bluuebunny/crossref_metadata_2025 huggingface dataset:
P6287Analysis of novel cardiac markers sST2 and IL-33 in chronic heart failure with reduced ejection fraction
Authors: Jirak P , Lichtenauer M , Wernly B , Paar V , Jung C , Yilmaz A , Hoppe U , Schulze P C , Kretzschmar D , Pistulli R
Published: October 2019

Background

Soluble (s) ST-2 has been recently evaluated as a monitoring parameter in heart failure (HF). Besides being a marker for cardiac strain and hemodynamic stress, studies also found an influence of ST2 on the immune system, above all mediated through its Janus-Face ligand IL-33, an alarmin released under stress conditions or by cellular death. In contrast to sST2, the role of IL-33 in HF is yet unknown.

Objective

In this project, we aimed for an analysis of the ST2/IL33 pathway in patients with heart failure with reduced ejection fraction (HFrEF).

Methods

In total, 200 patients were included in the study: 59 with ischemic (ICM), 65 with dilated (DCM) cardiomyopathy (mean LVEF 38%), as well as 76 control patients without coronary artery disease or signs of heart failure. Serum samples were analyzed by use of ELISA after informed consent.

Results

sST2 showed a significant elevation in all HF patients (p<0.0001) compared to the control group. No significant differences in levels of sST2 were observed between ICM and DCM patients. In contrast to sST2, no differences between HF patients and control group were observed for IL-33. Furthermore, sST2 showed a significant correlation with CRP (p<0.001, r=0.28), NT-pro-BNP (p<0.0001, r=0.40) and an inverse correlation with ejection fraction (p<0.0001, r=−0.40). Additionally, sST2 showed a significant elevation in patients in NYHA stages I-II (p=0.030) and NYHA stages III-IV (p<0.01). Again, no significant correlations were observed between IL-33 and parameters mentioned above.

Analysis of sST2 in heart failure

Conclusions

We observed a significant increase and correlation with disease severity of sST2 in chronic HFrEF patients of both ischemic and non-ischemic origin, but contrary to our expectations, no significant changes in serum levels of IL-33. Thus, a mechanism independent of ST2/IL33 axis could be responsible of sST2 secretion in HF. Further studies including acute decompensated patients could provide a better understanding of the IL-33 role in HF.
P6289Neuregulin-1 improves cardiac function through protecting the loss of endothelial barrier in septic rats via RhoA/ROCK pathway
Authors: Wang L O N G , Kang W E N , Cheng Y U E , Wang X I
Published: October 2019

Background

The main path of sepsis-induced cardiomyopathy is the loss of endothelial barrier function. Neuregulin-1 (NRG-1) has beneficial effects on endothelial function.

Purpose

To investigate the effect of NRG-1 treatment on the protection of cardiac endothelial cells and the changes of RhoA/ROCK signaling in sepsis.

Methods

Rats were randomly divided into three groups: sham, LPS, and NRG-1. After successful induction of sepsis by lipopolysaccharide (LPS, 10mg/kg), rats were administered either a vehicle or recombinant human neuregulin-1 (rhNRG-1, 10μg/kg/d) for one or two days. We recorded their survival rate at 48h after sepsis. Hemodynamic methods were performed to assess cardiac function. We used immunofluorescence assay to detect von Willebrand Factor (vWF). Intercellular adhesion molecule-1 (ICAM-1) and vascular endothelial growth factor (VEGF)levels in serum were measured by enzyme-linked immunosorbent assay (ELISA), and serum nitric oxide (NO) was detected by reductase method. We used transmission electron microscopy to observe changes in myocardial ultrastructure and western blot to assess expression of RhoA and ROCK1 protein.

Results

Sepsis impaired endothelial function manifested by increased ICAM-1, NO and VEGF levels in serum, NRG-1 treatment could significantly alleviate these increase (P<0.05). Compared with the vehicle, NRG-1 significantly decreased cardiac vascular permeability through increasing the expression of vWF on endothelial lining (P<0.05). Moreover, NRG-1 alleviated damages of ultrastructure of myocardial cells and suppressed the expression of RhoA and ROCK1 protein (P<0.05). Ultimately, NRG-1 improved the survival,and prevented hemodynamic derangement.

Levels of endothelial biomarker in serum ICAM-1 (pg/ml) VEGF (pg/ml) NO (pg/ml) Sham 24h 1564.74±94.41 0.84±0.28 203.27±1.81 Sham 48h 322.92±7.92 1.78±0.61 6.57±0.38 LPS 24h 5139.85±284.15† 3.11±0.04† 679.05±78.59† LPS 48h 950.41±25.23†‡ 4.65±0.30† 180.40±30.08†‡ NRG 24h 2772.18±164.45§ 0.30±0.04§ 355.14±23.41§ NRG 48h 578.57±28.97§‡ 1.02±0.45§ 104.67±2.13§‡ †p<0.05 vs. the sham group, §p<0.05 vs. the LPS group and ‡p<0.05 vs. the 24h group.

Effect of NRG-1 on endothelial cells

Conclusions

NRG-1 could alleviate endothelial injury in sepsis by strengthening the barrier function of vascular, reducing the secretion of endothelial-related biomarkers and inhibiting oxidative stress, thus improving cardiac function and survival rate, these effects may base on RhoA/ROCK signaling pathway. These may contribute to reverse the impaired endothelial cells in sepsis in the future.

