bluuebunny/crossref_metadata_2025_split huggingface dataset:
P3507Heterozygous cardiomyocyte-specific deletion of ErbB4 sensitizes to development of pregnancy-related cardiomyopathy
Authors: Feyen E , Vermeulen Z , Dugaucquier L , Hilfiker-Kleiner D , Segers V F M , De Keulenaer G W 
Published: October 2019

Abstract

Background
Peripartum cardiomyopathy (PPCM) is a potentially life-threatening disease in women without known cardiovascular disease; PPCM is characterized by left ventricular (LV) systolic dysfunction towards the end of pregnancy and/or in the first months postpartum. The underlying mechanisms of PPCM are incompletely understood, but there is recent evidence that impaired cardiomyocyte expression of the tyrosine kinase ErbB4 receptor plays a role. ErbB4 is the main receptor of neuregulin-1, a protective and regenerative paracrine factor in the heart. Homozygous deletion of ErbB4 is lethal.

Purpose
To test the hypothesis that mice with heterozygous (HZ) cardiomyocyte-specific deletion of ErbB4 (ErbB4+/−) are more susceptible to PPCM.

Methods
Cardiac morphology and function was evaluated by echocardiography with a Vevo 2100 Imaging System during 2 pregnancies and 6 weeks postpartum (n=7–9) or during non-pregnant control conditions in HZ (ErbB4+/−) and wild type controls (n=9–10). Then, hearts were excised for analyses of myocardial fibrosis, macrophage infiltration, capillary density and cardiomyocyte cross sectional area.

Results
When compared to pregnant wild type controls, pregnant ErbB4+/− mice developed significant LV dilatation (2 weeks after the 2nd delivery: LVIDd +16% ± 2%, p<0.05) and dysfunction (6 weeks after the 2nd delivery: EF −23% ± 3%, p<0.001), increased heart to body weight ratio (+7% ± 4%, p<0.05) and increased cardiomyocyte cross sectional area (+28% ± 7%, p<0.01). Non-pregnant ErbB4+/− mice also developed LV dilatation and dysfunction, albeit slower than pregnant ErbB4+/− mice. On histology, however, myocardial tissue of pregnant ErbB4+/− mice did not show macrophage infiltration, neither fibrosis, nor reduced capillary density.

Conclusions
Heterozygous cardiomyocyte-specific deletion of ErbB4 sensitizes to peripartum LV dilatation and cardiomyocyte hypertrophy and systolic dysfunction without profound cardiac injury, features that are frequently present in PPCM patients and may explain their high chance for recovery. These data reinforce a compensatory role for neuregulin-ErbB4 signaling during hemodynamic overload, and confirm that this signaling pathway is important to protect the maternal heart during peripartum stress.

Acknowledgement/Funding
Fund scientific research Flanders; University Antwerp
P3508A novel mouse model of sleep-disordered breathing is associated with contractile dysfunction and CaMKII overexpression
Authors: Lebek S , Schach C , Reuthner K , Tafelmeier M , Camboni D , Rupprecht L , Schmid C , Maier L S , Arzt M , Wagner S 
Published: October 2019

Abstract

Background
Patients with sleep-disordered breathing (SDB) develop arrhythmias and contractile dysfunction, but the mechanisms are poorly understood, possibly due to the lack of mouse models that mimic airway obstruction in spontaneously sleeping mice. Interestingly, New Zealand obese mice have been shown to develop airway obstruction with inspiratory flow limitation resulting in apneas, but these mice also develop diabetes.

Purpose
We developed a novel mouse model of increased airway obstruction in spontaneously sleeping lean mice and investigated the impact on sleep-related apneas and contractile function.

Methods and results
Male C57BL6 mice at 8–12 weeks of age were subjected to polytetrafluoroethylene (PTFE) injection (100 μl) into the tongue. This resulted in an increased tongue volume and reduced pharyngeal luminal diameter. Conscious mice behave normal and there was no difference in body weight between PTFE injected mice and untreated littermates (control). Whole body plethysmography was used to monitor spontaneous breathing for 8h in a quiet environment. Interestingly, compared to control, mice with PTFE injection showed a significantly increased frequency of apneas (lasting >1s, fig. A, * indicated P<0.05, t-test). Echocardiographic analysis revealed that ejection fraction was significantly reduced in PTFE-treated mice 8 weeks after surgery (vs. control, fig. B). In accordance, the developed force of isolated papillary muscles from hearts of PTFE mice was significantly reduced compared to control (fig. C). Ca/calmodulin-dependent protein kinase II (CaMKII) has been implicated in the development of heart failure. Intriguingly, compared to control, CaMKII expression was significantly increased in ventricular heart homogenates of PTFE-treated mice (fig. D). Moreover, the magnitude of CaMKII overexpression correlated significantly with the frequency of apneas (fig. E). Papillary muscle post-pause contractions can be used as measure of diastolic sarcoplasmic reticulum (SR) Ca leak, which is known to be enhanced by CaMKII. Compared to control, post-pause contraction amplitude was significantly smaller in PTFE-treated mice, indicating an increased SR Ca leak (fig. F).
Figure 1

