bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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