Acknowledgement/Funding

The national natural science foundation of China (81772044)
P6292Role of CXCL12gamma isoform and its interactions with heparan-sulfates in post-ischemic cardiac remodeling
Authors: Duval V , Zlatanova I , Sun Y , Alayrac P , Gomez I , Lemitre M , Vilar J , Silvestre J S , Levoye A
Published: October 2019

Introduction

Myocardial infarction (MI) is a severe ischemic disease precipitating long-term adverse remodeling and heart failure. The chemokine CXCL12/SDF-1 is essential for cardiovascular system development and plays a prominent role in physio-pathological processes such as inflammation, angiogenesis and tissue fibrosis. In addition to the binding to its cognate receptors CXCR4 and CXCR7, CXCL12 interacts with heparan-sulfates (HS) which coordinate its biological activity. We have previously highlighted the essential role of CXCL12/HS interactions in vascular growth and remodeling in the setting of critical limb ischemia. In addition, studies in experimental model of MI revealed a protective role for the CXCL12α isoform, through the regulation of cardiomyocyte survival and recruitment of inflammatory cells. However, in mice, three CXCL12 isoforms (α, β and γ) have been identified and, among them, the CXCL12γ isoform shows an unchallenged ability to cooperate with HS, suggesting a putative pivotal role in tissue repair.

Objectives

The aim of the study is to analyze the role of CXCL12γ isoform and the importance of CXCL12/HS interactions in post-ischemic cardiac remodeling in an acute model of MI.

Methods

MI was induced by permanent ligation of the left ascending coronary artery in mice carrying a Cxcl12 gene mutation that precludes interactions with HS (Cxcl12Gagtm) and in Cxcl12γ knock-in animals (Cxcl12γ-KI) harboring CXCL12γ deficiency. Alternatively, the impact of CXCL12γ overexpression and the importance of its interactions with HS was also evaluated in wild-type (WT) mice receiving transcutaneous echo-guided injections of adenovirus encoding WT Cxcl12γ or HS-binding-disabled Cxcl12γ in cardiac tissue. Cardiac function and remodeling have been assessed through echocardiography analysis, evaluation of infarct size, interstitial fibrosis, vascular growth (capillary and arteriole densities) and inflammatory cell infiltration into the cardiac tissue.

Results

After MI, Cxcl12Gagtm and Cxcl12γ-KI animals exhibit reduction in cardiac function and adverse left ventricular remodeling when compared to their respective WT littermates. Interestingly, overexpression of CXCL12γ in WT mice cardiac restored cardiac function by reducing the size of the infarcted area, interstitial fibrosis and promoting vascular growth. In sharp contrast, HS–binding disabled CXCL12gamma mutants failed to improve cardiac function and to abrogate adverse left ventricular remodeling.

Conclusion

We show that CXCL12γ isoform plays an important role in the regulation of post-ischemic cardiac function and remodeling and that its interactions with HS are essential for adequate cardiac repair in the setting of acute MI.
P6298Pericardial transplantation of adipose-derived stromal cells with self-assembling peptides scaffold prevents cardiac remodeling after myocardial infarction in mice
Authors: Kondo N , Nagai T , Aoki I , Kanda M , Takahashi T , Kobayashi Y
Published: October 2019

Introduction and purpose

Cardiac cell therapy to patients with heart failure after myocardial infarction (MI), has shown little improvement in cardiac function. The rate of engraftment after cell transplantation (TX) to the ischemic heart is low because of the leakage of transplanted cells without scaffold, the friction between the graft and thorax, and poor vascularization to the graft. We created a novel TX method (Figure 1) to transplant adipose-derived stromal cells (ASCs) with scaffold into the pericardial space where the pericardium protected the graft. We evaluated the therapeutic efficacy of pericardial TX of ASCs on the cardiac function and remodeling after MI.

Methods

We isolated ASCs from the brown adipose tissue of donor mice (C57BL6-Tg (CAG-EGFP), five weeks). ASCs increased and differentiated into spontaneously beating myocytes, endothelial cells, and pericytes three weeks after ex vivo culture. Cells were trypsinized and mixed with self-assembling peptides scaffold. Each graft (100μl gel scaffold) had 1×106 ASCs. To make recipient MI mice (C57BL6, 12 weeks), we ligated the left coronary artery through small chest incision without cutting rib bone to avoid postoperative adhesions. We confirmed the deterioration of cardiac function by echocardiography (n=21) and MRI (n=4) three weeks after MI. Then, recipient MI mice had TX (syngeneic, no immunosuppression). We opened the pericardium and transplanted the graft into the pericardial space. By suturing the pericardium, the graft was fixed on the MI scar area (Figure 1). We labeled donor cells with GFP and the scaffold with biotin. We evaluated cardiac function of TX group (n=10) and control group (MI with sham TX, n=11) by echocardiography.

Results

In the scaffold, donor cells increased three days to two weeks after TX, and slightly decreased four weeks after TX. The graft thickness was 0.9±0.2mm (two weeks after TX) and 0.7±0.2mm (four weeks after TX). There were many vWF positive vessels in the scaffold and some of which were GFP positive. Echocardiography showed that left ventricular diastolic dimension (LVDd) of TX group, did not increase four weeks after TX (ΔLVDd = −0.02mm, P=0.80). While, LVDd of control group significantly increased (ΔLVDd = +0.23mm, P=0.02) due to cardiac remodeling after MI. MRI confirmed the increase in left ventricular wall thickness in the MI scar area up to 4 weeks in TX group (n=2).

Conclusions

Pericardial transplantation of ASCs prevents cardiac remodeling. Its beneficial effect might be mediated by improved rate of engraftment, neovascularization, and increased ventricular wall thickness in the MI scar area.

Acknowledgement/Funding

Grants-in-Aid for Scientific Research
P6303Developmental origin of cardiac macrophages in steady state and myocardial infarction
Authors: Weinberger T , Thaler R , Schneider V , Messerer D , Massberg S , Schulz C
Published: October 2019

Background

Macrophages are the most abundant immune cells in the myocardial tissue in steady state. The sterile inflammation caused by myocardial infarction triggers a massive immune reaction, which leads to a profound influx of neutrophils and monocytes. In the postacute phase of infarction macrophages play an essential role in reparative processes. Recently, it has become clear that macrophages in the heart have a dual developmental origin from embryonic and bone marrow (BM) hematopoiesis. In this study, we sought to investigate the contribution of embryonic derived macrophages to the cardiac macrophage pool in steady state as well as the acute and chronic phase after ischemia/reperfusion injury.

