bluuebunny/crossref_metadata_2025 huggingface dataset:
The contribution of X-chromosome genomic imprinting to the bicuspid aortic valve and aortic coarctation prevalence in women with Turner syndrome
Authors: Klaskova E , Vrtel P , Vrtel R , Adamova K , Vrbicka D.I.T.A , Zapletalova J , Prochazka M , Pavlicek J , Lebl J , Stara V , Soucek O , Snajderova M , Hana V
Published: November 2020

Introduction

Turner syndrome (TS) is caused by the absence or structural abnormality of X chromosome. Compared with the general population, the prevalence of congenital heart defects is significantly higher in women with TS, especially with 45,X karyotype. Moreover, congenital heart defects represent the major risk for aortic dissection in TS individuals.

Purpose

There is a lack of reliable evidence whether the extremely variable cardiovascular phenotype including presence of aortic coarctation (CoA) and bicuspid aortic valve (BAV) in TS women may be influenced by the parental origin of the retained X chromosome.

Methods

DNA samples were collected from peripheral lymphocytes of 48 women with non-mosaic 45,X karyotype and from buccal swab of their biological parents' cheek. Subsequently, the single normal X-chromosome origin was identified. Based on genetic evaluation, patients were divided into two subgroups according to the parenteral original of X chromosome - maternal (XM), and paternal (XP). Complete cardiovascular examination (echocardiography, MRI of the heart and great vessels) was performed in each of our study patient. Differences between the prevalence of BAV and CoA in two above mentioned subgroups were tested by Student's t-test using R Statistical Software version 2.15.3.

Results

The origin of the single X chromosome was as follows: in 14 (29.2%) individuals was proved paternal and in 34 (70.8%) maternal origin of X chromosome. The prevalence of BAV in the whole group was 47.9%, in XP 58%, in XM 44.1%; the prevalence of CoA in the whole group was 8.3%, in XP 7.1%, in XM 8.8%. There was no statistically significant difference identified between the prevalence of BAV and CoA in XP and XM subgroups.

Conclusions

Our study confirmed an extremely high prevalence of BAV and CoA in non-mosaic women with X chromosome monosomy but no clear evidence for X-linked genomic imprinting effect on the CoA and BAV development in TS individuals was found. However, further studies of larger numbers of TS patients are crucial to finally clarify the real relationship of genomic imprinting and cardiovascular disease in TS.

Funding Acknowledgement

Type of funding source: Public grant(s) – National budget only. Main funding source(s): Supported by the grant from Ministry of Health of the Czech Republic VES 2017
Risk of myocardial infarction in middle aged and older patients with coarctation of the aorta
Authors: Fedchenko M , Mandalenakis Z , Giang K.W , Eriksson P , Rosengren A , Dellborg M
Published: November 2020

Introduction

Previous case-control studies have compared the risk of coronary artery disease/myocardial infarction (MI) in patients with coarctation of the aorta (CoA) with other congenital heart disease diagnoses, however, these studies have only included younger patients in their 20s and 30s, not older patients. As the atherosclerotic burden is increasing with increasing age, it is important to study the risk of MI in older patients (from early middle age and older) with CoA.

Purpose

The aim of our study was to investigate the risk of MI in older patients (≥40 years) with CoA, and to compare this risk with the risk in patients of the same age with ventricular septal defects (VSD), the most common congenital heart condition.

Methods

We used data from the Swedish National Patient Registry (NPR) to identify all patients alive at 40 years of age with a diagnosis of CoA or VSD, born during the period 1930–1970. The follow-up through the NPR and the Cause-specific Death Registry started in January 1970 and went on until December 2017.

Results

Altogether 1204 patients with CoA and 2079 patients with VSD were identified in the registers, and in total, 97 (8.1%) patients with CoA and 162 (7.8%) patients with VSD developed an MI during follow up. Mean follow up time was 20.6±10.3 years in CoA patients and 21.3±10.9 in the VSD group. The risk of MI was similar in CoA compared with VSD patients (HR 1.1, 95% confidence interval 0.9–1.5, p=0.3) Median age at MI was similar in CoA patients and in VSD patients; in CoA 59.8 years (range 40.1–87.5), in VSD 61.2 (range 40.2–87.5), p=0.3. Hypertension (diagnosed before MI or within a year after MI) was more common in CoA patients with an MI (58.8%) compared with VSD patients (37.7%), however, prevalence of diabetes mellitus and hyperlipidemia was similar in both patient groups (18.6% and 21.6% in CoA respectively, compared to 17.9% and 22.8% in VSD group). After adjustment for hypertension, diabetes mellitus and hyperlipidemia, the risk of MI remained similar in patients with CoA and VSD (hazard ratio 1.1, 95% confidence interval 0.8–1.4, p=0.5).

