bluuebunny/crossref_metadata_2025 huggingface dataset:
P3827Low dose of quinidine is effective to normalize the slow inactivation in mutant Kv4.3 channel identified in an early repolarization syndrome patient
Authors: Takayama K , Ding W G , Matsuura H , Horie M , Ohno S
Published: October 2019

Background

Early repolarization syndrome (ERS) is characterized by J-point elevation in the ECG and ventricular fibrillation (VF). Several mutations in genes encoding cardiac ion channels have been reported as the causes for ERS. For the treatment of ERS, clinical studies have shown that quinidine is effective for the suppression of electrical storm. However, the mechanism or the optimal concentration for quinidine to suppress the electrical storm has not been elucidated yet.

Purpose

The aim of the present study is to clarify pharmacological effect of quinidine on mutant Kv4.3 channel by electrophysiological analysis and to establish theoretically effective treatment for ERS.

Methods

A KCND3 mutation, p.G306A, identified heterozygously in a 12-year-old boy was examined by whole-cell patch-clamp methods using CHO cells. We performed functional analysis of the Kv4.3 channels encoded by KCND3 of wild-type (WT), heterozygous (WT/G306A), or homozygous (G306A) mutants. Pharmacological normalizing effects of quinidine to the WT and mutant channels were investigated by loading test in various concentration. The sensitivity of quinidine was evaluated in terms of the concentration of the clinical course and the loading test.

Results

The patient suffered VF while sleeping or under sedation. Significant J-point elevations in multiple leads were recorded and he was diagnosed as ERS. Quinidine administration in the serum concentration of 1.2 to 3.1 μM was effective to stop his VF storm. Mutant Kv4.3 currents showed significantly slow inactivation time course (Fig 1), which meant that the mutation caused the gain-of-function channel. Quinidine loading to the mutant Kv4.3 normalized the inactivation time course in concentration-dependent manner (Fig 2, 3). In the loading concentration of 1 μM, the peak currents were not changed regardless of the voltage (Fig 4). The optimal serum concentration of quinidine in clinical use as multi-ion-channels blocker is 6 to 15 μM and the concentration was higher than that of the patient to stop the VF storm. The electrophysiological analysis showed that the low dose loading of quinidine was effective to prevent the gain-of function change of mutant Kv4.3 channels.

Electrophysiological analysis

Conclusions

We showed the pharmacological mechanism of quinidine against the mutant Kv4.3 channels identified in an ERS patient. Even the low concentration of quinidine was effective to normalize the slow inactivation, gain-of-function, in mutant Kv4.3 channels. Our data would be helpful to confirm the optimal concentration of quinidine for ERS patients to avoid adverse effect.
P3832Dantrolene reduces CaMKII-mediated arrhythmogenesis
Authors: Mustroph J , Pabel S , Stehle T , Lebek S , Neef S , Maier L S , Sossalla S
Published: October 2019

Rationale

In atrial and ventricular rhythm disorders, an increased diastolic sarcoplasmatic reticulum (SR) calcium leak can induce a depolarizing transient inward current, serving as a trigger for cellular arrhythmias. Dantrolene has been shown to also stabilize the cardiac ryanodine receptor. However, the detailed mechanism of the mode of action remains unknown. This study aims to investigate the effects of dantrolene on calcium/calmodulin-dependent kinase II (CaMKII) mediated arrhythmogenesis.

Methods and results

Right atrial cardiomyocytes (CM) were isolated from patients with atrial fibrillation. To investigate SR Ca2+ leak, measurements of diastolic SR Ca2+ sparks were performed by confocal microscopy using Fluo-4 AM. Dantrolene (10 μmol/l) potently reduced Ca2+-spark-frequency (CaSpF) by 90±26% (p<0.05, n=21 cells dantrolene vs. 19 cells control) leading to a reduction of the calculated diastolic SR-Ca2+-leak by 91±31% (p<0.05, n=21 vs. 19). Interestingly, CaMKII-inhibition using Autocamtide-2-Related Inhibitory Peptide (AIP) did not further reduced SR Ca2+ leak compared to dantrolene alone in human cardiomyocytes. This observation may suggest (secondary) inhibitory effects of dantrolene on CaMKII. To elucidate the role of CaMKII in dantrolene-mediated antiarrhythmic effects, we investigated atrial CM from mice overexpressing CaMKII (TG) and respective wildtype controls (WT). CaSpF and SR Ca2+ leak were reduced by dantrolene in both TG and WT mice (p<0.005, TG: dantrolene vs. vehicle n=132 vs 127 cells (9 mice); WT: dantrolene vs. vehicle n=61 vs 61 cells (5 mice)). However, proarrhythmogenic Ca2+ waves were only significantly reduced by dantrolene in TG mice (p<0.05, TG: dantrolene vs. vehicle 10.8% vs. 26.2%, n=154 vs 164 cells). Correspondingly, the incidence of delayed afterdepolarizations (DADs) in TG cells was significantly diminished by dantrolene (p<0.05, TG: dantrolene vs. vehicle 1/14 vs. 9/15 cells, n=5 mice). In contrast, DADs were not reduced by dantrolene in WT cells without increased CaMKII activity (p=n.s., WT: dantrolene vs vehicle 3/16 vs 2/13 cells, n=5 mice). In preliminary in vivo experiments, intraperitoneal injection of 40 mg/kg body weight dantrolene reduced the inducibility of arrhythmias by ventricular burst stimulation in CaMKII TG mice compared to vehicle (dantrolene 0/2 mice vs. vehicle 2/2 mice, p<0.05 Chi-Square).

Conclusion

Dantrolene beneficially altered Ca2+ homeostasis in human AF CM and murine CM. Dantrolene seems to exert its antiarrhythmic potential in a CaMKII-dependent manner. Thus, dantrolene as an already clinically approved compound might be a potential antiarrhythmic drug that merits clinical investigation.