Methods/Results

To address the origin of macrophages in steady state we used different models of lineage tracing to determine the developmental origin of cardiac macrophages. Using FLT3-Cre mice and radiation-independent CD45.1/.2 bone marrow chimera, we found that the resident macrophage population in the heart is mainly independent of definitive hematopoiesis (approximately 70–80% of cardiac macrophages). The BM-dependent population on the other hand is replenished by blood-derived monocytes.

Further we used the radiation-independent CD45.1/.2 bone marrow chimera to characterize the origin of macrophages at different time points after I/R-injury. In the acute phase after myocardial infarction we observed a profound influx of BM-derived macrophages in the infarct region and also in the remote area. 30 days after I/R-injury the composition of the resident macrophage pool was mainly comprised of BM-independent macrophages, similar to steady state conditions. To address the role of BM-derived macrophages we used CCR2-ko mice, which have low numbers of inflammatory monocytes in peripheral blood. CCR2-ko mice showed reduced macrophage numbers in the acute phase after myocardial infarction. Using positron emission tomography we investigated the influence of CCR2-deficiency on cardiac function after I/R-injury. In comparison to WT mice, CCR2-ko mice showed a significantly increased infarct size. Cardiac remodeling, determined by end-diastolic volume, on the other hand was improved in CCR2-ko mice. The ejection fraction was similar in both groups.

Conclusion

The cardiac macrophage pool is mainly comprised of BM-independent macrophages. In response to I/R-injury monocyte-derived macrophages transiently enter the myocardium but do not persist in significant numbers over time. The influx of BM-derived macrophages after I/R-injury was reduced using CCR2-ko mice, which led to improved cardiac remodeling.

Our findings are of potential importance for understanding the cardiac immune response and for the therapeutic targeting of macrophages in inflammatory conditions.

Acknowledgement/Funding

German Society of Cardiology, German Centre for Cardiovascular Research, LMU Excellence, SFB 914
P6314Left- versus Bi-Ventricular Assist Device-mediated anti-HLA alloantibody induction in bridge-to-transplantation patients
Authors: Armenis I , Chaidaroglou A , Bonios M , Leontiadis E , Gkouziouta A , Kogerakis N , Fragkoulis S , Zarkalis D , Stavridis G , Degiannis D , Adamopoulos S
Published: October 2019

Background

Presence of anti-Human Leukocyte Antigen (anti-HLA) alloantibodies (allosensitization) in a heart transplantation candidate impedes the chance of finding a compatible transplant. Left Ventricular Assist Devices (LVADs) have been shown to induce allosensitization.

Purpose

The purpose of this study is to characterize anti-HLA allosensitization in adult patients receiving left (LVAD) versus biventricular- (BiVAD) assist devices as bridge to transplantation (BTT).

Methods

This study retrospectively assessed anti-HLA antibody induction in all adult patients who have received either LVAD or BiVAD as BTT at our institution. Anti-HLA alloantibody screening was performed before, and at multiple time-points after VAD implantation. Anti-HLA antibody detection was performed with a cytotoxic panel-reactive antibody (PRA) method until 2003, enzyme-linked immunoassay (ELISA) method from 2003 to 2005 and SAB assays on the Luminex platform from 2005 to 2017. Sensitization was defined either as PRA >10%, or as peak anti-HLA antibody mean fluorescence intensity (MFI) values of more than 1000. Baseline characteristics and sensitization in the two patient groups were evaluated using descriptive statistics.

Results

Between 2003 and 2018, 154 patients were placed on VAD support at our institution as BTT. Sensitization data were available for 130 patients. Fifty five (36.6%) patients were supported with an LVAD (median age, 48 years, 26% female) and 95 (63.4%) with a BiVAD (median age, 45 years, 28% female). Twenty-five (45.4%) of the LVAD and 49 (51.2%) of the BiVAD patients were eventually transplanted (p=0.47) with an average time to transplantation 588 and 562 days respectively. Fifteen (27.2%) LVAD and 35 (36.8%) BiVAD patients died before transplantation (p=0.23) with an average time on VAD support before death 269 and 302 days respectively. Evidence of sensitization pre-VAD was found in 17.1% of the LVAD and 12.5% of the BiVAD patients (p=0.53); these percentages rose to 40.0% (p=0.001) and 43.7% (p=0.0001) respectively at 2 to 12 months post-VAD implantation. However, the post-VAD allosensitization status was not statistically different between the LVAD and the BiVAD group. Among the 25 LVAD patients who were transplanted 7 (30.4%) were sensitized immediately before transplantation, compared to 22 (46.8%) out of 49 BiVAD patients (p=0.16).

Conclusion

Both LVADs and BiVADs are a factor of de novo anti-HLA antibody development in adult patients after implantation. Sensitization pattern does not seem to differ between LVAD and BiVAD patients. Additionally, patients supported by LVAD or BiVAD have similar chances of finding a suitable donor heart.
P6327Non-terminating ventricular arrhythmias during exercise testing reflect poorer prognosis and advanced disease severity in heart failure regardless of ejection fraction
Authors: Popovic D , Guazzi M , Arena R
Published: October 2019

Introduction

Electrocardiography is an integral component of cardiopulmonary exercise testing (CPET), a standard of care in patients with heart failure (HF). We hypothetized that ventricular arrhythmias during CPET that do not meet test-termination criteria (NTVA) set forth by current guidelines may help in phenotyping disease severity and prognosis in HF with either reduced (rEF), and mid-range (mrEF)/preserved (pEF) left ventricular (LV) ejection fraction.