Conclusion

In this large nationwide study, we found that in older patients with CoA (median age at MI 60 years, range 40–88 years) the risk of MI was not increased and similar to that of patients with VSD with similar age at MI. Adjustment for hypertension, diabetes mellitus and hyperlipidemia did not modify this finding which suggests that patients with CoA do not have an increased risk of MI, compared to patients with VSD.

Funding Acknowledgement

Type of funding source: Public grant(s) – National budget only. Main funding source(s): This work was funded by the Swedish state under an agreement between the Swedish government and county councils, the ALF agreement (Grant number: 236611) and the Swedish Heart-Lung Foundation (Grant Number: 20090724).
Early experience with selexipag for the treatment of adults with pulmonary arterial hypertension associated with congenital heart disease
Authors: Van Dissel A , Post M , Sieswerda G.T , Vliegen H.W , Van Dijk A.P.J , Duijnhouwer A.L , Mulder B.J.M , Bouma B.J
Published: November 2020

Background

Recently, selexipag, a new orally available and selective prostacyclin receptor agonist, has become available for treatment of pulmonary arterial hypertension (PAH), but experience in patients with PAH associated with congenital heart disease (CHD) is limited to patients with closed defects.

Purpose

We present our early multi-centre experience using selexipag in the heterogeneous PAH-CHD population.

Methods

We prospectively evaluated adults with PAH-CHD from five PAH-CHD expert centres who were treated with selexipag. Patients were titrated to highest tolerable individualized dose (200 to 1,600 μg twice daily), after which patients entered the maintenance phase. Data on functional class (FC), 6-minute walk distance (6MWD), imaging and biochemical (N terminal pro-brain natriuretic peptide [NT-proBNP]) parameters were collected.

Results

Thirty-four patients (age 43±14 years, 56% female, 60% Eisenmenger syndrome, 22% Down syndrome, 60% dual PAH therapy) were started on selexipag. All patients experienced at least 2 side effects during the initial uptitration phase. Most side effects were manageable and diminished after reaching the maintenance dose, but eight patients discontinued treatment due to side effects during the titration phase. The most frequent side effects were consistent with the known side effects of prostacyclins, including headache, nausea, diarrhoea and jaw pain. Majority (68%) of patients reached lower maintenance doses of 200–600 μg. At 12 months, FC improved in three patients and remained unchanged in the others. 6-minute walk distance remained stable throughout follow-up (475 to 470 m; p=n.s.) in patients who remained on-treatment compared to patients who stopped selexipag (485 to 370 m). NT-proBNP levels remained stable in patients on-treatment (520 to 600 ng/L) but worsened in patients who stopped (700 to 1000 ng/L). One patient died during follow-up from end-stage heart failure.

Conclusion

There is a promising role for selexipag in the treatment of adults with PAH-CHD. However, based on our experience, the use is challenging due to complexity in dosing and side effect profiles, which limit patients' tolerability and acceptance during the titration phase.

Funding Acknowledgement

Type of funding source: Other. Main funding source(s): Actelion Pharmaceuticals
Comparison between cheatham-platinum stent and self-expandable uncovered nitinol stent in patients with coarctation of aorta – a randomized controlled trial
Authors: Sadeghipour P , Shafe O , Moosavi J , Basiri H.A , Abdi S , Firouzi A , Khajali Z , Saedi S , Mohebbi B , Maleki M , Pouraliakbar H.R , Samiei N , Sadeghpour A , Alemzadeh M.J , Shahdi S
Published: November 2020

Background

Endovascular treatment is considered the main therapeutic approach for native coarctation of aorta (CoA) in adult patients. Balloon-expandable stents (BE) have been introduced as the primary choice for coarctoplasty. However during the recent years, self-expandable (SE) stents with acceptable radial force have been suggested as an alternative. Still, no randomized controlled (RCT) trials have compared the efficacy and safety of both strategies.

Methods

The present study is a prospective, single center, parallel-group, open-label RCT on patients with native CoA (Figure). Patients were randomized into Bare Cheatham-Platinum Stents and Uncovered Nitinol Stent (SE). All patients were scheduled to be followed in 1-, 6-, 12-month and 36-month intervals. The present report, focuses on the one-year outcome of the study.

