval was found in 12.6% of patients with LBBB and 19.2% of non-LBBB patients (P<0.001). In non-LBBB patients with PR prolongation event rate was significantly higher (54 vs 34%, p<0.001). In LBBB patients there was a non-significant difference (28 vs 20%, p=0.1). Regression analyses (figure 1) showed similar results, with a significantly higher odds of experiencing an event in non-LBBB patients with PR prolongation (HR 2.24 [1.68, 2.99], p<0.001), and a trend to significantly higher odds in LBBB patients with PR prolongation (HR 1.61 [1.02, 2.56], p=0.04)

Figure 1

Conclusion

In HF patients treated with CRT, PR prolongation is negatively associated with long term clinical outcome. The association seems to be stronger in non-LBBB patients than in LBBB patients.

Acknowledgement/Funding

None
P4538Effect of risk of malnutrition on 30-day mortality among older patients with acute heart failure in emergency departments
Authors: Martin Sanchez F J , Llopis Garcia G , Cuesta Triana F , Matia Martin P , Llorens P , Miro O
Published: October 2019

Introduction

There is a need to explore the risk of malnutrition as a modifiable prognostic factor in order to establish routine screening of malnutrition in the emergency setting among older patients with acute heart failure (AH.

Objectives

To determine the impact of risk of malnutrition on 30-day mortality risk among older patients attended for AHF in the Emergency Department (ED).

Methodology

We performed a secondary analysis of the OAK-3 Registry including all consecutive patients ≥65 years attended with AHF in 16 Spanish EDs over a 2-month period (January-February 2016). Risk of malnutrition was defined by the Mini Nutritional Assessment Short Form (MNA-SF) <12 points. Unadjusted and adjusted logistic regression models were used to assess the association between risk of malnutrition and 30-day mortality.

Results

We included 749 patients (mean age: 85 (SD 6); 55.8% females). Risk of malnutrition was observed in 594 (79.3%) patients. The rate of 30-day mortality was 8.8%. After adjusting for MEESSI-AHF risk score clinical categories (model 1) and after adding all variables showing a significantly different distribution among groups (model 2), the risk of malnutrition was an independent factor associated with 30-day mortality (adjusted OR by model 1=3.4; 95% CI 1.2–9.7; p=0.020 and adjusted OR by model 2=3.2; 95% CI 1.1–9.2; p=0.030) compared to normal nutritional status.

Conclusions

The risk of malnutrition assessed by the MNA-SF is associated with 30-day mortality in older patients attended with AHF in EDs. Routine screening of risk of malnutrition may help emergency physicians in decision-making and establishing a care plan.

Acknowledgement/Funding

Spanish Ministry of Health and FEDER (PI 18/00456, PI 18/00393, PI 17/00972, PI17/1732, PI15/00773, PI15/01019, and PI11/01021)
P4545ACUTE HF score: a new multi-parametric score for the prognostication of acute heart failure
Authors: Mandoli G E , De Carli G , Pastore M C , Rizzo L , Nannelli C , Lunghetti S , D'Ascenzi F , Focardi M , Valente S , Mondillo S , Cameli M
Published: October 2019

Background

Prognosis of patients with acute heart failure (AHF) and different etiologies remains a challenging issue for the Cardiologist.

Purpose

We aimed to evaluate clinical and echocardiographic indexes and blood tests values of patients admitted to Intensive Care Unit (ICU) for AHF to test their capability to predict events at short-, medium- and long-term follow-up.

Methods

We retrospectively enrolled 830 patients who entered the ICU of our third-level hospital between 2010 and 2013 for AHF. Exclusion criteria included: active malignances, heart transplantation, patients with left ventricular assist device. We evaluated in each subject: cause of admission, medical history, chest congestion severity at admission, blood tests, echocardiographic parameters and administered drugs during in-hospital stay. Primary endpoints included: mortality rate at 30 days, 6 months and 5 years after dismission, days of ICU stay and cardiology ward stay. Indexes with statistical significance at univariate analysis, were then tested by multivariate analysis.