Methods

319 patients with HF (199 HFrEF; 80 HFmrEF; 41 HFpEF) underwent CPET. Tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PASP) were measured by echocardiography. B-type natriuretic peptide (BNP) at rest and peak exercise were also determined. The patients were tracked for the primary [cardiac death] and secondary composite outcome [all-cause death, heart transplantation/left ventricular assist device implantation, hospitalization for cardiac reasons].

Results

47 (15%) of the patients demonstrated NTVA during CPET, regardless of coronary artery disease prevalence. Patients without arrhythmias had a significantly higher LVEF (p<0.05), TAPSE/PASP ratio (p<0.001), peak oxygen consumption (p<0.01), lower resting and peak BNP (p<0.001) and the minute ventilation/carbon dioxide production slope (p<0.001) compared to those with NTVA. 71 patients died during the tracking period, 54 for cardiac reasons. NTVA during CPX were a significant predictor of primary and secondary outcome in all patients with HF (HR: 5.3, 3.7; 95% CI: 3.1–9.1, 2.4–5.5, p<0.001, respectively) as well as in subgroups categorized according to reduced, middle range and preserved LVEF (p<0.001).

Conclusion

These results indicate that exercise-induced ventricular arrhythmias not reaching criteria for test termination are nonetheless indicative of an advanced disease severity phenotype and worse prognosis.
P6333Therapy-induced weight gain is associated with higher appendicular muscle mass in patients with heart failure
Authors: Stefaniak A , Ostrega W , Buczkowska M , Mroczek A , Zbrojkiewicz E , Niedziela J , Nowak J U , Gasior M , Leszek P , Rywik T , Rozentryt P
Published: October 2019

Background

The catabolic predominance in acute heart failure (HF) leads to significant weight loss. The low body weight before HF (preHF) and the loss during its natural course, both are risk factors of sarcopenia and worse clinical outcome in HF. Modern therapy can inhibit or even reverse catabolism resulting in oedema-free weight gain. It is unknown if therapy-induced weight gain can protect against low appendicular skeletal muscle mass (ASM) – the key prerequisite of sarcopenia.

Aims

We intended to assess whether therapy-induced oedema-free weight gain protects against low ASM.

Material and methods

In 802 patients with HF (age: 52±10 years 13% women, LVEF: 24±7%, NYHA: 2.6±0.7), we analysed weight changes from preHF to minimal oedema-free weight during HF (minHF), and then weight occurring after removal of all reversible factors aggravating HF with optimisation of therapy (indexHF). At index date we performed dual X-ray densitometry (DXA) calculating ASM as the sum of lean mass within the legs and arms adjusted to body size. The low ASM was defined as ≤7 and 6 kg/m2 in men and women respectively. The catabolic (C) and anabolic (A) components of weight change ware calculated based of formulas: C=100*(minHF-preHF)/preHF, A=100*(indexHF-minHF)/minHF. Using logistic regression we estimated the risk of low ASM after adjustment for potential confounders.

Results

The median C and A were −11.7% and 3.3% respectively. The low ASM was found in 230 (28.7%) patients. In multivariable model comprising age, gender, weight preHF, C and A, the odds for low as compared to normal ASM are shown in table 1.

Odds ratio ± 95% CI Normal ASM Low ASM Gender (man v. women) 1.0 0.87 (0.81–0.94), p=0.0002 Weight preHF (per 1 kg/m2 increase) 1.0 0.85 (0.83–0.87), p<0.0001 Age (per 5 years increase) 1.0 1.05 (1.02–1.08), p=0.0003 C (per 1% increment) 1.0 1.05 (1.04–1.06), p<0.0001 A (per 1% increment) 1.0 0.98 (0.97–0.99), p<0.0001

Conclusions

In HF higher body weight preHF and oedema-free weight gain decreases the risk of low ASM independently of age, gender and weight loss.
P6334Daily body weight in patients with chronic heart failure: improved diagnostic value by analysing prolonged time intervals
Authors: Gudmundsson K , Lynga P , Langius-Eklof A , Hagglund E , Hagg-Martinell A , Persson H , Hagerman I , Braunschweig F
Published: October 2019

Background

Daily body weight (BW) is a mainstay in the management of patients with chronic heart failure (HF). Guidelines recommend to take action if BW increases more than 2kg within 3 days. However, the evidence behind the 2kg/3d rule is unclear and studies have shown poor diagnostic performance of this algorithm.

Purpose

To assess the diagnostic value of different BW thresholds and time intervals to alert for imminent HF decompensation.

Methods

We studied 184 patients with HF (age 71±10 yr, EF 26±11%). 43% had been hospitalized for HF during the preceding year. They were assessed by daily BW using digital scales with direct data transfer to a central data base. The mean follow-up was 286 days.

To decrease day-to-day variability, BW was analysed based on a daily moving average over 3 days. We retrospectively calculated the sensitivity and false-positive rate of BW thresholds at 1.5, 2.0, 2.5, 3.0 and 3.5 kg and time intervals between 2 and 30 days. Threshold crossings occurring within 30 days prior to a hospitalization for decompensated HF were deemed a positive alert.

Results

The sensitivity of 2kg/3d was poor (13%). Prolonging the time interval of weight changes markedly improved sensitivity. Increasing the weight threshold decreased the false positive rate. Greatest sensitivity (60%) was achieved using a 14 day interval at a weight threshold of 1.5 kg. However, this was associated with a high rate of false alerts (3.1 per patient/year). A weight threshold of 3.5 kg resulted in excellent specificity (0.3 false alerts per patient/year), however sensitivity was low (20%, 20 day time interval).