Results

Of 101 patients with native CoA referred to our center, 93 patients have been randomized into BE- (47 patients) and SE-arm (46 patients). One year follow up is scheduled to be completed on March 2020. In the preliminary analysis of 62 patients, 1 intraprocedural stent migration has occurred in each group. No aortic perforation was detected in the study. Vascular access site complications were similar between the two groups (3 (6.3%) in BE versus 1 (2.1%) in SE, p value= 0.432). One nonfatal stroke occurred in BE group. No mortality or bailout surgical repair happened in one year study in the two groups. One patient with re-coarctations were detected during one year follow up in each of the groups (p value=0.210). No aortic pseudoaneurysm or aneurysmal formation were observed in 12-month follow up aortic CT angiography.

Conclusion

The preliminary results showed no significant difference in efficacy and safety of both treatment modalities. The final result is pending.

Study Flow Chart

Funding Acknowledgement

Type of funding source: None
Anatomical predictors of residual left-to-right shunt after percutaneous suture-mediated patent fossa ovale closure
Authors: Gaspardone A , De Santis A , Iamele M , D'Ascoli E , Piccioni F , D'Errico F , Giannico M.B , Summaria F , Gioffre' G , Sgueglia G
Published: November 2020

Background

Percutaneous suture-mediated patent fossa ovale (PFO) closure has recently been introduced in clinical practice to overcome most of the limitations of metallic PFO occluders with early results showing a favourable efficacy and safety profile in most PFO cases.

Purpose

To assess PFO anatomy in a large series of patients undergoing percutaneous suture-mediated PFO closure in order to identify anatomical predictors of significant residual right-to-left shunt (RLS) and thus appropriately select patients to be submitted to this technique.

Methods

Pre-procedural transesophageal echocardiogram of 230 patients undergoing suture-mediated PFO closure at our Institution were carefully reviewed both qualitatively and quantitatively. The following parameters were systematically assessed in all reviewed cases: presence and grade of baseline atrial RLS, presence of bidirectional shunt, PFO length and width, presence of atrial septal aneurysm and its maximal bulge, presence and size of an embryonic or foetal remnant.

Results

In 37 patients a residual atrial RLS ≥2 grade was found at a mean follow-up of 248±147 days. The following variable were found to be significantly associated with significant residual atrial RLS at follow-up: grade of baseline spontaneous and Valsalva manoeuvre RLS shunt (odds ratio 2.39, 95% confidence interval 1.48–3.89, p=0.001 and odds ratio 3.07, 95% confidence interval 1.22–7.23, p=0.017), baseline bidirectional shunt across the PFO (odds ratio 3.59, 95% confidence interval 1.47–8.77, p=0.005) and PFO width (odds ratio 2.61, 95% confidence interval 1.92–3.55, p=0.001).

At multivariable analysis, only PFO width ≥5 mm (odds ratio 10.97, 95% confidence interval 4.22–28.56, p=0.001) and grade of baseline RLS shunt (odds ratio 1.84, 95% confidence interval 1.05–3.21, p=0.032) were independent predictors of a significant atrial RLS at follow-up.

Conclusions

Suture-mediated PFO closure represents a valid alternative to traditional devices with an excellent safety and efficacy profile at follow-up. As for any new technique, it is extremely important to select the right anatomical and functional features predictive of a successful closure. The results of this study indicate that the suture-mediated closure of PFO is feasible in the majority of septal anatomies however wide PFO ≥5 mm are less likely to be closed with only one stitch.

Funding Acknowledgement

Type of funding source: None
Pulmonary vascular resistance and pulmonary artery compliance in a large cohort of patients with sinus venosus septal defect
Authors: Van De Bruaene A , Van Dessel L , Troost E , De Meester P , Budts W
Published: November 2020

Background

Left-to-right shunt in patients with sinus venosus septal defect (SVSD) may affect resistive (pulmonary vascular resistance – PVR) and elastic (pulmonary artery compliance-PAC) properties of the pulmonary arteries. This study aimed at evaluating (1) changes in hemodynamics over time and (2) the relationship between PVR and PAC in a large cohort of patients with SVSD.

Methods

Data of 136 patients with SVSD (median age at diagnosis 14 (IQR 5–48) years, 47% male) were included. Catheterization data was available in 87 patients. Pressures were measured and cardiac output evaluated using the Fick principle. PVR (mean pulmonary artery pressure (mPAP)-wedge pressure/cardiac output) and PAC (stroke volume/pulse pressure) were calculated and indexed for body surface area.