Conclusion
PTFE injection in mice results in an increased frequency of spontaneous apneas. PTFE-treated mice develop mild contractile dysfunction, which is accompanied by CaMKII overexpression. This novel mouse model offers great opportunities for investigation of sleep-related breathing disorders.

Acknowledgement/Funding
This study was supported by the Medical Faculty of the University of Regensburg (ReForM programme).
P3516Sex differences in cardiac function and muscular dystrophy in lamin A/C genotype positive family members
Authors: Skjolsvik E , Dejgaard L A D , Lie Ø.H , Klaboe L G , Hasselberg N E , Orstavik K , Edvardsen T , Haugaa K H 
Published: October 2019

Abstract

Background
Lamin A/C dilated cardiomyopathy is a highly penetrant inheritable cardiomyopathy with some patients developing muscluar dystrophy. Studies have indicated higher morbidity and mortality in men compared to women with lamin A/C.

Purpose
To explore sex differences in cardiac function, arrhythmias and muscular dystrophy in lamin A/C genotype positive family members of lamin A/C probands.

Methods
We included consecutive lamin A/C genotype positive family members recruited for cardiological evalutation based on the identification of lamin A/C genotype by cascade genetic screening. Cardiac function was assessed by echocardiography. Impaired cardiac function was defined according to guidelines as left ventricular ejection fraction (LVEF) <52% in men, <54% in women. Presence of AV-block, atrial fibrillation and ventricular arrhythmias were evaluated by12-lead ECG, Holter monitoring, and interrogation of cardiac implantable electronic devices. Presence of muscular dystrophy was assessed retrospectively from medical records, and defined as present or not based on description of typical symptoms and/or findings on neurological exam.

Results
We included 55 lamin A/C genotype positive family members (age 35±15 years, 49% female). Men were younger at time of evaluation (31±15 years vs. 40±14 years, p=0.047). Despite lower age, men had significantly lower LVEF (48±12% vs. 55±9%, p=0.016) (Figure left panel), and showed worse survival free from impaired cardiac function compared to women (log rank p=0.019) (Figure, mid panel). Male sex was a marker for impaired cardiac function when adjusted for age (adjusted OR 5.3 [95% CI; 1.5–18.8]). Women had higher prevalence of muscular dystrophy compared to men (35% vs. 0%, p=0.004) (Figure right panel). We observed no sex related differences for AV-block, atrial fibrillation, nor ventricular arrhythmias.

Conclusions
Male lamin A/C genotype family members had earlier penetrance and more frequently impaired cardiac function compared to women. AV-block and arrhythmic disease did not differ. Muscular dystrophy was more frequent in women. These findings indicate sex differences in the phenotypical expression of lamin A/C disease.
P3524Biomechanic and neuroautonomic adaptation to acute blood volume displacement in patients with ischemic dilated cardiomyopathy
Authors: Scicchitano P , Acanfora D , Massari F , De Palo M , Acanfora C , Cortese F , Antonelli Incalzi R , Ciccone M M 
Published: October 2019

Abstract

Background
Chronic heart failure (CHF) is associated with neuroautonomic unbalance.

Purpose
We aimed at verifying the biomechanical and neuroautonomic adaptation to tilt test-induced volume displacement in patients with ischemic CHF.

Methods
Fifty-four CHF patients with a previous inferoapical/inferolateral (IA-IL) or basal/apical septal (BS-AS) myocardial infarction, free from residual ischemia, were enrolled. They underwent head-up tilt test, radionuclide ventricular function monitoring using the ambulatory ventricular function monitoring device (VEST), sympatho-vagal balance evaluation (low [LF] and high [HF] frequencies) and isoproterenol test (CD25).