Conclusion

Monitoring daily BW using a 2kg/3d algorithm is associated with poor diagnostic performance. Generally, by analyzing stable trends over time (moving average) and using prolonged time intervals, BW monitoring with digital scales can achieve a clinically meaningful diagnostic performance. This new approach to BW monitoring may improve early detection of imminent HF decompensation.
P6341Impact of left-ventricular hemodynamics on treadmill exercise intolerance in conscious rats: pilot evaluation in animals with diastolic dysfunction
Authors: Ferguson B S , Bennett N , Zambataro C , Shimkunas R , Del Rio C L
Published: October 2019

Introduction

Exercise intolerance is a clinical hallmark of patients with hypertrophic cardiomyopathy and/or impaired diastolic function. Elevated LV filling pressures, particularly in response to acute exercise bouts, are thought to play a role limiting exercise capacity in ventricles with abnormal relaxation/compliance. However, it is experimentally difficult to obtain in vivo hemodynamic measures necessary for the evaluation of centrally mediated dysfunction. Leveraging radio-telemetry, we evaluated central hemodynamic parameters as mediators of exercise intolerance in obese ZSF1 rats with diabetes, hypertension, and diastolic dysfunction.

Methods

Both ZSF1 (637+12g, n=8) and age-matched (28 weeks) healthy control (CTRL, 543+14g, n=4, P<0.05) rats were instrumented for telemetric left-ventricular pressure (LVP) recordings. Following surgical recovery rats were familiarized to treadmill running and subsequently challenged with an exercise protocol aimed at increasing heart rate by 200 beats/min (5° incline, 15 m/min, increased by 3 m/min every 2-min) until volitional exhaustion. LV pressures were collected continuously during cage resting, treadmill resting, and post-exercise until heart rate returned to baseline. Additionally, resting echocardiographic and blood glucose measures were collected.

Results

At rest, ZSF1 rats had preserved ejection fraction (73+6 vs 79+9%), elevated (P<0.05) blood glucose (237+83 vs 94+23 mg/dL), end-systolic (147+18 vs 103+13 mmHg), and end-diastolic pressures (16+3 vs 9+3 mmHg), with preserved indexed end-diastolic volumes (670+95 vs 741+89 μL/kg), suggesting impaired diastolic compliance. ZSF1 rats terminated exercise prematurely (8:26+1:20 vs 10:27+1:18 min, P<0.05), indicating a limitation in exercise capacity. This early volitional exhaustion was noted while end-diastolic pressures were not further increased (17+7 mmHg), suggesting that other pathological derangement may play a role modulating exercise capacity. For instance, ZSF1 rats tended to have a blunted increase in the systolic index dP/dt40 (+2589+1450 vs +3938+749 mmHg/s, P<0.1) despite achieving comparable increases in HR (193+34 vs 196+38 bpm) with exercise.

Conclusion

This pilot study demonstrates the feasibility for evaluation of left-ventricular hemodynamics during exercise in rodents with diastolic dysfunction, establishing a platform to evaluate both the mechanisms of exercise intolerance as well as potential therapeutic approaches to rescue exercise capacity.

Acknowledgement/Funding

MyoKardia
P6342Subcutaneous delivery of NPA7, first-in-class novel bispecific designer peptide: enhances cardiorenal function and suppresses renin and aldosterone in vivo and in vitro
Authors: Sugihara S , Ichiki T , Chen Y , Harty G J , Heublen D M , Iyer S R , Huntley B K , Pan S , Sangaralingham S J , McCormick D J , Burnett J C
Published: October 2019

Introduction

The rapid increase of patients of heart failure (HF) is a major health burden worldwide. Most importantly is the need to develop innovative new drugs for treatment of HF, such as sacubitril/valsartan which in part functions by enhancing the natriuretic peptides (NPs). We engineered NPA7 as a novel 30 amino acid bispecific designer peptide which activates the particulate guanylyl cyclase A receptor (pGC-A)/cGMP and for which the NPs both ANP and BNP are ligands and the Mas-receptor (MasR)/cAMP pathways for Angiotensin 1–7 (Ang1–7) is the endogenous ligand. We previously reported that acute intravenous (IV) administration of NPA7 shows cardiorenal protective and renin-aldosterone suppressing actions that go beyond the native peptides, BNP or Ang 1–7, which may have therapeutic potential for HF.

Purpose

To support the clinical development of NPA7 as a potential therapy in HF which promotes NP and MasR pathways, we investigated the actions and stability of subcutaneous (SQ) administration of NPA7 in normal canines. We also defined NPA7's peptide stability and metabolites in canine plasma.

Methods

Plasma and urinary cGMP, cardiorenal and renin-aldosterone responses to SQ injection (10μg/kg) were determined over 4 hours in normal canines (n=5) in vivo. Ex vivo, we established stability of NPA7 and key metabolites in canine serum using liquid chromatography-mass spectrometry (LC-MS). Data are expressed as mean ± SEM. * P<0.05 vs. BL.

Results

In vivo, SQ NPA7 resulted in a sustained increase at 2 hours in plasma (BL: 10±3; 120 min: 30±6* pmol/ml) and urinary (BL: 1033±198; 120 min: 5792±857* pmol/min) cGMP, GFR (BL: 29±6; 120 min: 70±12* ml/min) and sodium excretion (BL: 18±10; 120 min: 144±33* ueq/min). We observed a gradual reduction in BP at 60 min (BL: 109±4; 60 min: 99±7* mmHg) with a sustained decrease in PCWP at 4 hours (BL: 5±0.9; 240 min: 3.1±0.6* mmHg). SQ NPA7 also suppressed plasma renin and aldosterone up to 3 hours after SQ injection. LC-MS revealed that NPA7 was highly stable with both the pGC-A and MasR activating moieties intact ex vivo in canine serum with a disappearance time of 2 hours. We also identified 2 major NPA7 metabolites NPA71–27 and NPA71–28.

Conclusions

SQ NPA7 possesses cGMP activating, cardiac unloading, diuretic, natriuretic, and renin-aldosterone suppressing actions in normal canines. NPA7 is also highly stable in serum. These studies support SQ administration as an effective delivery strategy for NPA7, a first-in-class innovative bispecific dual pGC-A/MasR activator now in preclinical development for HF.
P6347Wireless optogenetic inhibition of cardiac sympathetic nerve activity to improve cardiac function and remodeling in chronic post-infarction canines
Authors: Yu L , Zhou L , Jiang H
Published: October 2019

Background

Our previous study has shown that optogenetic modulation of left stellate ganglion (LSG) nerve activity suppresses ventricular arrhythmia (VA) after acute myocardial infarction (MI).