Acknowledgement/Funding

Deutsche Forschungsgemeinschaft (MA 1981/5-1 and 7-1 to LSM). Marga und Walter Boll-Stiftung (SS).
P3844Percutaneous coronary intervention in the age of frailty
Authors: Bergami M , Manfrini O , Cenko E , Kedev S , Vavlukis M , Vasiljevic Z , Zdravkovic M , Scarpone M , Milicic D , Badimon L , Bugiardini R
Published: October 2019

Background

Although guidelines from the European Society of Cardiology and American Heart Association/American College of Cardiology recommend early percutaneous coronary intervention (PCI) in all patients with non-ST-elevation myocardial infarction/ unstable angina (NSTE-ACS), in day-to-day practice persists uncertainty as to whether to follow guidelines in patients aged 75 years or older. Indeed, recommendations are based on large randomized trials where patients aged 75 years or older are under-represented.

Purpose

We aimed to investigate whether patients aged 75 years or older would benefit from an early invasive strategy versus a conservative strategy. We also analyzed the factors associated with the choice of an early PCI in this population.

Methods

The research was conducted on the population of the International Survey of Acute Coronary Syndromes (ISACS-TC) registry. The study population consisted of 6826 eligible patients with NSTE-ACS. Of these patients, 1496 were 75 years old or older and were included in the analysis. The primary outcome measure was 30-day mortality. Key secondary outcomes were bleeding complications during the index hospitalization. Multivariate logistic regression analyses were conducted to establish outcomes and factors associated with outcomes. We evaluated specific ranges of ages: 75–79 years, 80–84 years, and 85 years or over. Further, data were sorted by sex and diabetes mellitus status.

Results

The mean age of our study population was 80.0 (interquartile range: 77–82) years old. Elderly patients treated with early PCI and medical therapy were significantly younger than those treated with only medical therapy were (78.9 vs 80.5, p<0.001), with each one-year increase in age corresponding to a 7% reduction in likelihood of receiving invasive treatment (OR 0.93, 95% CI 0.91–0.96). Crude 30-day mortality was significantly lower in the overall invasively managed population (5.4% vs 13.1%, p<0.001). After multivariable logistic adjustment for demographic and clinical features, early PCI was associated with lower mortality (OR 0.47, 95% CI 0.30–0.76). No significant differences in outcomes were observed between sexes (interaction, p=0.54) or by the presence of diabetes mellitus (interaction, p=0.61). In addition, no differences were seen among age groups (75–79 vs 80–84, interaction p=0.47; group 80–84 vs ≥85, interaction p=0.69). In early PCI, the group between 75–79 years had 5 (1.6%) major and 5 (1.6%) minor bleeding complications whereas the older groups had 1 (1.1%) and 1 (2.7%) major and 3 (3.2%) and 2 (5.4%) minor bleeding complications for patients aged 80–84 and ≥85, respectively.

Conclusions

In the real-life clinical setting, early PCI is a safe and efficacious treatment option in very elderly patients presenting with NSTE-ACS. Revascularization is better than medical therapy whatever the age is.
P4139Prediction of atrial fibrillation in embolic stroke of unknown source
Authors: Range F T , Peters D P , Zeus T , Jander S , Mueller P , Kelm M
Published: October 2019

Background

Atrial fibrillation (AF) is one of the leading cardiogenic causes for embolic stroke of unknown source (ESUS). Its incidence is growing with patients' age. Detection and rule out of AF is complex and cumbersome. The best method is an implantable loop recorder (ILR). In patients elder than 60 years, incidence of AF is reported incongruently and reliable patient characteristics that can predict a low or high risk for AF are scarce.

Purpose

This study reports real life incidences of AF in a group of patients undergoing ILR after ESUS. It aims to depict age dependency of AF and to identify potential confounding factors.

Methods

In a single center study, we analysed 111 patients (age=62±13 years, nmale=65) who received an ILR in our centre following ESUS. Patient characteristics, brain imaging, hemodynamic monitoring, blood pressure, electrocardiography, holter ecg and echocardiography data from the initial hospital stay and ILR follow-up over a mean of 460 days were analysed. Primary endpoint was the recording of AF during follow-up.

Results

AF was detected in 23% of all patients. Patients with AF were significantly elder than those without AF (p=0.01). Incidence of AF was in Patients <60y: 14%, 60–69y: 13%, 70–79y: 45%, >80y: 67%. We observed a significant difference in AF incidence comparing patients younger and elder than 70 years (p=0.034).

Both, CHADS-Vasc (p=0.036) and HATCH-scores (p=0.018) were higher in the AF group while the simple CHADS2 Score missed significance (p=0.068). PQ duration was longer in AF patients (p=0.022) and baseline heart rate at admission was lower (p=0.027). NIHSS scores were lower in the AF group at admission (2.97 vs. 4.10; p=0.049) but due to less neurological improvement in the AF group, this difference faded until dismission (1.09 vs 1.79 p=ns).

Conclusions

In our real life ILR group following ESUS, strongest predictor of AF was age. Pivot point rather was at 70 than at 60 years of age.
P4144Pericyte-specific deletion of ninjurin1 induces abnormal vasa vasorum formation and persistent inflammation and enhances intimal hyperplasia of injured vasculature
Authors: Horiuchi K , Minoshima A , Kabara M , Kano K , Tomita Y , Yoshida Y , Hayasaka T , Takehara N , Hasebe N , Kawabe J
Published: October 2019

Introduction

Atherosclerosis is fundamental pathological condition inducing severe ischemic diseases such as ischemic heart disease and stroke. New concept has been proposed that adventitial abnormalities including enhanced malformation of adventitial microvessel, vasa vasorum are associated with development and vulnerability of atherosclerotic plaque. However, the role of vasa vasorum malformation in vascular remodelling has not been fully clarified. We recently reported that Ninjurin1 (Ninj1) is critical adhesion molecule to associate pericytes (PCs) with endothelial (EC) tubes to form stabilized mature neovessels. The purpose of this study is to examine if formation of adventitial microvessels affects the vascular remodelling of injured vessels using PCs-specific Ninj1 deletion mouse model.