Results

Ninety percent had abnormal pulmonary venous connection. Median shunt ratio was 2.5 (IQR 2.0–2.9). Repair was performed in 128 (94%) at a median age of 13 (IQR 5–43) years. During a median follow-up time of 31 (IQR 17–55) years, 12 (9%) patients died, 13 (10%) developed heart failure, 19 (14%) atrial arrhythmia, 6 (4%) sick sinus syndrome and 7 (5%) required pacemaker implantation. PVR indexed and PAC indexed was 3.5 (IQR 2.4–7.5) WU·m2 and 1.8 (IQR 1.3–2.5) mL/mmHg·m2. There was an inverse, hyperbolic relationship between PVR and PAC with an RC time of 6.6 (IQR 4.4–8.9) sec. When comparing patients with age at catheterization <10 years, 10–50 years and >50 years, shunt ratio (2.5±0.6 vs 2.5±0.8 vs 2.5±0.6; p=0.836) and PVR indexed (2.9 (2.3–3.4) vs 3.1 (2.0–9.0) vs 6.6 (3.6–8.8) WU·m2; p=0.132) were not statistically different, whereas mPAP (19 (16–22) vs 21 (16–24) vs 28 (22–34) mmHg; p=0.002); wedge (6 (4–8) vs 13 (8–16)vs 14 (10–19) mmHg; p<0.0001) and PAC indexed (2.2 (1.5–2.9) vs 2.0 (1.4–2.8) vs 1.3 (0.9–1.7) mL/mmHg·m2; p=0.002) differed significantly.

Conclusion

SVSD is associated with late morbidity and mortality. In SVSD, PVR and PAC are inversely related. Over time, the changes in elastic resistance (PAC or pulsatile load) are more profound than changes in resistive (PVR – steady load).

Figure 1

Funding Acknowledgement

Type of funding source: None
Outcome of patients with tetralogy of Fallot repair over 50 years of age
Authors: Antal A , Szegedi M , Takacs E , Szabo B , Solymosi B , Vincze V , Ablonczy L , Kornyei L , Temesvari A , Andreka P , Balint H
Published: November 2020

Purpose

To report the outcomes of patients with repaired tetralogy of Fallot (TOF) above 50 years of age.

Methods

We reviewed records of TOF patients who were followed in our institution since 2000. Demographic data, surgical reports and long-term outcomes were analyzed retrospectively.

Results

Thirty-five of 297 (12%) patients who underwent TOF repair were above 50 years of age (25 men [60%]) at the last follow-up. Eighteen patients (48%) had prior palliative surgery. The mean age at the first repair was 18±13 years (5 patients after 40 years of age). Reoperation with pulmonary valve replacement was performed in 10 (28%) patients, and a second redo surgery in 6 (17%) patients. During a mean 17± 2 years follow-up 7 (8.5%) patients died (n=6 end-stage heart failure, n=1 infective endocarditis). At the last follow-up 21/35 patients (60%) were treated with tachyarrhythmia, 19/35 (54%) with chronic heart failure and 17/35 (48%) with comorbidities (hypertension, coronary artery disease/peripherial artery disease, diabetes mellitus, renal failure). Using multivariate analysis the only predictor of death was heart failure (OR: 6.8). Furthermore atrial tachycardia (OR: 8.8) and at least grade II tricuspid regurgitation (OR: 5.0) were identified as predictors of heart failure.

Conclusion

This historical cohort of TOF patients with late repair has a high morbidity rate later in life. Approximately half of the patients require treatment for chronic heart failure, arrhythmias and cardiovascular related comorbidities. Atrial tachycardia and tricuspid regurgitation are strong predictors for heart failure. In this population the strongest predictor for death is heart failure.

Funding Acknowledgement

Type of funding source: None
Right atrial mechanics by strain echocardiography in chronic thromboembolic pulmonary hypertension
Authors: Ferreira Fonseca M , Baptista R , Samouco G , Soeiro P , Martins R , Castro G , Goncalves L
Published: November 2020

Introduction

Chronic thromboembolic pulmonary hypertension (CPTEH) is the result of thromboemboli leading not only to mechanical obstruction but also pulmonary vascular remodelling and progressive increase in right heart afterload. Prognostic assessment in CPTEH is complex and multifactorial.