Objective

This study introduced a fully implantable, battery-free wireless optogenetic neuromodulation system to investigate whether chronic optogenetic inhibition of LSG nerve activity could reduce myocardial infarct size and improve left ventricular (LV) function and remodeling in a post-MI canine model.

Methods

Eighteen beagles were randomized into the normal control group (saline injection without MI, n=6), the MI group (AAV2/9-CAG-GFP injection plus MI, n=6) and the optogenetics group (AAV2/9-CAG-ArchT-GFP injection plus MI, n=6). Four weeks after AAV/saline microinjection into LSG, MI was induced and LED device (Figure 1A) was implanted (Figure 1B, C) to perform illumination (565nm) for optogenetic modulation 1h per day for 4 weeks.

Results

Chronic optogenetic modulation significantly attenuated LSG function and neural activity as compared to the MI group. Chronic optogenetic modulation significantly reduced myocardial infarction size and improved LV function (LV ejection fraction: 53±1.3% vs. 45.9±1.8%, P<0.05) as compared to the MI group. Furthermore, chronic optogenetic modulation suppressed MI-induced LSG sympathetic remodeling and LV fibrosis.

Figure 1

Conclusion

Chronic optogenetic modulation using this fully implantable, battery-free wireless optogenetic system significantly inhibited LSG nerve activity, reduced myocardial infarction size, improved LV function and remodeling in a post-MI canine model (Figure 1D).
P6359Utility of collagen-derived peptides as markers of organ injury in patients with acute heart failure: a prospective cohort study
Authors: Maruichi S , Nagao K , Inada T , Sato Y , Hata R , Kawae Y , Kadota K , Tanaka M
Published: October 2019

Background

Organ injury in heart failure (HF) might evoke profibrotic response, which might adversely affect prognosis.In patients with HF, liver fibrogenesis marker, type IV collagen 7S (P4NP 7S), correlates with pulmonary artery pressure and right-side cardiac pressure such as right atrial and ventricular pressure. The present study aimed to investigate the prognostic utility of two collagen markers (N-terminal propeptide of procollagen III [PIIINP] and P4NP 7S) in patients with acute HF.

Methods and results

We conducted a prospective cohort study including 390 patients admitted for HF to three territorial hospitals. The pre-specified primary outcome measure was cardiac death and HF hospitalization at early (90-day) and late (365-day) post-discharge period. Follow-up ratio was 99% at 90 day and 97% at 365 day, respectively. Cardiac death and HF hospitalization occurred in 61 and 114 patients at 90 days and 365 days, respectively. The dichotomization the patients based on the median value of the collagen marker at discharge revealed that patients with high P4NP 7S correlated with significant excess risk relative to those with low P4NP 7S for 90-day (adjusted hazard ratio [HR]; 1.89, 95% confidence interval [CI]); 1.11–3.26, P=0.02) and 365-day (adjusted HR; 1.50, 95% CI; 1.02–2.21, P=0.04) outcome. 10% increase in P4NP 7S was associated with 8% increase for primary outcome measure at 90 day (P=0.04). P4NP 7S showed incremental prognostic value on top of the conventional prognostic factors including age, sex, estimated glomerular filtration rate (eGFR), ejection fraction (EF) <40%, B-type natriuretic peptide (BNP), hemoglobin and sodium <140mmol/L (P=0.038 for net reclassification improvement, P=0.0068 for integrated discrimination improvement). PIIINP weakly correlated with P4NP 7S (Spearman's r=0.24, P<0.0001), but it neither correrated with the marked excess risk not associated with significant excess risk for 90 and 365-day primary outcome measure nor enhanced the discrimination.

Conclusions

This study suggests a possible role of P4NP 7S in the risk stratification of patients with acute HF.

Acknowledgement/Funding

None
P6369Prevalence of severe hypertension in a sub-Saharan African community
Authors: Gaye B , Janeczek A L , Jouven X , Luu D , Marijon E , Kramoh K E , Anzouan J B , Nguetta R
Published: October 2019

Background

Individuals with SH have high 10-year risk of cardiovascular disease, especially when additional risk factors or target organ damage are present. Though some data from in-hospital or selected populations are available, there are no studies reporting community-level prevalence of Severe Hypertension (SH) in sub-Saharan Africa.

Purpose

Using a cross-sectional design in Abidjan (Ivory Coast), we assessed prevalence of Severe Hypertension among adults.

Methods

Study participants were recruited within the framework of The Heart Fund's global health initiative. Data were collected in August 2016 from 6 randomly selected sites, ensuring representativeness of both urban and rural areas. Blood pressure (BP) was measured twice, 10 minutes apart, after optimal resting time. Blood pressure measurement were standardized between sites and SH was defined as systolic blood pressure ≥180 and/or diastolic blood pressure ≥110 mmHg at both readings. Demographics and data on cardiovascular history/risk factors were collected in the field. Ethics approval for the study was obtained from the National Ethical Committee of Côte d'Ivoire and written informed consent was obtained from all adult patients.

