bluuebunny/crossref_metadata_2025_split huggingface dataset:
P703The small conductance Ca2+-activated K+-channel inhibition tool compound AP14145 protected the guinea pig heart from ventricular arrhythmia during hypokalemia whereas dofetilide was pro-arrhythmic
Authors: Bentzen B H , Abildgaard L , Edvardsson N G , Soerensen U S , Grunnet M , Diness J G 
Published: October 2019

Abstract

Background
Hypokalemia is commonly encountered in the clinic. Hypokalemia reduces the cardiac repolarization reserve and causes increases in intracellular calcium. This prolongs the QT-interval and increases the risk of ventricular arrhythmia; a risk that can be further exacerbated by concomitant administration of classical class 3 anti-arrhythmic agents.
Small conductance Ca2+-activated K+-channels (SK-channels) are a promising new atrial selective target for treatment of atrial fibrillation (AF). Under physiological conditions SK channels play an insignificant role in ventricular repolarization. However, this might change under hypokalemia because of concomitant increases in intracellur calcium.

Purpose
To study the effects of SK channel inhibition with the tool compound AP14145 or ICA under hypokalemic conditions as compared to the class 3 anti-arrhythmic agent dofetilide and time matched controls (TMC).

Methods
Guinea pig hearts were isolated and retrogradely perfused with normokalemic (4.5 mM K+) Krebs-Henseleit solution, followed by perfusion with drug or vehicle control. The perfusion was then changed to hypokalemic solution (2.5 mM K+) in presence of drug for 20 min, followed by 20 min perfusion with normokalemic solution in presence of drug. A total of 24 animals were included in the study and randomly assigned to 4 groups: ICA, AP14145, dofetilide or TMC. QT-interval, ventricular effective refractory period, extra systoles and incidence of ventricular tachycardia (VT) or fibrillation (VF) were recorded for each perfusion period.

Results
Hypokalemia caused a small increase in QT-interval. Application of SK channel inhibitors did not cause further changes, whereas dofetilide prolonged QT compared to hypokalemia alone. During hypokalemia 3 out of 6 hearts in the TMC group developed VF (one spontaneously, two following S1S2 stimulation) whereas 4 out of 6 hearts developed VF in the dofetilide group (one spontaneously, three following S1S2 stimulation). In comparison only 1 heart out of 6 developed VF when treated with the SK channel inhibitor ICA (spontaneously) or AP14145 (following S1S2 stimulation).

Conclusion
Hypokalemia was associated with an increased risk of VF, an effect that was exaggerated by co-administration of dofetilide. In comparison, the structurally and functionally different SK channel inhibitors, ICA and AP14145, protected the heart from hypokalemia induced VF. These results with the tool compound AP14145 support that SK inhibition may be associated with a better safety and tolerability profile than dofetilide.

Acknowledgement/Funding
Innovation Fund Denmark
P727Metabolic and functional differences between male and female endothelial cells from umbilical cords (HUVEC) of twin pairs
Authors: Lorenz M , Blaschke B , Benn A , Hammer E , Witt E , Kirwan J , Fritsche-Guenther R , Gloaguen Y , Kramer F , Kappert K , Brunner P , Dreger H , Stangl K , Knaus P , Stangl V 
Published: October 2019

Abstract

Background
Personalised Medicine is one of the hallmarks of future medicine. Sex and gender differences exist in the incidence, clinical manifestation and outcome of cardiovascular diseases. Gonadal hormones are thought to account for most of these sex differences. However, besides hormones, sexual dimorphisms at the cellular level may also contribute to physiological and pathophysiological cardiovascular differences between women and men.

Purpose
To analyse intrinsic sex differences at the cellular level, we aimed to elucidate sex-specific differences in endothelial cell migration and energy metabolism under pro-migratory conditions in male and female HUVECs. To reduce biological variability, we used HUVECS obtained from umbilical cords from twin pairs of the opposite sex. These cells are exposed in utero to the same maternal environment, and therefore represent a valuable tool to study intrinsic sex-specific differences at the cellular level.