Purpose

We used two-dimensional strain echocardiography (2D-STE) to quantify right atrial (RA) mechanics and its correlation with invasive hemodynamics, load-dependent biomarkers and well-known prognostic markers in patients with CTEPH.

Methods

A total of 44 patients (24 females, mean age 61±15.6 years) with CTEPH were recruited. 2D-STE was used to measure right atrial reservoir strain (RASr) (Figure 1) which was then compared to conventional ultrasound measurements, right heart catheterisation (RHC) measurements, the percentage of obstruction in ventilation-perfusion pulmonary single-photon emission computed tomography (V/Q SPECT), B-type natriuretic peptide (BNP) values and 6-minute walk test (6MWT) performance. All patients underwent transthoracic echocardiographic evaluation with a maximal time distance of three months to RHC.

Results

There was a significant positive correlation of RASr with RV longitudinal function determined by tricuspid annular plane systolic excursion (TAPSE) (r=0.488, p=0.003), tricuspid annular peak systolic velocity (S') (r=0.490, p=0.002), right ventricular outflow tract velocity time integral (RVOT VTI) (r=0.457, p=0.005), as well as with 6MWT (r=0.491, p=0.004). There was a significant negative correlation of RASr with mean pulmonary artery pressure (r=−0.513, p=0.002), pulmonary vascular resistance (r=−0.439, p=0.011) and right atrial pressure (RAP) (r=−0.513, p=0.002). RASr was also correlated with Log-transformed BNP values (r=−0.552, p<0,001), and in a multivariate linear regression model, RASr was an independent predictor of Log-transformed BNP values (β=−0.448, 95% CI: −0.046 to −0.009; p=0.005). There was no correlation between RASr and the percentage of obstruction in V/Q SPECT (r=0.164, p=0.388).

Conclusion

2D-STE-derived RA mechanics demonstrated to be a useful, non-invasive, surrogate measurement of RHC parameters. It also predicted important clinical/laboratory prognostic measurements, such as BNP and 6MWT performance. The absence of correlation between 2D-STE values and the percentage of vessel obstruction determined by SPECT may suggest that RV maladaptive response to the obstruction, rather than the degree of obstruction, dictates right heart failure in CTEPH.

Right atrial strain components

Funding Acknowledgement

Type of funding source: None
Right ventricular myocardial work in patients with HFrEF
Authors: Butcher S.C , Fortuni F , Montero J.M , Ajmone Marsan N , Delgado V , Bax J.J
Published: November 2020

Background

Right ventricular myocardial work (RVMW) is a novel method of non-invasively quantifying right ventricular (RV) systolic function. Through the use of speckle tracking echocardiography-derived RV pressure-strain loops, RVMW provides a quantitative evaluation of afterload-dependent RV systolic function.

Purpose

To investigate RVMW in patients with heart failure and reduced ejection fraction (HFrEF) and compare to that of patients without cardiovascular disease (CVD) and a structurally and functionally normal heart.

Methods

Noninvasive analysis of RVMW was performed in 23 HFrEF patients and 23 patients without cardiovascular or structural heart disease. The novel indices of RV global constructive work (RVGCW), RV global work index (RVGWI), RV wasted work (RVWW) and RV global work efficiency (RVGWE) were analysed utilizing proprietary software originally developed for the assessment of left ventricular myocardial work by speckle tracking echocardiography. Parameters of RVMW were then compared between the two patient groups.

Results

The HFrEF group had lower left ventricular (LV) ejection fraction (18.7% [±6.7] vs 60.1% [±4.6], p<0.0001), LV global longitudinal strain (−3.6% [±1.6] vs −20.4% [±2.1), p<0.0001) and RV global longitudinal strain (−10.0% [±4.2] vs −22.0% [±3.1], p<0.0001) when compared to those with no CVD. Estimated pulmonary artery systolic pressure (42.5mm Hg [±12] vs 22.5mm Hg [±3.7], p<0.0001) and estimated right atrial pressure (8mm Hg (5 to 15) vs 5mm Hg (5 to 5), p<0.0001) were significantly higher in the HFrEF group. RVGWI (259.7mmHg% [±135.0] vs 385.3mmHg% [±103.1], p=0.001), RVGWW (83.7mmHg% [±58.6] vs 14.5mmHg% [8.5 to 20.5], p<0.0001) and RVGWE (77.2% [11.4] vs 95.5% [93.5 to 97], p<0.0001) were significantly lower in the HFrEF group when compared to those without CVD. There was no statistically significant difference in RVGCW between the two groups (353.5mmHg% [±118.4] vs 417.2 [±102.1], p=0.057).