Results

Among 1,785 subjects examined, 1,182 aged between 18 and 75 years were included in this analysis. The prevalence of SH was 14.1% (12.5% females vs 17.0% males; P=0.03) (Figure). Among participants with severe hypertension, 28.9% were either undiagnosed or untreated. Alarmingly, subjects at high cardiovascular risk (age ≥60 years and/or obese) had even higher prevalence of overall SH (29.6% and 24.9%, respectively) as well as undiagnosed/untreated SH (29.4% and 24.6%). SH prevalence was almost double in urban compared to rural areas (17.0% vs. 9.2%, P=0.02); however, conversely, undiagnosed/untreated SH was significantly higher in rural areas (50.4% vs 21.9%). Compared to normal bodyweight, those who were overweight and obese had a 1.95-fold (95% CI, 1.30–2.93; P<0.001)and 4.24-fold (95% CI, 2.68–6.74; P<0.001)increased odds of SH (adjusting for age and sex), respectively. Similarly, participants ≥60 years had a 6.04-fold (95% CI, 3.93–9.36; P<0.001)increased risk of undiagnosed SH compared to under 50 years. Finally, men had higher odds of SH compared to women (OR 1.71, 95% CI, 1.19–2.47; P=0.004).

Figure 1

Conclusion(s)

Our community-based study revealed very high prevalence of SH among adults in Abidjan area, with almost one out of every seven having SH. This underscores SH as a growing public health problemin sub-Saharan Africa.More concerning, a significant (almost one third) proportion of them were either undiagnosed or untreated.
P6374Effectively treated hypertension: secrets of blood rheology
Authors: Svirida O , Ageev F T , Fgeeva N V , Smirnova M D , Blankova Z N , Vitsenya M V , Fofanova T V
Published: October 2019

Background

The contributions of the effectively treated hypertension on blood viscosity remain unclear, as well as impact of clinical and demographic parameters, biochemical variables, level of anxiety.

Aim

Aim of the study is to research viscosity state in patients with effectively treated hypertension and to reveal factors affecting blood viscosity.

Materials

58 treated hypertensive patients (36 females and 24 males aged 62,9±9,7 years) with achievement of target blood pressure (BP) level (systolic BP was 130,9 (126,6; 135,4), diastolic BP - 81,4 (79,7; 83,1) mmHg. 71.7% of patients were treated with beta-blockers, 46.7% - angiotensin converting enzyme inhibitors (ACE inhibitors), 31.7% - angiotensin II receptor blockers, 38.3% - calcium channel antagonists, 18.3% - diuretics, 71.3% - statins, 60% - acetylsalicylic acid. Coronary heart disease (CHD) were presented in 24 (40%). The average cholesterol level was 5.11 (4.76; 5.46) mmol/l, creatinine 71.83±12.6 mmol/l, sodium 143.4 (143.0; 143.9) mmol/l. The level of anxiety disorders determined on Sheehan's Patient-Rated Anxiety Scale (SPRAS) was 33.7 (23.1; 39.2) points.

Methods

Whole blood viscosity at high (η1) and low (η2) shear rates, plasma viscosity (ηpl) were measured by a rotational viscometer. Aggregation of erythrocytes (η2/ η1) was studied also. The statistical analysis was carried out by nonparametric method of Spearman and multivariate regression analysis with STATISTICA 6.

Results

Hemorheological profile was as follows: η1 4,7 (4,7; 5,0) sec–1, η 2 24,6 (23,5; 26,5) sec–1, η2/η 1 5,4 (4,9; 5,3), η pl 1,52 (1,51; 1,55) sec–1. Blood viscosity in men was higher than in women in all indices studied: η1 5,4 (5,1; 5,7) sec–1 in men vs 4,6 (4,6; 5,0) sec–1 in women (p<0,001), η 2 28,6 (26,0; 31,9) sec–1 vs 23,0 (21,6; 25,8) sec–1 (p=0,004), η2/η1 - 5,3 (5,1; 5,6) vs 4,9 (4,7; 5,2) (p=0,03) respectively. It was revealed η1 correlation with patient growth (r=0,468, p=0,001), η2 –with creatinine (r=0,551, p=0,001) and sodium (r=0,488, p<0,001) level. η2 /η1 positively correlated with the level of creatinine (r=0,383, p 0,04), sodium (r=0,543, p=0,0001), and with the level of anxiety as well (r=0,374, p=0,01). The level of anxiety is defined as an independent predictor of η2/η1 in the model including gender, age, creatinine, sodium, anxiety level. In patients treated with an ACE inhibitor η2/η1 was higher compared to patients who were not prescribed: 5,3 (4,6; 5,2) vs 5,0 (5,0; 5,5), (p=0,04). However, a multivariate analysis showed a loss of the prognostic value of antyhypertesive treatment (in model included gender, age, height, creatinine, sodium). Blood viscosity does not depend on the level of total cholesterol, the presence of CHD.

Conclusion

In effectively treated hypertensive patients the level of anxiety, indirectly reflected the activity of the sympatho-adrenal system, proved to be an independent predictor of a higher value of η2/η1.
P6381Cardiac arrest patients presenting to hospitals at weekends are not subject to the weekend effect: insights from ACALM big data, United Kingdom
Authors: Potluri R , Ainslie M , Chandran S , Patel B , More R , Chalil S
Published: October 2019

Introduction

Patients presenting to hospital with a cardiac arrest are associated with significant mortality in the United Kingdom. The evidence for the weekend affect involving cardiac arrests is unclear and we investigated this further with ACALM big data.

Methods

Anonymous information on patients presenting to hospital with a cardiac arrest was obtained from several hospitals in UK between 2000–2014. ICD-10 and OPCS-4 codes were used to trace patients coded for primary cardiac arrest, co-morbidities and mortality data.

Results

Details of 4803 patients presenting with cardiac arrest is shown in Table1. Cox regression model including age, gender, ethnic group, Charlson score and the top ten causes of death in the UK showed that weekend presentation did not contribute to increased mortality (OR 1.01; 95%C.I 0.94–1.11; p=0.692)

Table 1. Demographics and co-morbidities of cardiac arrest patients presenting on weekdays and weekends Weekday Weekend N (%) 3892 (81.0) 919 (19.0) Mean age ± S.D (years) 67.7±16.6 67.4±17.5 Male, % 55.4 54.1 Co-morbidities   Mean Charlson Index 1.52 1.33   Heart Failure % 21.4 20.4   IHD % 38.4 37.1   Cancer (Lung, Breast or Colon) % 5.2 3.8   Cerebrovascular Disease % 6.4 6.3   COPD % 15.0 12.0   CKD % 9.4 7.7   Dementia % 4.7 2.6   Pneumonia % 14.7 14.4 Outcomes   Crude 30 day mortality % 25.4* 32.8*   Crude 1 year mortality % 41.0* 44.3* *Cox regression analyses showed no significant differences in mortality between weekend and weekday presentation.