Methods and results

Deletion of Ninj1 gene in NG2-positive PCs was induced by tamoxifen (Tam)-treated NG2-CreER/Ninj1loxp mice (Ninj1KO, n=9). Tam-treated-NG2-CreER (n=4) or Tam-nontreated NG2-CreER/Ninj1loxp (n=5) mice were used as Control (Ct1 and Ct2 respectively). Femoral arteries were injured by insertion of coiled wire. After 4 weeks of surgery, blood vessels were stained by venous injection of FITC-lectin. Isolated femoral arteries were fixed with paraformaldehyde and decolorized with CUBIC reagent. Wire-mediated vessel injury induced intimal hyperplasia, as assessed by intima/media (I/M) ratio and accordingly grew microvessels in adventitia. Intimal hyperplasia in Ninj1KO were significantly enhanced compared to Controls. Although there was no significant difference in total length of adventitial microvessels among three groups, extravasation of FITC-lectin from adventitial microvessels were significantly enhanced in Ninj1KO. The number of infiltrated macrophages in adventitia were increased in Ninj1KO.

Conclusion

Deletion of Ninj1 in PCs contributes to formation of immature microvessels in adventitia of injured vasculature and to adventitial microbleeding, and subsequently enhances intimal hyperplasia. Ninj1 is an attractive target to normalize microvessels for anti-atherosclerotic therapy.
P4160Safety and efficacy of triple combination therapy with parenteral prostanoids in patients with Eisenmenger physiology
Authors: D'Alto M , Balint O H , Giannakoulas G , Romeo E , Argiento P , Farro A , Russo M G , Sarubbi B , Skoro-Sajer N , Gatzoulis M A , Dimopoulos K
Published: October 2019

Aim

While combination therapy is currently strongly advocated for idiopathic pulmonary arterial hypertension (PAH) patients, evidence to support its use in patients with PAH related to congenital heart disease (CHD), especially patients with Eisenmenger syndrome, is lacking. We evaluated the efficacy and safety of sequential triple combination therapy with parenteral prostanoids after failure of double oral therapy in patients with PAH-CHD and Eisenmenger physiology.

Methods

This is an international, multicentre, retrospective cohort study conducted in adult patients with Eisenmenger physiology on double oral PAH therapy in whom intravenous or subcutaneous prostanoid treatment was added due to clinical deterioration or failure to reach the treatment goals. Clinical status, 6-minute walk test distance (6MWD), biomarkers and haemodynamics were assessed at baseline and during the follow-up.

Results

A total 28 patients with Eisenmenger syndrome (6 [21%] male, age 37.6±14.3 years) were included. A post-tricuspid shunt was present in 16 (57%), 86% of whom had a ventricular septal defect. The majority (89%) were treated with subcutaneous treprostinil. At 27±14 months follow-up, WHO functional class improved in 18 (64%), remained unchanged in 8 (29%), and deteriorated in 2 (7%) patients. There was also an increase in 6MWD (mean 339±145 versus 233±140m, p=0.0001, fig 1A) and a reduction in NT-proBNP levels (median 1125 [123–5882] versus 3087 [234–7428] pg/mL, p<0.0001, fig 1B). On follow-up cardiac catheterization, an improvement in right atrial pressure (8±2 versus 11±5 mmHg, p=0.01), mean pulmonary artery pressure (68±12 versus 72±17 mmHg, p=0.005), cardiac index (2.3±0.3 versus 2.0±0.5 l/min/m2, p=0.005, fig 1C), and pulmonary vascular resistance (17±7 versus 21±10, p=0.008, fig 1D), was observed compared to baseline. No patients discontinued treatment. Five (18%) patients died during follow up.

Figure 1

Conclusions

Triple combination therapy with subcutaneous treprostinil or endovenous epoprostenol in patients with Eisenmenger syndrome is safe and well tolerated at 2 years follow-up, resulting in a significant improvement in clinical status, exercise tolerance and haemodynamics.
P4163Long term comparison between homograft vs stented bio-prostheses for pulmonary valve replacement in tetralogy of Fallot patients
Authors: Cocomello L , Meloni M , Baquedano M J , Ordonez M V , Biglino G , Bucciarelli C , Rapetto F , Pieles G , Benedetto U B , Caputo M
Published: October 2019

Background

Tetralogy of Fallot (TOF) repair results in long term chronic pulmonary regurgitation requiring pulmonary valve replacement (PVR). Homograft and stented bio-prosthesis are currently used for PVR but whether one should be considered superior to another remains unknown.

Aim

To compare echocardiographic and clinical outcomes after PVR with Homograft vs stented bioprosthesis in patients with previous TOF repair.

Methods

137 patients who underwent PVR with stented bioproshesis were compared with 80 patients who received an homograft using Mixed linear model and multivariate Cox regression.

Results

Homograft were associated with a significantly lower transpulmonary gradient postoperatively (P=0.04) and after a mean follow-up 6 years (table). Homograft were associated with a significantly lower risk of reintervention (HR 0.24; 95% CI 0.07–0.85, p=0.026) while long term mortality was comparable between the two groups (P=0.1).