Results
IA-IL patients had lower values of stroke volume, cardiac output and ejection fraction.The end-diastolic volume (EDV) increased in the IA-IL group (F=36.41, P<0.001) during tilt-test, more than BS-AS patients (F=4.12, P<0.05). The end-systolic volume (ESV) similarly increased in both groups. Norepinephrine (IA-IL Supine→ Tilting 499.5±28.8 → 719.3±41.5 pg/ml vs BS-AS Supine → Tilting 533.9±33.3 → 768.8±47.9 pg/ml, P<0.001) and epinephrine plasma concentrations (IA-IL Supine → Tilting 125.7±9.8 → 193.7±9.6 pg/ml vs BS-AS Supine → Tilting 118.8±8.9 → 191.7±10.2 pg/ml, P<0.001) increased in both groups.
LF/HF ratio not-significantly increased in IA-IL patients and decreased in BS-AS. CD25 was similar in IA-IL and BS-AS patients (IA-IL patients = 4.6±0.94 μg and BS-AS patients = 5.0±1.06 μg, P=0.79). The severity of ventricular dysfunction rather than its site correlated with the unbalance in biomechanical and neuroautonomic response.

Conclusions
Ischemic CHF patients showed altered biomechanical adaptation to volume displacement and compensatory sympathetic overdrive. Caution should be used with drugs interfering with the sympathetic response due to increased risk of syncope in response to volume displacement.

Acknowledgement/Funding
None
P3526Heart Failure hospitalization and mortality in non-valvular Atrial Fibrillation: The ENGAGE-AF TIMI 48 Trial
Authors: Inciardi R M , Giugliano R , Nordio F , Ruff C , Antman E , Rutman H , Braunwald E , Solomon S D 
Published: October 2019

Abstract

Introduction
Atrial Fibrillation (AF) is associated with increased risk of cardiovascular (CV) morbidity and mortality. Heart Failure (HF) represents the most common CV complication, more common than thromboembolic events.

Purpose
We aimed to determine clinical factors associated with HF hospitalization and mortality in a contemporary cohort of patients with AF without previous history of HF.

Methods
The Effective Anticoagulation with Factor Xa Next Generation in AF–Thrombolysis in Myocardial Infarction 48 (ENGAGE-AF TIMI 48) study tested the oral factor Xa inhibitor edoxaban in comparison with warfarin for the prevention of stroke or systemic embolism, in 21,105 patients with AF. We assessed the composite endpoint of HF hospitalization, death due to HF or sudden cardiac death in 8981 patients without a history of HF. Cox proportional hazard models were used to evaluate the significant clinical predictors associated with the endpoint of interest.

Results
Over a median follow-up of 2.8 years, 589 patients (6.5%) experienced the composite endpoint. Older patients, cardiovascular risk factors (hypertension, diabetes, heart valve disease), history of stroke and coronary artery disease, impaired renal function (ClCr ≤50 ml/min), heart rate at baseline and diuretic use were associated with increased risk of the composite endpoint (model c-statistic 0.66) (Figure 1). Outcomes were not affected by randomization to edoxaban or warfarin. In patients with available cardiac-derived biomarkers, elevated levels of both NT-proBNP and Troponin I were significantly associated with the endpoint after adjustment for the clinical predictors (Figure 1). The addition of the biomarkers to clinical predictors enhanced risk estimation (c-statistics 0.69, NRI 0.40, IDI 0.01, all p<0.001 for NT-proBNP and c-statistics 0.70, NRI 0.43, IDI 0.03, all p<0.001 for Troponin I).
Figure 1

Conclusions
HF hospitalization and mortality are important complications in AF patients without a history of HF. The addition of cardiac biomarkers to clinical characteristics enhances risk estimation. These findings may improve risk stratification.
P3530Right ventricular remodelling as part of the cardiorenal syndrome
Authors: Verikas D , Bugaite J , Gabartaite D , Cerlinskaite K , Krivickiene A , Zaliaduonyte-Peksiene D , Kavoliuniene A , Mebazaa A , Celutkiene J 
Published: October 2019

Abstract

Introduction
The relationship of glomerular filtration rate (GFR) to the remodelling of right (RV) and left ventricle (LV) in acute settings is not well studied.

Purpose
To investigate the relationship of renal function to LV and RV echocardiographic parameters in acute dyspnoea patients.

Methods
Echocardiography was performed in 438 patients with acute dyspnoea in prospective multicentre observational study during the first 48 hours after presentation. Echocardiographic quantification included the following parameters: tricuspid annular plane systolic excursion (TAPSE), velocity of the tricuspid annular systolic motion (RV S'), RV fractional area change (FAC), RV basal diameter, entire RV strain, strain of free RV wall, inferior vena cava (IVC) and LV parameters. Patients were divided into groups according to the GFR (ml/min/1.73m2): Normal or mildly decreased GFR (≥60), moderately decreased GFR (30–59) and severely decreased GFR (≤29). Data were analysed using One-way ANOVA.