Conclusion

We have demonstrated that the “weekend effect” is not present in patients admitted to hospital with cardiac arrest. Our findings can perhaps be explained by the presence of 24/7 cardiac arrest teams present in acute hospitals.
P6390Macrophages as contributors to chronic inflammation and cardiac fibrosis in patients with myocardial infarction
Authors: Gombozhapova A , Rogovskaya Y , Rebenkova M , Kzhyshkowska J , Ryabov V
Published: October 2019

Introduction

The functional characteristics of tissue macrophages associated with the progression of cardiac fibrosis in clinic are still unknown.

Purpose

The purpose was to study cardiac macrophage phenotypes contributing to the development of chronic inflammation and fibrosis in patients with myocardial infarction (MI).

Methods

The study included 41 patients with fatal MI type 1. Group 1 (n=24) comprised patients who died within 72 hours of MI (the inflammatory phase) and group 2 (n=17) comprised patients who died 4–28 days after MI (the regenerative phase). Macrophage infiltration (number of cells) in the heart was assessed by double immunofluorescence in the non-infarct area. Each area was evaluated in 20 random fields. We used CD163, CD206, stabilin-1, α-smooth muscle actin (α-SMA), interleukin-10 (IL-10) as markers of M2-like macrophages.

Results

The number of CD163+/CD206− (p=0.087) and CD163+/206+ (p=0.072) macrophages was higher during the regenerative phase of MI. The number of CD163-/CD206+, stabilin-1+/α-SMA-, stabilin-1+/α-SMA+, stabilin-1+/IL-10−, stabilin-1+/IL-10+, stabilin-1-/IL-10+ did not significantly change throughout the entire period of MI. The comparison of various M2 macrophage subpopulations into groups revealed following. In group 1 the number of CD163+/CD206− and CD163+/CD206+ cells prevailed over CD163−/CD206+ (p=0.033 and p=0.003, respectively), stabilin1+/α-SMA− cells over stabilin-1+/α-SMA+ (p<0.001), and stabilin-1+/IL-10+ cells over stabilin-1+/IL-10− (p=0.018). In group 2 the quantity of stabilin-1+/α-SMA− macrophages prevailed over stabilin-1+/α-SMA+ (p=0.005) and stabilin-1+/IL-10+ over stabilin-1−/IL-10+ (p=0.028). In group 1 the number of CD163+/CD206+ cells correlated with the absolute and the relative number of peripheral blood monocytes prior to the onset of death (R=0.97), while the quantity of stablin-1+/α-SMA+ cells correlated with the absolute number of peripheral blood monocytes at admission (R=-0.53). In group 2 the quantity of CD206+/CD163− cells correlated with the absolute and the relative number of monocytes in the peripheral blood at admission (R=0.73 and R=0.59, respectively), the quantity of CD163+/CD206− macrophages with the incidence of recurrent MI (R= 0.54), and the number of stabilin-1+/α-SMA+ macrophages with the age of patients (R=-0.58).

Conclusions

We have suggested that the key cardiac macrophage phenotypes contributing to the development of chronic inflammation and cardiac fibrosis in the regenerative phase of MI were stabilin-1+/α-SMA− and stabilin-1+/IL-10+. We revealed subpopulation of stabilin-1+/α-SMA+ macrophages, that indicated the possibility of cellular transdifferentiation and macrophage plasticity. Thus, our results supports that understanding the role of macrophages in initiation, progression, and resolution of cardiac fibrosis is one of the most promising goal in the design of anti-fibrotic treatment strategies for patients with MI.
P6392Under the weather: acute myocardial infarction and subsequent case fatality with influenza burden - a nationwide observational study
Authors: Bergh C , Mohammad M A , Tham J , Koul S , Rylance R , Erlinge D , Frobert O
Published: October 2019

Background

Influenza may precipitate cardiovascular disease but influenza typically peaks in winter coinciding with other triggers of myocardial infarction (MI) such as low air temperature, high wind velocity, low air pressure and short sunshine duration. We aimed to study week-to-week variation in influenza cases and acute MI after meteorological confounder adjustment in a nationwide setting.

Methods

Weekly laboratory-confirmed influenza case reports were obtained from the Public Health Agency of Sweden from 2009 to 2016 and merged with the nationwide SWEDEHEART MI registry. Weekly counts of MI were studied with regard to influenza cases stratified into tertiles, 0–16, 17–164 and >164 influenza cases/week. Incidence rate ratios were calculated for each category and compared to a reference period of the year with no influenza. A negative binomial regression model was applied to adjust for weather parameters.

Results

A total of 133 562 MIs were reported to the registry during the study period of which 44 055 were ST-elevation MIs. Weeks with influenza cases were associated with higher risk of MI. For 0–16 influenza cases/week the unadjusted incidence rate ratio (IRR) for MI was 1.04 (95% confidence interval [CI] 1.01–1.07, p=0.007); for 17–163 cases/week the IRR=1.07 (95% CI 1.04–1.10, p≤0.001) and for ≥164 cases/week the IRR=1.08 (95% CI 1.05–1.11, p≤0.001). Results were consistent across a large range of subgroups and after adjusting for confounders. In addition, all-cause mortality was higher in weeks with highest reported rates of influenza cases.

Conclusion

In this nationwide observational study, we found an association between occurrence of MI and number of influenza cases beyond what could be explained by meteorological factors.