Echocardiographic findings BIO HOMOGRAFT P N 137 80 Preoperatively   TV regurgitation (mean, sd) 1.80 (0.63) 1.94 (0.81) 0.353   TV regurgitation pressure drop (mean,sd) 35.15 (15.49) 45.34 (25.24) 0.009   PV regurgitation (mean,sd) 3.63 (0.52) 3.34 (0.64) 0.004   PV systolic peak gradient (mean, sd) 25.07 (17.05) 30.68 (21.70) 0.138 Early postoperatively   TV regurgitation (mean,sd) 1.52 (0.54) 1.54 (0.55) 0.858   TV regurgitation pressure drop (mean,sd) 30.10 (13.82) 29.13 (13.98) 0.733   PV regurgitation (mean,sd) 1.50 (0.54) 1.64 (0.53) 0.224   PV systolic peak gradient (mean,sd) 24.05 (11.10) 20.16 (14.19) 0.045 Latest follow_up   TV regurgitation (mean,sd) 1.63 (0.61) 1.83 (0.80) 0.195   TV regurgitation pressure drop (mean,sd) 37.46 (18.84) 32.58 (13.47) 0.233   PV regurgitation (mean,sd) 2.06 (0.77) 2.07 (0.94) 0.982   PV systolic peak gradient (mean,sd) 32.22 (18.17) 21.25 (13.47) 0.001 TAPSE: Tricuspid annular plane systolic excursion; TV: tricuspid valve; PV: pulmonary valve.

PV re-intervention

Conclusions

When compared to stented bio-prostheses, homografts were associated better early and late hemodynamic profile and a significantly lower risk of re-intervention. Homograft should be considered the first choice in patients undergoing PVR after TOF repair.
P4171Population characteristics, interventions and outcomes in hospitalized orthotopic heart transplant patients with sudden cardiac arrest: a nationwide United States analysis from 2007 to 2015
Authors: Jazayeri M.-A , Mohammed M , Mastoris I , Sheldon S , Reddy M , Haglund N , Sauer A , Shah Z
Published: October 2019

Background

Sudden cardiac arrest (SCA) is a leading cause of death in the United States (US), claiming up to 450,000 lives annually and accounting for ∼25% of deaths following orthotopic heart transplantation (OHT),

Purpose

We sought to characterize OHT patients suffering SCA and their subsequent management, in comparison to the general, native heart (NH) population, using a large national inpatient database.

Methods

A cross-sectional analysis was performed among US OHT & NH patients hospitalized with incident SCA or ventricular fibrillation/flutter. We analyzed demographics, baseline characteristics, procedural utilization and outcomes. Groups were compared with standard statistical techniques. A P-value <0.05 was considered significant.

Results

From 2007–2015, 920 SCA admissions were identified among 121,083 (0.8%) OHT hospitalizations, compared to 1,731,658 (0.6%) in the general population (P<0.001). OHT patients were younger (P<0.001) and predominantly men (P<0.001). More OHT patients had diabetes (P=0.01), while the NH group had more coronary disease (P=0.01). Mechanical circulatory support use was similar in both groups overall, and OHT patients were more likely to undergo transplantation (P=0.015). Pacemaker/defibrillator implants were more common in NH than OHT patients (P<0.001). Acute kidney injury and in-hospital mortality were significantly greater in OHT patients.

Table 1. SCA in OHT & general populations Orthotopic Heart Transplant General Population P-value (N=121,083) (N=278,463,550) Sudden cardiac arrest (SCA) events, n (%) 920 (0.8%) 1,731,658 (0.6%) <0.001 Age, mean (SD) 57 (17) 66 (16) <0.001 Male sex, n (%) 644 (72%) 1,004,362 (58%) <0.001 Coronary artery disease, n (%) 275 (30%) 675,908 (39%) 0.012 Mechanical circulatory support, n (%) 64 (7%) 104,151 (6%) 0.230 Repeat heart transplantation, n (%) 5 (0.5%) 1199 (0.1%) 0.015 Pacemaker or defibrillator implant, n (%) 45 (5%) 136,314 (8%) <0.001 In-hospital mortality, n (%) 555 (60%) 932,812 (54%) 0.014 Cardiogenic shock, n (%) 78 (8%) 208,778 (12%) <0.001 Acute kidney injury, n (%) 418 (45%) 608,035 (35%) 0.003

Conclusions

SCA hospitalizations occur more often and with higher mortality in OHT patients compared to the general population. Earlier recognition of at-risk patients may result in improved utilization of potentially life-saving therapies.
P4358The role of the “halo sign” for the accurate quantification of atrial septal defect size by 3D TEE
Authors: Aggeli C , Dimitroglou I , Kastellanos S , Drakopoulou M , Moldovan K , Latsios G , Vavuranakis M , Toutouzas K , Tousoulis D
Published: October 2019

Introduction

In patients undergoing percutaneous closure of secundum atrial septal defect (ASD), device selection is based on defect sizing by transoesophageal echocardiography (TEE) and in particular 3D measurement as well as 2D balloon-stretched derived measurements. We sought to investigate whether in patients with the presence of the “halo sign”, defined as increased tissue thickness at the edge of the ASD rims, there is an agreement between the aforementioned sizing methods with a view to avoid balloon sizing.

Methods

Consecutive patients referred to our department for single ASD closure without complex anatomy were included in our study. TEE was performed in all patients before and during the intervention. 3D datasets for ASD quantification as well as X-PLANE data sets for measurement of balloon-stretched 2D dimensions were acquired and analysed offline. During the analysis of 3D datasets, researchers were blinded to the 2D balloon-stretched measurements. Patients were stratified according to the presence of the halo sign and the correlation between 3D dimensions and balloon-derived diameter was calculated.

Results

Thirty-eight patients (14 males, 36.8%) with median age 46 [32–56] were included in our study. The “halo sign” was present in 16 patients (42.1%). In the whole study population, the median maximal and median minimal diameter measured by 3D TEE were 1.79cm [1.54–2.10] and 1.57cm [1.15–2.00] respectively while median circumference and area were 5.26cm [4.14–6.44] and 2.20cm2 [1.25–3.30] respectively. Median balloon-stretched diameter was 1.8cm [1.4–2.1]. In patients with the “halo sign” there was no significant difference between the medians of the ASD diameter calculated from 3D measurements and the 2D derived diameter (1.53cm; 1.6cm, p=0.170) whereas in patients with no “halo sign” there was significant difference (1.79cm; 2.0cm, p=0.001) (figure 1). The discrepancy between the aforementioned diameters was significantly lower in patients with the halo sign (0.04cm; 0.19cm, p=0.001). There was a good correlation between closure device size and 3D derived ASD circumference in the whole study population (R2=0.897) which was even higher in patients with the halo sign (R2=0.981). In this subgroup, the selected size of the closure device would not have differed significantly even without balloon sizing (p=0.414).