Results
Mean GFR in this cohort was 63±26 ml/min/1.73m2. The severity of RV remodelling and venous congestion was significantly different in three subgroups of renal dysfunction.
The distribution of parameters Normal or mildly decreased GFR Moderately decreased GFR Severely decreased GFR N=233 (52%) N=166 (38%) N=39 (9%) TAPSE (cm) 1.8±0.3 1.5±0.5 1.4±0.4* RV FAC (%) 41±15 38±13 29±12*§ RV S' (cm/s) 11.0±3.3 9.7±3.4 9.1±4.2*§ Strain of RV free wall (%) −19±7 −16±6 −13±5*§ Strain of entire RV (%) −15±5 −12±5 −11±5* IVC collapsibility (%) 46±26 38±25 36±28* PASP (mmHg) 44±16 48±15 51±16*§ LVEF (%) 43±15 38±14* 46±16§ LV internal diameter in diastole (cm) 4.6±2.1 4.3±2.3 4.4±2.0 LV myocardial mass index (g/m2) 119±40 122±39 114±25 NT-proBNP (ng/l) 1485 [471; 3409] 5282 [1499; 10695] 6677 [1971; 15522]*§ Troponin T (ng/l) 55±18 92±19* 95±12* Admitted due to AHF (%) 59 72* 67 Admitted due to pulmonary causes (%) 22 21 28 *p<0.05 compared to GFR ≥60 ml/min/1.73m2, §p<0.05 compared to GFR (30–59 ml/min/1.73m2).

Conclusions
The progressive impairment of renal function coupled with larger congestion is associated with a significant right-sided but not left-sided ventricular remodelling in acute dyspnoea patients.

Acknowledgement/Funding
The work was supported by the Research Council of Lithuania, grant Nr. MIP-049/2015 and approved by Lithuanian Bioethics Committee, Nr. L-15-01.
P3532Quantifying hemodynamic cardiac stress and cardiomyocyte injury in hypertensive and normotensive acute heart failure
Authors: Kozhuharov N , Wussler D , Twerenbold R , Walter J , Du Fay De Lavallaz J , Flores D , Strebel I , Breidthardt T , Mueller C 
Published: October 2019

Abstract

Background
Better characterization of the different pathophysiological mechanisms involved in normotensive and hypertensive acute heart failure (AHF) might help to develop novel individualized treatment strategies.

Methods
The extent of hemodynamic cardiac stress and cardiomyocyte injury was quantified by measuring B-type natriuretic peptide (BNP) as well as high-sensitive cardiac troponin T (hs-cTnT) in 1,152 unselected patients presenting with AHF to the emergency department (derivation cohort). Systolic blood pressure (SBP) of 90 - 140 mmHg at presentation was used to define normotensive AHF. Findings regarding hemodynamic cardiac stress and cardiomyocyte injury were validated in a second independent AHF cohort (validation cohort; n=324).

Results
In the derivation cohort 667 (58%) patients had hypertensive AHF. Hemodynamic cardiac stress, as quantified by BNP levels, was significantly higher in normotensive AHF as compared to hypertensive AHF (1,105 pg/mL versus 827 pg/mL, p<0.001). In addition, the extent of cardiomyocyte injury, as quantified by hs-cTnT, was significantly higher in normotensive AHF as compared to hypertensive AHF (41 ng/L versus 33 ng/L, p<0.001). These findings were confirmed in the validation cohort.
Table 1. Cardiac stress and myocardial necrosis as quantified by BNP and hs-cTnT plasma concentrations Overall Hypertensive AHF Normotensive AHF p-value BNP in pg/ml, median (IQR) 974 (536–1,712) 827 (448–1,419) 1,105 (611–1,956) <0.001 hs-cTnT in ng/L, median (IQR) 37 (22–67) 33 (19–59) 41 (24–71) <0.001 BNP = B-type natriuretic peptide; hs-cTnT = high-sensitivity cardiac Troponin T; IQR = inter-quartile range.
Figure 1

Conclusion
Biomarker profiling revealed that the extent of hemodynamic stress and cardiomyocyte injury is different in patients with normotensive and hypertensive AHF. This characterization could help to understand AHF phenotypes better, which in turn may lead to more specific management in future, thus improving the dismal prognosis in these patients.