Methods
Vascular endothelial growth factor (VEGF)-stimulated migration was determined with IBIDI migration chambers. Sex-specific levels of proteins were studied using proteome profiling. Cellular metabolism was measured by Seahorse and levels of intracellular metabolites were analysed using GC-MS based technology.

Results
Female cells showed significantly higher VEGF-induced cell migration than male HUVECs. Proteomic profiling revealed a sex-specific response to VEGF treatment. Mitochondrial respiration rate was higher in VEGF-stimulated male HUVECs compared to female cells. Whereas mean glycolytic rates did not significantly differ between sexes, the ratio of glycolysis/mitochondrial respiration after VEGF stimulation was higher in female than in male HUVECs. Female cells had higher intracellular ATP levels after serum starvation and treatment with VEGF. Under both conditions, female cells showed altered levels of metabolite pools compared to male HUVECs.

Conclusions
Higher intracellular ATP and metabolite levels in female cells after serum starvation and VEGF may contribute to the observed functional sexual dimorphisms, and may also point to an increased stress tolerance of female cells. The results of our study provide a strong argument to discriminate between male and female cells in in vitro experiments.

Acknowledgement/Funding
The work was supported by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research).
P755The impact of levothyroxine on cardiac function in older adults with subclinical hypothyroidism: a randomized clinical trial
Authors: Gencer B , Moutzouri E , Blum M R , Feller M , Collet T H , Buffle E , Monney P , Gabus V , Muller H , Kearney P , Gussekloo J , Westendorp R , Scott D J , Bauer D C , Rodondi N 
Published: October 2019

Abstract

Importance
Subclinical hypothyroidism has been associated with heart failure, but no conclusive clinical trial assessed whether treating subclinical hypothyroidism with levothyroxine has an impact on cardiac function.

Objective
To assess the impact of levothyroxine treatment on cardiac function in subclinical hypothyroidism.

Design
This is a randomized, double-blind placebo-controlled, multicenter Swiss substudy within the TRUST trial.

Participants
Participants aged ≥65 years with subclinical hypothyroidism.

Intervention
Levothyroxine to achieve TSH normalization, or placebo including mock titrations.

Main outcome measures
Primary outcomes, assessed by echocardiography at the end of the trial were the left ventricular ejection fraction (LVEF, normal defined as >50%) for systolic function and the ratio between mitral peak velocity of early filling (E) to early diastolic mitral annular velocity (e' (E/e' ratio) for diastolic function. Secondary outcomes included transmitral E and A waves, e' lateral/septal, left atrial (LA) volume index and systolic pulmonary artery pressure.

Results
Of 217 randomized Swiss participants of the TRUST trial, 185 (mean age 74.1 years, 47% women, mean TSH at baseline 6.35 ± SD 1.95 mIU/L) underwent echocardiography. After a median treatment duration of 18.4 months, the mean TSH among participants randomized to levothyroxine (n=95) decreased to 3.55 mIU/L, whereas it remained elevated in the placebo group (n=89; 5.29 mIU/L). The mean LVEF was similar in both arms (adjusted between-group difference 0.4%, 95% CI −1.8% to 2.5%, P=0.72) and no significant differences were found for the E/e' ratio (adjusted between-group difference 0.4, 95% CI −0.7 to 1.4, P=0.47). In intention-to-treat and per-protocol analyses, no clinically significant differences were found for secondary diastolic function parameters: e' lateral 8 vs. 8 cm/s, P=0.54; e' septal 6 vs. 6 cm/s, P=0.75; LA volume index 34 vs. 33 ml/m2, P=0.57; E/A ratio 0.8 vs. 0.8, P=0.94; E deceleration time 225 vs. 216 ms, P=0.27, except for systolic pulmonary artery pressure (37 mm Hg in the levothyoxine group vs. 33 mm Hg in the placebo group, P=0.02 intention-to-treat and P=0.06 per protocol)

Conclusion
Treatment of subclinical hypothyroidism with levothyroxine was not associated with benefits regarding systolic and diastolic heart function in older adults with subclinical hypothyroidism.
P760Clinical profile of African-American and non-Hispanic caucasian patients with Takotsubo cardiomyopathy syndrome in a large urban hospital in the United States of America
Authors: Westman P , Ravindra K , Chiabrando J , Kadariya D , Maehara G , Dell M , Van Wezenbeek J , Moeller G , Keyser-Marcus L , Gal T S , Ma L , Abbate A 
Published: October 2019