Figure 1

Conclusion

The ASD sizing by 3D echocardiography is accurate in patients with the “halo sign”. This study justifies further investigation concerning the reliability of 3D imaging in this population for the selection of the ASD device size with a view to avoid balloon sizing, decrease procedural time and thus simplify the procedure.
P4373Post systolic shortening in the apex of the left ventricular is a typical finding in patients with PLN mutation
Authors: Bruin De- Bon H A C M , Verstraelen T E , Taha K , Brink Van Den R B A , Tan H L , Amin A S , Wilde A A M , Bouma B J
Published: October 2019

Introduction

The p.Arg14del founder mutation in the gene encoding phospholamban (PLN) is associated with an increased risk of malignant ventricular arrhythmia and heart failure. Ejection fraction (EF) is the gold standard of systolic left ventricular (LV) function, however new technics using global longitudinal strain (GLS) are able to detect LV dysfunction early, e.g. in patients with chemotherapy. Moreover, strain analysis on post systolic shortening (PSS) can show distinct pattern in various diseases, e.g. patients with myocardial fibrosis and amyloid. The goal of this study was to investigate whether speckle tracking (GLS and PSS) of the LV can detect LV dysfunction in patients with PLN mutations and whether these patients have a specific PSS pattern.

Method

72 Patients (49 female, mean age 32 years) diagnosed with the genetic PLN mutation p.Arg14del and 21 controls (10 female, mean age 27 years) underwent complete Echocardiographic exam including LVEF, GLS and PSI of all LV segments. LVEF <50% was considered as LV dysfunction. The diagnostic characteristics of GLS and PSI were determined.

Results

Pearson correlation is in PLN patients between PSI apex and EF 0.677 (P <.0001) PSI apex and GLS 0.692 (P <.0001)

PLN patients appeared to have a typical pattern with a high PSI in the apical segments. An apical PSI >20 was the strongest diagnostic parameter indicating LV dysfunction.

Apical PSI >20 and LVEF <50% have a sensitivity and specificity of 78% and 85%.

Diagnostic characteristics PLN Controls P-value LVEF, % 55.2 59.3 0.033 GLS, % 15.5 17.3 0.163 PSI basal 8.5 10.1 0.326 PSI mid 5.6 2.9 0.070 PSI apical 15.6 2.1 0.01 LVEF, left ventricular ejection fraction; GLS, Global longitudinal strain; PSI, post systolic index.

PSI

Conclusion

PLN patients have a typical pattern of high PSI in the apex of the left ventricular which can be used as a diagnostic test to detect LV dysfunction.
P4381Improvement of the PISA method in the setting of mitral regurgitation of complex geometry
Authors: Papolla C , Adda J , Habib G , Rieu R
Published: October 2019

Background

Doppler echocardiographic methods, such as proximal isovelocity surface area (PISA) are used to quantify mitral regurgitations. However, their accuracy and reproducibility are still discussed, especially in case of mitral regurgitations of complex geometry.

Purpose

The aim of this study was to test in-vitro the accuracy of the PISA method depending on the shape and number of regurgitant flows.

Methods

Several regurgitant volumes (RV) were produced through various regurgitation severities and shapes in a left heart double activation simulator. Circular mitral regurgitation (MR) was performed with a circular orifice in a rigid plate. Triangular and oblong MR were performed by suturing the extremity of a bioprosthesis leaflet to the annulus. Multiple jets regurgitation was performed by suturing centrally the two leaflets of an anatomically shaped mitral valve made of hydrogel. A transesophageal echocardiography probe was used to acquire the data. The RV was calculated with the classical PISA method (hemispheric assumption), or by considering the PISA as a hemicylinder or a double hemisphere. It was then compared to a reference value obtained from an electromagnetic flowmeter measurement (accuracy ± 2 ml/min).

Results

A central and circular orifice was correctly quantified, as expected, with the hemispheric assumption (bias 0.2±1.9 ml, p=0.46). For a triangular central jet, the hemispheric assumption best estimated the RV (−3.5±14.8 ml, p=0.10). An oblong MR was underestimated with the hemispheric assumption (−18.3±14.9 ml, p<0.01) whereas the hemicylindrical assumption was more accurate (−0.2±5.8 ml, p=0.85). In case of 2 regurgitant jets, considering only the largest jet led to an important underestimation (−10.9±5.6 ml, p<0.01), whereas adding the two RV was more accurate (−1.2±8.2 ml, p=0.50).

Conclusions

In case of a single central orifice, the hemispheric assumption correctly quantified the MR. In case of an oblong orifice, the hemicylindrical assumption provided a good quantification with simple measurements. In case of multiple jets of different sizes, it was more accurate to consider both jets for RV calculation.

Acknowledgement/Funding

Képhalios part of Affluent Medical
P4397Health related quality of life is not reduced in elder familial hypercholesterolemia patients
Authors: Souto A C , Coutinho E , Miname M H , Jannes C E , Pereira A , Santos R D
Published: October 2019

Background

Familial hypercholesterolemia (FH) is a genetic disorder associated with high risk of early major cardiovascular events (MACE) that can impact on elderly's self-appraisal of health-related quality of life (HRQoL), however, this association is unclear.

Purpose

This study evaluated HRQoL of elder individuals (from 60 to 88 years old), index cases (IC) and first-degree relatives (FDR) at high risk of FH.