Results

The study population (average age 72.2±13 y) had an ejection fraction (EF) 36±12% at ICU admission. Best predictors of prognosis in the populations, after multivariate analysis, resulted to be: renal failure, EF, age, mitral regurgitation (MR) more than mild, use of non-invasive ventilation support during ICU stay, previous stroke or transient ischemic attack (TIA). With these indexes, we created a multi-parametric prognostic score composed by: 0.7*[age >76 years] + 1.4*[plasmatic creatinine >2mg/dl] + 0.8*[non-invasive mechanical ventilation] + 0.9*[previous stroke/TIA] + 0.8*[EF <30%] + + 0.7*[previous hospitalization for AHF] + 0.5*[moderate/severe MR]. According to the score, we stratified the population in 3 tertiles with increasing mortality risk: low if <1.5, medium if 1.5–3, high risk if >3 (Figure 1). At ROC curve analysis, the score showed a greater prognostic accuracy than each parameter (30 days AUC 0.75, 6 months AUC 0.78, 5 years AUC 0.79).

Figure 1

Conclusions

A combined clinical, humoral and echocardiographic score could represent a new tool in the prognostication of patients with AHF since the admission in ICU.
P4551Prognostic utility of Palliative Prognostic Index for prediction of 30-day and 1-year outcome in patients with acute decompensated heart failure
Authors: Sumi T , Umemoto N , Kajiura H , Inoue S , Iio Y , Shibata N , Sugiura T , Taniguchi T , Asai T , Yamada M , Shimizu K , Murohara T
Published: October 2019

Background

The prognosis of heart failure remains poor similar to the terminal cancer patients, although recent progress in medical treatment. Palliative Prognostic Index (PPI) is a widely used prognostic index for terminal cancer patients (PPI includes: Palliative Performance Scale, oral intake, oedema, dyspnea at rest and delirium), suggesting the short-term prognostic marker of terminal cancer patients.

Purpose

The purpose of this study was to evaluate the impact of PPI on 30-day mortality, 1-year mortality and 1-year events (including all-cause mortality, readmission due to heart failure and new onset of cerebral infarction after hospital discharge) among acute decompensated heart failure (ADHF) patients.

Method

Study subjects comprised of consecutive 764 patients who admitted due to ADHF and followed up for 1-year. PPI were calculated at the time of hospital admission. Study subjects were divided into two groups based on the PPI: L-PPI (PPI<6) and H-PPI (6≤PPI). We calculated the C-index, net reclassification improvement (NRI) and the integrated discrimination improvement (IDI) to evaluate the improvement of prediction ability on 30-day mortality.

Result

H-PPI showed significantly higher 30-day mortality than L-PPI [7.9% vs 2.0%, log rank p<0.001, Hazard retio (HR): 1.26, 95% confidential interval(CI): 1.14–1.37, p<0.001], 1-year mortality [20.0% vs 12.7%, log rank p=0.022, HR 1.15, 95% CI 1.09–1.21, p<0.001]and 1-year events [45.5% vs 31.1%, log rank p<0.001, HR 1.13, 95% CI 1.09–1.17, p<0.001]. Multivariate cox proportional hazard models adjusted with several covariates revealed that PPI was an independent predictor of 30-day mortality (HR: 1.23, 95% CI: 1.10–1.36, p<0.001), 1-year mortality (HR: 1.10, 95% CI: 1.04–1.16, p<0.001) and 1-year events (HR: 1.11, 95% CI: 1.07–1.15, p<0.001), respectively.

A reference model for prediction of 30-day mortality was determined including left ventricular ejection fraction and serum albumin concentration by multivariable logistic regression analysis. (P<0.05) (C-index: 0.720) Adding PPI to the reference model (C-index: 0.773) significantly improved both NRI (0.458, p=0.038) and IDI (0.046, p=0.007), respectively.

Conclusion

We suggest that assessment of PPI showed good prognostic ability for 30-day and 1-year outcome, while PPI provided additional prognostic information in patients with ADHF.
P4552The prognostic impact of worsening and improved renal function in acute decompensated heart failure with and without plasma volume expansion
Authors: Kawai T , Yamada T , Morita T , Furukawa Y , Tamaki S , Iwasaki Y , Kawasaki M , Kikuchi A , Seo M , Fukunami M
Published: October 2019

Background

Recent studies showed that both worsening renal function (WRF) and improved renal function (IRF) during hospitalization are associated with poor prognosis in patients with acute decompensate heart failure (ADHF). On the other hand, plasma volume (PV) expansion plays an essential role in ADHF. However, there is little information about the difference of prognostic impact of WRF and IRF in ADHF patients, relating to PV status (PVS).