Abstract

Background
Takotsubo (stress) cardiomyopathy is an acute reversible heart failure syndrome initially described in Japanese patients, but now well characterized in Caucasians patients in Europe or of European descent. An initial observation has suggested a lower incidence of Takotsubo in non-Caucasian subjects, particularly in the African-American (AA) population in the United States of America. The purpose of this study was to assess whether epidemiologic and clinical differences were present in Takotsubo in a large urban hospital in Virginia, USA.

Methods
We used an informatics-based system to query electronic health records (TriNetX, Cambridge, MA, USA) to search for cases of Takotsubo between 2010 and 2018 and a corresponding cohort of patients with non-ST segment elevation acute myocardial infarction (NSTEMI). We then performed a chart-level review of 160 cases and obtained additional clinical information including symptoms, risk factors, co-morbidities, and in-hospital outcomes. This retrospective study was approved by the Institutional Review Board of our institution.

Results
We identified 260 cases of Takotsubo and 6,270 of NSTEMI in the same time period (1:24, 4.2%). Being AA was associated with an odds ratio of Takotsubo versus NSTEMI of 0.38 [0.29–0.50] (P=0.0001). With further evaluation of patients with Takotsubo (N=160), AA (N=44, 27.2%) and Non-Hispanic Caucasian (C) (N=110, 67.9%) had no differences in age and sex. AA patients with Takotsubo however were more likely than C patients to be affected by type II diabetes mellitus (38.6% versus 14.5%, P=0.002, OR 3.70 [1.65–8.28]), have history of drug abuse (27.3% versus 9.1%, P=0.009, OR 3.75 [1.48–9.49]) and of cocaine use in particular (9.1% versus 0.9%, P=0.024, OR 11.0 [1.19–101.4]). The pattern of wall motion abnormality was not different between the 2 groups. AA patients presented with a lower ratio of brain natriuretic peptide (BNP) to troponin I (41.9 [12.7–258] pg./ml versus 281 [42–890] pg/ml, P=0.022). There was no significant difference of in-hospital mortality between the AA and C groups (9.1% versus 25%, respectively, OR 0.40 [0.13–1.24], P=0.11).

Conclusions
The incidence and clinical characteristics of Takotsubo (stress) cardiomyopathy appear to be different between African-American and Non-Hispanic Caucasian patients. African-American patients are more likely to have diabetes and illicit drug usage, but have a lower BNP/troponin I ratio. Both AA and Non-Hispanic Caucasian patients have similar in-hospital mortality.
P774Transcoronary transfer of Wharton's jelly mesenchymal pluripotent stem cells in patients with chronic ischaemic heart failure shows safety and unprecedented high-grade myocardial uptake
Authors: Kozynacka A , Kwiecien E , Mazurek A , Drabik L , Skubera M , Czyz L , Szot W , Urbanczyk M , Banys P , Duplicka M , Kostkiewicz M , Kijowski J , Majka M , Podolec P , Musialek P 
Published: October 2019

Abstract

Background
Chronic ischaemic heart failure (CIHF) remains an important health problem on the patient/family- and society level. In animal models, Wharton's jelly (umbilical cord matrix) multipotent stem cells (WJMSCs) effectively promote angiogenesis, can differentiate to cardiomyocytes, and drive functional myocardial regeneration. Effective uptake of regenerative cells in ischaemic-impaired tissue is fundamental for any therapeutic effect.

Purpose
To evaluate safety and myocardial uptake of WJMSCs transcoronary transfer in CIHF applied as a novel myocardial regeneration strategy employing allogenic yet hypo-immunogenic, off-the-shelf “unlimited” source of therapeutic cells (NCT03418233 pilot cohort).