Methods

From 1030 participants of FH genetic cascade screening, 250 were ≥60 and 205 were eligible for this study. Data collection was performed before awareness of molecular diagnosis results. Individuals were divided into 4 groups according to molecular diagnosis: IC with (IC+) and without (IC-) identified mutations (n=38 and n=54, respectively), and their affected (FDR+, n=74) and non-affected (FDR-, n=39) FDR. HRQoL measurements, mental (MCS) and physical component (PCS) scores, were carried out with the SF-12 questionnaire. Associations were tested by multivariate models.

Results

The mean age was 68±7 years, 32.2% were men, MACE had occurred in 47.8%. HRQoL dimensions measure (variance of physical, mental and health quality component scores) did not differ between FH and non-FH individuals. Lower PCS were associated with female sex (p=0.043), lower education (p=0.047), previous MACE occurrence (p<0.001), arterial hypertension (p=0.005), depression (p=0.004) and Alzheimer's disease (p=0.016). Lower MCS were associated with the previous diagnosis of depression (p<0.001) and Alzheimer's disease (p=0.011). Lower HQS were associated with lower education level (p=0.001), previous MACE (p<0.001), arterial hypertension (p<0.001), depression and Alzheimer (p=0.004 and p=0.006). MACE and hypertension were predictive of lower PCS (p=0.003 and p=0.035). Depression was predictive of lower MCS (p<0.001). Education, MACE and depression were predictive of health quality self-appraisal. No association was found with either molecular defect or lipid-lowering therapy.

Conclusion

HRQol in elder suspected FH individuals relates more to a consequence of elevated cholesterol levels i.e. MACE and co-morbidities rather than molecular defects or pharmacological treatment.
P4408Cardiovascular response in diabetic patients submitted to treadmill electrocardiographic exercise stress test
Authors: Faia Carvalho Dias G , Oliveira M , Faria B , Von Hafe P , Cardoso A F , Almeida F , Lourenco A
Published: October 2019

Introduction

Diabetes mellitus (DM) is an entity commonly associated with neuropathy, a factor that may have repercussions on the cardiovascular system, specifically in its capacity to respond to stimuli.

Objectives

To evaluate the cardiovascular response to exercise in diabetic patients, comparing it with a control group.

Methods

Patients who underwent treadmill eletrocardiographic exercise stress test (EST) between January 2016 and November 2018 without the influence of negative chronotropic medication were included.

Results

A total of 187 patients were identified, having a mean age of 57±13 years, of whom 120 (64%) were of the male gender. Eighty-four (45%) were diabetic. The group of diabetic patients had a higher prevalence of arterial hypertension, however the number of classes of antihypertensive drugs was not significantly different between diabetic and non-diabetic patients. There were no significant differences in the remaining demographic variables. Patients with DM presented lower maximal heart rates (HR) (141±14 vs 148±19 beats/minute, p=0.015), lower HT reserve (59±16 vs 67±21 beats/minute, p=0.005), as well as a lower rate of HR fall in the recovery period (13±5 vs 16±5 beats/minute2, p<0.001). Total EST time was also lower in diabetic patients (median 7.0 IQR=3 vs 7.3 IQR=3.5 minutes, p=0.044). Additionally, the number of years since the time of diagnosis of DM was inversely correlated with the degree of increase in systolic blood pressure (SBP) with exercise (r=−0.22, p=0.045), and the pre-test SBP (median 135 IQR=24 vs 130 IQR=20 mmHg, p=0.048) and post-test SBP (median 150 IQR=20 vs 140 IQR=25 mmHg, p=0.007) were higher in patients with DM.

Discussion

In this study it was found that patients with DM present an impaired chronotropic response, both in exercise and recovery periods, and it was observed that the capacity to increase SBP is inversely correlated to the duration of DM. These data may reflect the neuropathic involvement in DM and its influence in the cardiovascular response to exercise.
P4427Cardiovascular outcomes among runners of a marathon race - a 17 years' experience
Authors: Poon W L , Lee K L , Chan K
Published: October 2019

Introduction

Over the past 17 years (2002–2018), 898,831 people participated in the Hong Kong Standard Chartered Marathon (HKSCM).

Purpose

We aim to study the incidence of marathon-related sudden cardiac arrest (SCA) and non-fatal myocardial injury (NFMI).

Methods

All the HKSCM related admissions between 2002 and 2017 were retrieved from the accident and emergency department admission records. We reviewed the data of HKSCM runners admitted for SCA and NFMI.

Results

Fourteen and thirty-nine runners were admitted for SCA (Mean age 38±13 years-old, 12 men) and NFMI (Mean age 42±12 years-old; 34 men) respectively.

Among the SCA runners, the arrest rhythms could not be retrieved in 3 cases. In the remaining 11 SCA runners, the arrest rhythms were ventricular fibrillation (VF) (N=6), pulseless-electrical activity (PEA) (N=3), and asystole (N=2). Nine of the 14 SCA runners were successfully resuscitated. Only 2 out of the 14 SCA runners had significant atherosclerotic coronary artery disease (CAD) requiring coronary angioplasty. Among the SCA runners, the etiologies of cardiac arrest were myocardial infarction (MI) (N=2), ischemic cardiomyopathy with VF (N=1), idiopathic VF (N=3), malignant coronary anomaly (N=1), and idiopathic (N=5). Percutaneous coronary intervention (PCI) was performed in 2 SCA runner with MI. Implantable cardioverter-defibrillators were implanted in 1 resuscitated runner with VF. Postmortem examination of the 3 deceased runners showed significant CAD in two and was unrevealing in one.

Among the 39 NFMI runners, coronary angiograms (CAG) or CT coronary angiogram were performed in 14 cases (36%), which showed minor CAD or unremarkable findings in 7 runners, and significant CAD in 7 runners. PCI and coronary artery bypass were performed in 5 and 2 NFMI runners respectively. Only 8 out of 39 NFMI runners reported chest pain. Significant ischemic ECG changes were detected in 9 out of 39 NFMI runners. Invasive CAGs were not performed in the remaining NFMI runners due to low pre-test likelihood of CAD and normal non-invasive test results.