Conclusion

The novel parameters of RVGWI, RVGWW and RVGWE were significantly reduced in patients with HFrEF when compared to those without CVD. Further exploration of the clinical role and prognostic value of these afterload dependent parameters of RV systolic function is warranted.

Funding Acknowledgement

Type of funding source: None
Short term effect of Selexipag in comparison to parenteral prostacyclin analogues in pulmonary arterial hypertension patients started on double-combination therapy with ERA and PDE-5 inhibitors
Authors: Dardi F , Zuffa E , Palazzini M , Pasca F , De Lorenzis A , Guarino D , Magnani I , Ballerini A , Rotunno M , Manes A , Galie N
Published: November 2020

Background

The event-driven, phase 3, randomized, double-blind, placebo-controlled GRIPHON trial demonstrated that Selexipag reduces the risk of a composite end point of death or morbidity events in patients with pulmonary arterial hypertension (PAH). Despite the advantage of a per os formulation, its efficacy in comparison to parenteral prostacyclin analogues in patients already on oral double-combination therapy with endothelin receptor antagonist (ERA) and phosphodiesterase-5 inhibitor (PDE5-I) is not known.

Purpose

The aim of this study was to compare the effects of Selexipag (S) vs subcutaneous Treprostinil (T) vs intravenous Epoprostenol (E) in PAH patients initially started with double-combination therapy with ERA and PDE5-I.

Methods

We enrolled patients on double combination therapy with ERA + PDE5-I starting S, T or E. Drugs were gradually uptitrated to the maximum tolerated/approved dose. All patients were systematically assessed with WHO-functional class (FC), six minute walk test (6MWT) and right heart catheterization before treatment and 3 months after reaching a stable dose of the drug. Baseline characteristics and changes in 6MWT and haemodynamic parameters were analyzed using Wilcoxon signed-rank test and compared between the 3 drugs with Kruskal-Wallis test.

Results

One hundred and seventy-one patients with PAH were enrolled. Results are shown in the Table. Patients with a complete re-evaluation were 61% of S, 85% of T, 79% with E.

Conclusions

S was prescribed to the oldest and least severe PAH patients. E was prescribed to the youngest and most severe PAH patients and led to the strongest improvement of exercise capacity and haemodynamic profile. T has intermediate characteristics.

Table 1

Funding Acknowledgement

Type of funding source: None
Time trends of pulmonary endarterectomy in patients with chronic thromboembolic pulmonary hypertension
Authors: Hobohm L , Keller K , Munzel T , Konstantinides S.V , Lankeit M
Published: November 2020

Background and purpose

Chronic thromboembolic pulmonary hypertension (CTEPH) is considered as a rare but severe complication after acute pulmonary embolism (PE) and is potentially curable by pulmonary endarterectomy (PEA). We aimed to evaluate, over an 11-year period, time trends of in-hospital outcomes of PEA in CTEPH patients in the German nationwide inpatient sample.

Methods and results

We analyzed data on the characteristics, comorbidities, treatments and in-hospital outcomes for all CTEPH patients treated with PEA in Germany between 2006 and 2016. Overall, 1,398 inpatients were included. The annual number of PEA increased from 67 in 2006 to 194 in 2016 (β 0.69 [95% CI 0.51 to 0.86]; p<0.001) in parallel with a significant decrease of in-hospital mortality (10.9% in 2008 to 1.5% in 2016; β −1.85 [95% CI: −2.46 to −1.24]; p<0.001). Patients' characteristics shifted slightly towards older age and higher prevalence of chronic renal insufficiency and obesity over time, whereas duration of hospital stay decreased over time. Independent predictors of in-hospital mortality were age and right heart failure, and in-hospital complications such as ischemic stroke and bleeding events.

Conclusions

The number of CTEPH patients treated with PEA increased markedly in Germany between 2006 and 2016, in parallel with a decrease of in-hospital mortality. Our findings may suggest that the perioperative management of PEA and the general patients' selection have improved over time and might draw more attention to predictors for in-hospital mortality for CTEPH patients hospitalized for PEA.