Material and methods
In ten consecutive patients (age 62.6±2.5), with stable CIHF and no current need for revascularization (LVEF 29.3±3% by echo and 26.3±6% by SPECT; NT-proBNP 1746±329pg/mL; myocardial scar tissue 39.9±3.9% by SPECT) and patency of at least two major native coronary arteries or by-pass graft(s), the CardioCell Investigational Medical Product, based on 30x106 WJMSCs, was administered to viable yet hypokinetic segments using a novel algorithm including a dedicated catheter for transcoronary delivery of cellular therapies. The cells were labeled with 99mTc-extametazime to routinely evaluate their myocardial uptake magnitude.

Results
No symptoms or signs of novel myocardial ischaemia occurred with cell delivery and no patient showed any adverse periprocedural events. One hour after administration, myocardial WJMSCs uptake (SPECT) was 40.3±6%; see Fig for a typical raw data image. By 6 months there were no adverse events in the study cohort.
Figure 1

Conclusions
This work indicates safety and unprecedented high-grade myocardial uptake of WJMSCs in CIHF patients. Together with animal data, this provides basis for continued assessment of this strategy in an endpoint-powered randomized controlled clinical trial employing CardioCell as an “unlimited” off-the-shelf cellular therapy strategy.

Acknowledgement/Funding
K/ZDS/005644 and 265761 (National Centre for Research and Development STRATEGMED)
P796Intensive blood pressure treatment significantly increases visit-to-visit systolic blood pressure variability. A randomized clinical trial
Authors: Rueda-Ochoa O L , Rojas Sanchez L Z , Ikram M A , Deckers J W , Franco O H , Rizopoulos D , Kavousi M 
Published: October 2019

Abstract

Background
Intensive blood pressure lowering is increasingly gaining attention. Besides higher baseline blood pressure, visit-to-visit variability has showed association with target organ damage and major adverse cardiovascular outcomes in multiple medical reports.

Purpose
Our aim was to assess the effect of intensive treatment on systolic blood pressure (SBP) visit-to-visit variability in the SPRINT trial population during follow-up.

Methods
We included 9068 SPRINT participants with 128139 repeated SBP measurements. Participants were randomly assigned to intensive (SBP <120 mmHg) vs standard treatment (SBP between 135–139 mmHg). The primary outcome was a composite outcome of myocardial infarction, other acute coronary syndromes, acute decompensated heart failure, stroke, and cardiovascular mortality. We calculated the coefficient of variation (CV) and standard deviation (SD), taking into account all SBP measurements prior to the SPRINT primary outcome. Comparison of CV between intensive and standard treatment in the total SPRINT population and among different subgroups was made.

Results
CVs in intensive treatment groups were higher in total population and in all groups under study (See table). While second and third CV quartile showed a larger tendency to increase the risk for the primary SPRINT outcome in the intensive treatment compared to the standard treatment group, fourth CV quartiles were significantly associated with increase in primary SPRINT outcome in both intensive and standard treatment groups.
Coefficient of variation in SPRINT trial Group Intensive treatment Standard treatment Total population 9.80 (3.22)* 8.52 (2.96) Females 10.46 (3.29)* 9.18 (3.15) Black person 9.99 (3.38)* 8.82 (3.15) Prevalence CKD 10.14 (3.22)* 9.12 (3.06) Prevalence CVD 10.28 (3.32)* 8.93 (3.23) ≥75 year 10.40 (3.18)* 9.01 (3.07) SAEs 10.30 (3.39)* 9.08 (3.13) (CKD: chronic kidney disease; CVD: cardiovascular disease; SAEs: serious adverse events. *P<0.05).

Conclusions
Intensive blood pressure treatment significantly increases SBP visit-to-visit variability in total SPRINT population and in all subgroups under study. Additional longitudinal studies with long-term follow-up are warranted to evaluate the impact of increases in SBP visit-to-visit variability due to intensive treatment on risk of major cardiovascular events.
P811Functional assessment of microcirculation in Takotsubo cardiomyopathy - a pilot study
Authors: Brazdil V , Hudec M , Stipal R , Bocek O , Jerabek P , Poloczek M , Kanovsky J , Kala P 
Published: October 2019

Abstract

Background
Takotsubo cardiomyopathy (TTC) is a severe cardiologic disorder with an increasing incidence that often mimics acute coronary syndrome. Both of the entities are characterized by systolic dysfunction of the left ventricle myocardium. However, this dysfunction is reversible in most cases of TTC. Takotsubo syndrome affects predominantly postmenopausal females, typically with a direct link to emotional or physical stress factors. The pathophysiology of TTC remains unclear. In this study, we aimed to assess the pathophysiology of TTC using the invasive functional testing of coronary microcirculation.