Conclusions

The incidence of SCA and mortality among HKSCM runners was 1.56 per 100,000 and 0.56 per 100,000 respectively. The incidence of NFMI was 4.3 per 100,000. Coronary artery disease, coronary anomaly and idiopathic VF were the commonest etiologies of SCA.
P4428Physical exercise during uncontrolled systemic arterial hypertension
Authors: Urbano Pagan L , Gomes M J , Damatto R L , Cezar M D M , Reyes D R A , Damatto F C , Campos D H S , Lima A R R , Polegato B F , Fernandes A A H , Laurindo F R , Okoshi M P , Okoshi K
Published: October 2019

Introduction

Physical exercise reduces systemic arterial blood pressure and improves cardiac remodeling. However, the effects of exercise during uncontrolled arterial hypertension remains poorly understood. This study evaluated the influence of physical training on cardiac remodeling in untreated spontaneously hypertensive rats (SHR).

Methods

Four experimental groups were used: sedentary (W-SED n=27) and trained (W-EX, n=31) normotensive Wistar rats, and sedentary (SHR-SED, n=27) and exercised (SHR-EX, n=32) hypertensive rats. At 13 months old, the exercise groups underwent treadmill exercise five days a week, for four months. Echocardiogram was performed to evaluate cardiac structures and function. In vitro myocardial function was analyzed in left ventricular (LV) papillary muscle preparations. Myocardial collagen was quantified by histology and hydroxyproline concentration and antioxidant enzyme activity was assessed by spectrophotometry. NADPH oxidase activity was analyzed by lucigenin reduction. Protein expression was quantified by Western blot. Matrix metalloproteinases (MMP) activity was evaluated by zymography. Statistical analyzes: two factor ANOVA and Bonferroni or Kruskal-Wallis and Dunn tests.

Results

Systolic blood pressure was higher in SHR groups. Exercised groups had greater physical capacity. Frequency of heart failure features was higher in hypertensive groups than controls; SHR-EX had a lower frequency of pleural effusion and tachypnea than SHR-SED. Echocardiogram showed lower LV wall thickness, LV relative wall thickness, left atrium diameter, and relaxation time in SHR-EX than SHR-SED. Myocardial function was better in SHR-EX (positive derivative of developed tension) than SHR-SED. SHR-EX had higher antioxidant enzyme activity than SHR-SED. Lipid hydroperoxide concentration, myocyte diameters, and phosphorylated JNK and total IkB protein expression were higher in hypertensive than control groups. Hydroxyproline, malondialdehyde, NADPH oxidase activity, and protein expression of collagen III, lysyl oxidase, TIMP-1, total JNK, phosphorylated p38, phosphorylated and total p65, and phosphorylated IkB did not differ between groups. Interstitial collagen fraction, MMP-2 activity, and protein expression of total p38, and total and phosphorylated ERK were higher in SHR-SED than W-SED. Exercise reduced MMP-2 activity and phosphorylated ERK in hypertensive rats.

Conclusion

Physical exercise improves physical capacity, reduces the frequency of heart failure features, and attenuates cardiac remodeling in spontaneously hypertensive rats. In addition, exercise increases antioxidant enzyme activity, decreases ERK phosphorylation and MMP-2 activity, and attenuates total ERK protein expression.

Acknowledgement/Funding

Fapesp, CNPq, Capes and UNESP
P4435Effects of interleukin 6 inhibitor tocilizumab on endothelial glycocalyx, vascular and myocardial function compared to prednisolone
Authors: Ikonomidis I , Pavlidis G , Katsimbri P , Andreadou I , Triantafyllidi H , Tsoumani M , Varoudi M , Thymis I , Triantafyllou C , Kostelli G , Frogoudaki A , Vrettou A R , Boumpas D , Alexopoulos D , Iliodromitis E
Published: October 2019

Background/Introduction

Tocilizumab, a humanised monoclonal antibody against the human interleukin-6 receptor, is used for the treatment of rheumatoid arthritis (RA).

Purpose

We investigated the effects of tocilizumab on arterial function, LV myocardial deformation and endothelial glycocalyx in RA patients.

Methods

80 patients with rheumatoid arthritis were randomized to tocilizumab (n=40) or prednisolone (n=40) for 3 months. At baseline and after 3-month treatment we assessed: a) carotid-femoral pulse wave velocity (PWV-Complior SP ALAM), b) LV longitudinal strain (GLS), systolic (LongSr) and diastolic (LongSrE) strain rate using speckle tracking echocardiography, c) perfused boundary region (PBR) of the sublingual arterial microvessels (ranged from 5–25μm) using Sideview Darkfield imaging (Microscan, Glycocheck). Increased PBR is considered an accurate index of reduced endothelial glucocalyx thickness, d) flow mediated dilatation (FMD) of the brachial artery after and percentage difference of FMD (FMD%) after hyperemia, e) coronary flow reserve (CFR) of the LAD using Doppler echocardiography, and f) malondialdehyde (MDA), protein carbonyls (PCs) and C-reactive protein (CRP) plasma levels.

Results

At baseline, all patients had similar disease activity score and markers of vascular and myocardial function. Compared to baseline, all patients had reduced CRP post treatment, while MDA and PCs levels were reduced only after tocilizumab treatment (p<0.05). The percent decrease of MDA was correlated with percent increase of GLS (p<0.001). Compared to baseline, tocilizumab-treated patients reduced PWV (11±3% vs. 10.3±2m/sec) and PBR (2.11±0.2 vs. 1.95±0.18μm) (Figure 1) and increased GLS (−16.1±2.9 vs. −17.6±2.5%), CFR (2.73±0.8 vs. 3.06±1), and FMD% (5.9±2.9 vs. 11.6±3.6) (p<0.05 for all comparisons). No significant changes were observed among prednisolone-treated patients.