Funding Acknowledgement

Type of funding source: Public grant(s) – National budget only. Main funding source(s): This study was supported by the German Federal Ministry of Education and Research (BMBF 01EO1503).
Quality of life 3 and 12 months after acute pulmonary embolism: analysis of 617 patients from the prospective multicentre FOCUS study
Authors: Valerio L , Barco S , Jankowski M , Rosenkranz S , Lankeit M , Held M , Gerhardt F , Bruch L , Ewert R , Faehling M , Freise J , Ardeschir Ghofrani H , Gruenig E , Halank M , Konstantinides S.V
Published: November 2020

Background

Few data are available on the long-term course and predictors of quality of life (QoL) after acute pulmonary embolism (PE).

Aims

To evaluate the kinetics and determinants of QoL at 3 and 12 months after acute PE.

Methods

The Follow-Up after acute pulmonary embolism (FOCUS) study prospectively followed consecutive adult patients with objectively diagnosed PE. For this analysis, we considered patients who completed the Pulmonary Embolism QoL (PEmb-QoL) Questionnaire at two predefined visits 3 and 12 months after PE. PEmb-QoL, studied as total score and in its six dimensions, ranges from 0% (best QoL) to 100% (worst QoL). We studied the course of PEmb-QoL and the impact of baseline characteristics using multivariable linear regression.

Results

In 617 included patients (44% women, median age 62 years), overall QoL improved from 3 to 12 months, with a decrease of the mean PEmb-QoL score from 25.3% to 21.5% (p-value <0.001). Intra-individual correlation between PEmb-QoL score at 3 and 12 months was high; Figure A. The improvement was consistent across all PEmb-QoL dimensions; Figure B. Female sex, cardiopulmonary diseases, and higher body mass index were the main factors associated with a worse QoL; Table. Age and smoking affected QoL only at 12 months. The improvement in QoL was faster in patients without cardiopulmonary diseases (−4.2%; 95% CI: −5.2% to −3.1%), without previous VTE (−4.3%; −5.5% to −3.2%), and in non-smokers (−4.2%; −5.3% to −3.1%).

Conclusions

In a large cohort of patients with pulmonary embolism, we quantified the improvement of QoL between 3 and 12 months after diagnosis. We identified factors independently associated with lower QoL and slower recovery of QoL that may reflect special patient needs. These estimates may facilitate the planning and interpretation of clinical trials with QoL as a study outcome.

Figure 1

Funding Acknowledgement

Type of funding source: Public grant(s) – National budget only. Main funding source(s): University Medical Center of the Johannes Gutenberg University, Mainz, Germany; German Federal Ministry of Education and Research
Functional outcomes and quality of life during long-term follow-up after acute pulmonary embolism: analysis of the prospective multicentre FOCUS study
Authors: Barco S , Valerio L , Jankowski M , Hoeper M.M , Klok F.A , Leuchte H.H , Mayer E , Meyer F.J , Neurohr C , Opitz C , Seyfarth H.J , Trudzinski F , Wachter R , Wilkens H , Wild P.S
Published: November 2020

Background

It is unclear to which extent persistence of symptoms and/or residual haemodynamic impairment clinical course of pulmonary embolism are associated with worse quality of life (QoL).

Aims

To study the correlation between symptoms and haemodynamic impairment with QoL during the first year after acute pulmonary embolism (PE).

Methods

The Follow-Up after acute pulmonary embolism (FOCUS) study prospectively enrolled and followed consecutive adult patients diagnosed with acute symptomatic objectively diagnosed PE. In the present analysis, we considered patients who completed the Pulmonary Embolism QoL (PEmb-QoL) Questionnaire at predefined visits 3 and 12 months after acute PE. The PEmb-QoL score ranges from 0% (best QoL) to 100% (worst QoL). We evaluated at these two time points the correlation between persisting symptoms (group: symptoms), elevation of natriuretic peptides or residual right ventricular dysfunction (group: RVD), or their combination (group: symptoms + RVD) and QoL.

Results

A total of 617 patients were included; their median age was 62 years, 44% were women; 8% had active cancer, and 21% previous venous thromboembolism. At 3 months, patients with neither symptoms nor RVD (n=302) had the highest quality of life (median score 18%, 25th–75th percentile: 8%–34%), followed by those without symptoms but with RVD (n=255; median score 19%, 25th–75th percentile: 7%–34%), and by those with symptoms only (n=131; median PEmb-QoL 31%, 25th–75th percentile: 18%–49%). Patients with both symptoms and RVD (n=170) had the worst quality of life (median score 38%, 25th–75th percentile: 19%–53%); Figure 1A. At 12 months, we found an overall improvement of PEmb-QoL score. The degree of this QoL improvement varied across groups, being largest for patients who recovered from having symptoms + RVD at 3 months to normalization of at least one at 12 months. The change in QoL from 3 to 12 months was smaller both in patients who had neither symptoms nor RVD and in patients who had no recovery in either symptoms or RVD; Figure 1B.