Methods
Ten female patients diagnosed with TTC in line with interTAK Diagnostic Criteria were included in this pilot study. In all subjects we measured fractional and coronary flow reserve in the left anterior descending and left circumflex coronary arteries (FFR LAD, FFR LCx, CFR LAD, CFR LCx), and the index of microcirculatory resistance in the same arteries (iMR LAD, iMR LCx) in addition to acute and late (after 12 weeks) transthoracic echocardiography (TTE) and acute cardiac biomarkers (troponin and NT-proBNP). The results of the microcirculatory assessment were statistically compared with normal population values.

Results
In all subjects, the troponin level was elevated in the acute phase and repeated TTE revealed transient dysfunction of the left myocardial ventricle. Whilst fractional flow reserve was normal in both assessed epicardial artery territories for all patients (mean FFR LAD: 0.92±0.04; mean FFR LCx: 0.98±0.046), both mean values of coronary flow reserve disclosed pathological microcirculatory findings (CFR LAD: 1.9±1.197; CFR LCx: 1.75±0.742) and were pathological in nine out of ten subjects. Index of microcirculatory resistance revealed abnormal values in five out of ten patients for LAD (31.03±18.515) and three out of ten for LCx (23.8±17.86).

Conclusions
Our pilot study confirmed non-obstructive findings in the epicardial coronary arteries assessed by FFR. On the other hand, the investigation of both CFR and iMR, microcirculatory functional testing, revealed pathological findings in a significant number of evaluated subjects. From this aspect, our study validates further research in the field of microcirculatory functions as a possible mechanism in the origin of TTS.

Acknowledgement/Funding
Supported by MH CZ - DRO (FNBr, 65269705)
P816Mortality during weekend admission for takotsubo syndrome: a national cross sectional large scale study
Authors: Malanchini G , Lombardi F 
Published: October 2019

Abstract

Background
Higher mortality rates in patients admitted for an acute myocardial infarction during weekends has been recently confirmed. Differences in staffing and in lower rates of early reperfusion therapy are thought to affect outcomes of these patients particularly of those presenting with ST segment elevation. Patients affected by Takotsubo cardiomyopathy may present themselves mimicking those affected by heart attack and are frequently admitted with supposed diagnosis of acute coronary syndrome. No data is available about influence on mortality in relation to the time of admission among patients with Takotsubo cardiomyopathy.

Rationale
The aim of this study is to assess the effect on mortality due to admission during weekend among patients discharged with diagnosis of Takotsubo cardiomyopathy.

Methods
We retrieved administrative data about every admission to National Healthcare System hospitals in Italy between 2009 and 2017 with final diagnosis of Takotsubo cardiomyopathy according to ICD9-CM classification of diseases (code 429.83). Date of admission was used to determine the weekend (Saturday and Sunday) or weekdays exposure (Monday to Friday). The primary outcome was in-hospital mortality. Demographical characteristics of patients (age and sex) were included in a multivariate logistic regression analysis. We also analyzed the impact of weekend admission on time to coronary angiography and on length of hospital staying. Analyses were performed using Stata 13.0.

Results
A total of 10,861 Takotsubo admissions were identified. Mean age was 70.7 years and 91.7% were women. The in-hospital mortality was 2.21%. We found that there was no significant increase in the risk of death among patients admitted during weekends (OR 1.07; 95% CI 0.77–1.44). The variability explained by the model was of 4.2% (pseudo R-squared 0.042). Men have a higher risk of mortality as compared to women (OR 2.37, 95% C.I 1.69–3.33). Patients admitted during weekend tends to stay in hospital longer, but they do not seem to wait more days to get a coronary angiography.

Conclusions
At variance with patients with ST elevated acute myocardial infarction, subjects admitted during weekends for Takotsubo cardiomyopathy did not show an excess of in-hospital mortality in comparison to those admitted during week days.