Methods

We prospectively studied 348 patients admitted for ADHF. PVS was defined as follows: actual PV = (1 - hematocrit) × [a + (b × body weight)] (a=1530 in males and a=864 in females, b=41.0 in males and b=47.9 in females); ideal PV = c × body weight (c=39 in males and c=40 in females); and PVS = [(actual PV - ideal PV)/ideal PV] × 100 (%). WRF and IRF were defined as an increase and a decrease in serum creatinine of ≥0.3 mg/dl from admission to discharge, respectively. The endpoint was readmission for worsening heart failure (WHF) within 1 year.

Result

Median PVS was 6.7% (IQR: −4.1%–16.7%). 43 and 21 patients had WHF in groups with high PVS (PVS ≥ median) and low PVS (PVS > median), respectively. In high PVS group, multivariate Cox analysis showed that IRF was independently and significantly associated with WHF (p=0.016, HR: 2.4 [1.2–4.8]), but WRF was not (p=0.55, HR: 0.7 [0.3–2.1]). On the other hand, in low PVS group, WRF was independently associated with WHF (p=0.035, HR: 3.0 [1.1–8.1]), but IRF was not (p=0.27, HR: 2.1 [0.6–8.0]). Kaplan-Meier analysis revealed that only patients with IRF had a significantly higher risk of WHF than those with stable renal function (SRF) in high PVS group, while patients with WRF had a significantly higher risk of WHF than those with SRF in low PVS group.

Worsening heart failure-free rate curves

Conclusion

In ADHF patients with PV expansion, IRF during hospitalization could predict poor outcomes, but WRF could not. On the other hand, in ADHF patients without PV expansion, not IRF but WRF could predict poor outcomes. PVS guided-therapy may be considered in secondary prevention for WHF.
P4554Central-acting aminopeptidase a inhibitors for new treatment of hypertension: from discovery to clinical trial
Authors: Llorens-Cortes C , Marc Y , Hmazzou R , Keck M , Flahault A , Roques B P , Balavoine F , Azizi M
Published: October 2019

The hyperactivity of the brain renin–angiotensin system (RAS) has been implicated in the development and maintenance of arterial hypertension (HTA).

Our aim was to demonstrate that normalizing brain RAS hyperactivity could constitute a new therapeutic approach for HTA treatment

We first demonstrated in the brain that aminopeptidase A (APA) is the enzyme generating angiotensin III (AngIII) from AngII. Then, using the specific and selective APA inhibitor, EC33 ((3S)-3-amino-4-sulfanyl-butane-1-sulfonic acid), we showed that AngIII is one of the main effector peptides of the brain RAS, exerting a tonic stimulatory control over blood pressure (BP) in hypertensive rats. This suggests that brain APA may be a potential therapeutic target for HTA treatment. We then designed RB150 {4,4-dithio[bis(3-aminobutyl sulfonic acid)]}, an orally active prodrug of EC33. RB150, given orally in conscious deoxycorticosterone acetate-salt (DOCA-salt) rats or spontaneously hypertensive rats, crosses the intestinal, hepatic and blood-brain barriers, enters the brain, where it is cleaved by brain reductases, generating two active molecules of EC33 which inhibit brain APA activity, block the formation of brain AngIII and induce a marked and sustained decrease in BP. The RB150-induced BP decrease is due to a reduced vasopressin release, which increases diuresis, reducing extracellular volume, a decrease in sympathetic tone, leading to a reduction of vascular resistances and the improvement of the baroreflex function (Figure below). RB150 was renamed firibastat by OMS. Phase Ia/Ib clinical trials showed that firibastat is clinically and biologically well-tolerated in healthy volunteers.

Firibastat could constitute the first drug candidate of a new class of antihypertensive agents targeting the brain RAS, the clinical efficacy of which (Phase IIa and Phase IIb) in hypertensive patients was achieved.