Figure 1

Conclusions

IL-6 inhibition improves endothelial function and oxidative stress resulting to improved vascular function and LV myocardial deformation.
P4467PCSK9 and Lp(a) levels of children born after assisted reproduction technologies: results from a pilot study
Authors: Koutagiar I , Vlachopoulos C , Terentes-Printzios D , Kosteria I , Sakka S , Gkourogianni A , Skoumas I , Miliou A , Papassotioriou I , Gardikioti V , Solomou E , Rigatou A , Chrousos G , Kanaka-Gantenbein C , Tousoulis D
Published: October 2019

Background

Since the introduction of Assisted Reproduction Technologies (ART) in clinical practice several studies have addressed concerns regarding the long-term health of the offspring and have revealed indications of an adverse cardiovascular/cardiometabolic outcome. Proprotein convertase subtilisin/kexin type 9 (PCSK9) and lipoprotein (a) (Lp[a]) levels have been associated with cardiovascular risk.

Purpose

To investigate PCSK9 and Lp(a) levels of children born after ART compared with naturally conceived (NC) controls.

Methods

In this case-control study, 73 sex- and age-matched children (mean age 98±35 months) of ART (intracytoplasmic sperm injection [ICSI]: n=33, classic in vitro fertilization [IVF]: n=40) and 73 NC children were assessed. Blood lipid profile, including PCSK9 and Lp(a) levels, was measured. Children were grouped according to age (<8 years, 8–10 years, ≥10 years).

Results

In the univariate model of the overall population, circulating PCSK9 levels were related to total cholesterol (r=0.186, P=0.025), LDL-C (r=0.180, P=0.029) and SBP (r=0.199, P=0.021). Similarly, circulating Lp(a) levels were related to age (r=0.269, P=0.001), apoB (r=0.214, P=0.01), birth weight (r=−0.183, P=0.037), height (r=0.263, P=0.001), waist-to-hip ratio (r=−0.350, P<0.001), HOMA-IR (r=0.319, P<0.001), insulin (r=0.316, P<0.001), and hsCRP (ρ=0.241, P=0.018). No significant differences were observed regarding lipid biomarkers between ART and NC children. (p=0.515 for PCSK9 and p=0.277 for Lp(a) values). It is noteworthy that a significant interaction was found between age groups and conception method (P<0.001) showing that PCSK9 levels increase with age in ART children, while they decline with age in NC offspring (Figure 1). IVF children showed higher levels of adjusted mean Lp(a) than ICSI (13.5 vs. 6.8 mg/dl, P=0.010) and NC children (12.3 vs. 8.3 mg/dl, P=0.048).

Mean LogPCSK9 concentrations with the st

Conclusions

PCSK9 and Lp(a) levels did not differ between ART and NC children. Nonetheless, PCSK9 levels increase with age in ART children indicating a gradual deterioration of lipidemic profile that could lead to increased cardiovascular risk. Moreover, our results imply that ART method may be of importance given that classic IVF is associated with higher levels of Lp(a). The impact of the method of conception on PCSK9 and Lp(a) values should be validated in larger patient series.
P4468Dietary plant derived omega-3 fatty acid alpha linolenic acid prevents age-dependent arterial stiffness and improves outcome after stroke in mice
Authors: Bonetti N R , Diaz-Canestro C , Pasterk L , Liberale L , Vdovenko D , Gobbato S , Luescher T F , Camici G G , Beer J H
Published: October 2019

Background

A fundamental determinant of cardio- and cerebrovascular diseases is vascular aging, characterized by arterial stiffness. Arterial stiffness is an independent predictor of adverse cardio- and cerebrovascular events and mortality.

Fish-derived omega-3 fatty acids (n3-FA) have been described to decrease cardiovascular events in high risk populations. Little is known on the effects of the plant-derived n3 FA alpha-linolenic acid (ALA). More insight is urgently needed, because of the low costs and abundant global supply of ALA. Thus, we aimed to investigate the effects of a long-term dietary intervention with ALA on age-dependent arterial stiffness and the magnitude of these effects on a specific vascular endpoint – ischemic stroke – in a mouse model of aging.

Methods

C57BL/6 wildtype males were either fed an ALA-rich (high ALA, 7.3 g%) or a respective control (0.3 g%) diet for 12 months, starting from 6 months of age.

At 9, 15 and 18 months, arterial stiffness was assessed by measuring pulse wave velocity (PWV) in the right common carotid artery using a Vevo 3100 system (VisualSonics, Fig. 1A).

At 18 months, ischemic stroke was induced by transient middle cerebral artery occlusion (30 mins/48 h). Stroke size was assessed by triphenyl tetrazolium chloride staining and neurological function by a Bederson based score.

Results

Arterial stiffness steadily and significantly increased in controls over time, while ALA clearly and effectively prevented it (PWV at 9 vs. 18 months: controls + 95%; p<0,0001 vs. High ALA + 15%; ns) (Fig 1A).

Stroke size at 18 months was significantly decreased in ALA-fed animals compared to controls (28.39 mm3 vs. 51.77 mm3 p=0.0017) (Fig. 1B). In line with the morphological changes, controls performed significantly worse neurologically (Fig. 1C). Additionally, post-stroke survival at 48 h was improved in ALA-fed animals compared to controls, with 85% survival compared to 57% (Fig. 1D).

Figure 1

Conclusion

We demonstrate that long-term dietary supplementation with the plant-derived ALA fully prevents the development of age-dependent arterial stiffness.

The magnitude of this effect is clearly reflected in biologically relevant decreased stroke size, improved neurological performance and even post-stroke survival.

This study not only demonstrates vasoprotective effects of ALA, but also links them to improved outcome of a specific clinical endpoint. Future analyses will aim at delineating the molecular basis of the observed benefits. This will result in a better understanding of some ambiguous results from clinical trials and likely define the population which benefits from ALA.