Acknowledgement/Funding
European Union, Swiss National Science Foundation, Swiss Heart Foundation, Cardiovascular Research Foundation Basel, University of Basel
P3533The other side of the medallion in heart failure: Reverse Metabolic Syndrome
Authors: Ozcan Cetin E H , Cetin M S , Yaman N M , Ozeke O , Topaloglu S , Aras D , Temizhan A 
Published: October 2019

Abstract

Background
As a risk factor for developing heart failure, metabolic syndrome (MetS) is associated with a reduced heart failure mortality. This paradox is also seen in most of the chronic diseases and also in the elderly population. Parameter changes representing the deteriarion of the balance in favor of catabolism including the low body mass index (BMI) and low blood pressure as well as low blood cholesterol have been associated with poor prognosis in several populations. Apart from high-density lipoprotein, which is further decreased, inverted changes in the components of MetS have been seen in heart failure population which led to the introduction of the concept of the “reverse metabolic syndrome” (RMetS).

Purpose
We aimed to investigate the effect of MetS and RMetS on hemodynamic parameters and long-term prognosis in patients with heart failure and reduced ejection fraction (HFrEF).

Methods
400 consecutive patients who were followed with HFrEF and performed right heart catheterization were examined. 96 patients with cardiac cachexia and morbid obesity were excluded and the remaining 304 patients with BMI 18–40 kg/m2 were included. The presence of MetS is defined according to the NCEP-ATP III criteria. RMetS was accepted as having BMI <22 kg/m2 with total cholesterol level <160 mg/dL and/or systolic or diastolic blood pressures <110 mmHg and <70 mmHg respectively. Composite endpoint (CEP) was defined as either of the occurrence of all-cause mortality, assist device implantation or cardiac transplantation. Endpoints were analyzed in two step approach: first we grouped patients accoding to the presence of MetS, then we added the RMetS category and stratifed patients into three groups as metabolic syndrome, reverse metabolic syndrome and metabolic healthy

Results
304 patients were followed up for a median of 16 (0–48) months. 110 patients had all-cause mortality and 148 patients had CEP. In the first step, patients with MetS (110 patients) had reduced all-cause mortality and CEP than patients without MetS (194 patients). In the second step, RMetS group had the highest all-cause mortality and CEP (chi-square: 22.187 p<0.001 and chi-square: 30.980, p<0.001, respectively) Cardiac output, cardiac index were lower and PCWP was higher in RMetS group. The endpoints were similar between MetS group and metabolically healthy patients.

Conclusion
Although individuals with MetS seem to have a better prognosis than patients without MetS, the latter group contains RMetS population, which had the poorest prognosis. This population may contribute to the false- assumption of the relative better findings of MetS population with regard to the non-MetS population. Further clinical studies are needed to clarify this pathologic phenomenon.
P3541Change in left ventricular ejection fraction and outcome in heart failure patients with mid-range ejection fraction: from the HIJ-HF prospective study
Authors: Tsukamoto K , Suzuki A , Shiga T , Sakai M W , Tanaka Y , Kouno E , Osada A , Matsuura J , Hayashi N , Nagara K , Ogiso M W , Nomura H , Kikuchi N , Hagiwara N 
Published: October 2019

Abstract

Introduction
Heart failure (HF) is categorized on the basis of the eft ventricular ejection fraction (LVEF). The European Society of Cardiology has proposed mid-range EF (HFmrEF) as a new category of HF that includes patients with an LVEF of 40–49%. However, the clinical characteristics, change in LVEF following treatment, and outcome of patients with HFmrEF remain clear.

Methods
We conducted a prospective observational study of Japanese hospitalized HF patients between 2015 and 2018 at a single-center (HIJ-HF III). HFmrEF was defined as 40–49% of LVEF on echocardiography at admission. We followed these patients and performed echocardiography to assess LVEF per year after hospital discharge. Clinical outcome was death from any cause.

Methods and results
We studied 138 patients with HFmrEF (median age 71 years, 69% male). They had 32% of ischemic heart disease, 9% of New York Heart Association functional class III or IV at discharge. During median follow-up of 20 [13–28] months, we assessed change in LVEF for 110 patients with HFmrEF. One year after hospital discharge, 49 patients (44%) improved LVEF (≥50%) and 21 patients (19%) reduced LVEF (<40%). HFmrEF patients who reduced LVEF (<40%) were significantly higher mortality rate than those who improved LVEF (≥50%) (14% vs. 2%, p<0.05) (Figure).

Conclusions
This study demonstrated that 44% of HFmrEF patients improved LVEF following treatment but 19% patients reduced LVEF. Reduced LVEF was associated with poor prognosis.