Acknowledgement/Funding

INSERM, College de France, ANR LabCom, Quantum Genomics
P4558Hemodynamic management of resistant hypertension
Authors: Chacon-Lozsan F J , Rojas R , Rodriguez M
Published: October 2019

Background

Hypertension is the most prevalent chronic disease worldwide and is is related with high probability of cardiac disease, kidney disease and cerebrovascular events. Blood pressure measurement was used in the last decades to diagnose and guide antihypertensive therapy; however blood pressure is the result of interaction of more complex hemodynamic parameters previously reserved to experimental studies or critical care patients management using invasive methods. Since 1996 few studies has proposed the use of hemodynamic parameters to classify and guide hypertension therapy with good results.

Purpose

The present study purpose was to measure hemodynamic parameters in patients with non-controlled resistant hypertension and use it to guide pharmacologic treatment in order to archive control blood pressure values according to the European Society of Cardiology guidelines.

Methods

A total of 84 patients between 32 and 95 years old diagnosed with non-controlled primary resistant hypertension were recruited and after previous therapy washout hemodynamic parameters were measured using noninvasive methods: preload by central venous pressure (CVP) using inferior vena cava diameter, cardiac index and systemic vascular resistance using Lyljestrand & Zander modified formula. Patients were classified in 3 basic groups depending on which parameter was above normal value: hyperdynamic (HD) for high cardiac index >3.5 L/min/m2, fluid overload (FO) for CVP >8cmH2O and high systemic vascular resistance index (HSVRi) >2500 dynes/sec/m2/cm–5, also 3 combined groups were a patient had 2 simultaneous hemodynamic alterations (HD+FO, HD+HSVRi and FO+HSRVi), according to this classification pharmacotherapy was guided indicating Bisoprolol in HD group, Amlodipine to HSVR patients and Hydrochlorothiazide to FO patients, in combined groups, combined therapy was given. Patients were observed for 6 months period taking as primary endpoint blood pressure control, acute cardiovascular events and hypotension.

Results

A significant reduction of hemodynamic parameters and blood pressure was observed since the first month of treatment obtaining a 100% hemodynamic and blood pressure goals in all patients at the third month of therapy without hypotension or acute cardiovascular event during this period, the HD+FO group reach goals at the 6th month of treatment without reported complications.

Conclusions

In this preliminary studied we observed that hemodynamic guided high blood pressure control may be a useful tool to a better understanding, classifications and treatment in patients with resistant hypertension; however a larger outcome studies to confirm this hypothesis.
P4562Bilateral sphenopalatine ganglion block reduces blood pressure in never treated hypertensive patients. A randomized controlled study
Authors: Triantafyllidi H , Arvaniti C , Schoinas A , Benas D , Voutsinos D , Ikonomidis I
Published: October 2019

Background

Sphenopalatine ganglion (SPG) area is connected through sympathetic fibers with the central nervous system. We aimed to study the effect of SPG block in blood pressure (BP) in never treated patients with stage I-II essential hypertension.

Methods

We performed bilateral SPG block with lidocaine 2% in 53 newly diagnosed and never treated hypertensive patients (study group, mean age 49+12 years, 38 men) and a sham operation with water for injection in 11 patients (control group, mean age 51+12 years, 8 men). All patients have been subjected to 24 hour ambulatory blood pressure monitoring prior and a month after the SBG block in order to estimate any differences in blood pressure parameters derived from ABPM (blood pressure, heart rate, blood pressure load and variability). We defined as responders to SBG block those patients with a 24h average SBP decrease >5 mmHg.

Results

In the study group, a month after SPG block: a. 24h average SBP and DBP were reduced by 1.3+7mmHg and 1.8+5 mmHg, respectively, and b. 24h average DBP (p=0.03), daytime DBP (p=0.01) and daytime DBP load (p=0.01) were significantly decreased. Interestingly, in the responders group (14/42, 33%) a month after SPG block: a. 24h average SBP and DBP were reduced by 9+4mmHg and 6.5+3 mmHg, respectively, b. SBP and DBP were decreased during overall 24h and daytime (p<0.001) and night-time periods (p=0.002 and p=0.02, respectively) and c. SBP load was decreased during daytime and night-time while DBP load was decreased during daytime (p<0.001). As it was expected, no differences regarding BP were found in the sham operation group.

BP decrease after SPG block

Conclusions

We have proved that the minimally invasive option of the SPG block leads to blood pressure decrease, probably through SNS modulation. Moreover, due to its short-term anesthetic effect, SPG block might act as a method of selection of those hypertensives with an activated SNS before any other invasive procedure.