Conclusions

Persistent symptoms after PE, especially in patients with elevated biomarkers or residual echocardiographic dysfunction, were the main drivers of QoL at 3 months as well as of the course of QoL over time.

Figure 1

Funding Acknowledgement

Type of funding source: Public grant(s) – National budget only. Main funding source(s): University Medical Center of the Johannes Gutenberg University, Mainz, Germany; German Federal Ministry of Education and Research
Combined pre- and post-capillary pulmonary hypertension defined by new criteria is worse prognosis group in patients with heart failure
Authors: Ibe T , Wada H , Sakakura K , Ugata Y , Yamamoto K , Seguchi M , Taniguchi Y , Mitsuhashi T , Momomura S , Fujita H
Published: November 2020

Background

The 6th World Symposium on Pulmonary Hypertension suggested major revision about definition of pulmonary hypertension (PH) as mean pulmonary artery pressure (mPAP) >20 mmHg. The definitions of two subsets of PH due to left heart disease (PH-LHD) also revised. The aim of this study was to investigate clinical characteristics and outcomes of subsets of PH-LHD defined by new criteria.

Methods

We analyzed 701 patients admitted for symptomatic heart failure (NYHA ≥2) and underwent right heart catheterization at compensated stage between 2007 and 2016. These patients were divided into 4 groups as follows: (i) Isolated post-capillary PH (Ipc-PH); mPAP >20 mmHg and pulmonary artery wedge pressure (PAWP) >15 mmHg and pulmonary vascular resistance (PVR) <3 WU, (ii) Combined pre- and post-capillary PH (Cpc-PH); mPAP >20 mmHg and PAWP >15 mmHg and PVR ≥3 WU, (iii) pre-capillary PH; mPAP >20 mmHg and PAWP ≤15 mmHg, (iv) no PH; mPAP ≤20 mmHg. Kaplan-Meier curves were applied to investigate whether each groups predict heart failure (HF) death or HF readmission.

Results

The study patients were divided into Ipc-PH (n=268), Cpc-PH (n=54), Pre-capillary PH (n=112), and no PH (n=267). Cpc-PH was significantly associated with HF death or HF readmission as compared to other groups (Figure).

Conclusions

Cpc-PH defined by new criteria was significantly associated with poor long-term clinical outcomes, which suggests new criteria of two subsets of PH-LHD could be strict risk stratification for symptomatic heart failure.

Figure1. Kaplan-Meier curves.

Funding Acknowledgement

Type of funding source: None
Long-term outcomes in newly diagnosed pulmonary arterial hypertension (PAH) patients receiving initial triple oral combination therapy: insights from the randomised controlled TRITON study
Authors: Galie N , Sitbon O , Doelberg M , Gibbs J.S.R , Hoeper M.M , Martin N , Mathai S.C , McLaughlin V , Perchenet L , Simonneau G , Chin K
Published: November 2020

Introduction

Long-term outcomes are important in PAH.

Purpose

To evaluate the long-term efficacy and safety of initial triple oral therapy with selexipag, macitentan and tadalafil vs initial double oral therapy with macitentan and tadalafil in PAH.

Methods

TRITON, a multicentre, double-blind, placebo-controlled, phase 3b study, randomised 1:1 newly diagnosed, treatment-naïve PAH patients to initial triple vs double therapy. Macitentan and tadalafil were initiated at randomisation and selexipag/placebo at day 15 (uptitrated to wk 12). Efficacy and safety were assessed in a blinded manner until the last patient randomised completed wk 26 (end of observation period). Pulmonary vascular resistance (PVR; primary endpoint) and 6-minute walk distance (6MWD) were assessed at wk 26. Other secondary endpoints included time to first disease progression event (centrally adjudicated) to end of observation period +7 days. Time to all-cause mortality up to end of observation period was analysed post-hoc.

Results

247 patients were randomised to initial triple (n=123) or initial double therapy (n=124); baseline characteristics were balanced between groups. Median follow-up was 77.6 (initial triple) and 75.8 wks (initial double). Initial triple and initial double therapy improved PVR (by 54% and 52%) and 6MWD (by 55 and 56 m), with no difference between groups. A 41% reduction in the risk of first disease progression event driven by PAH-related hospitalisation and all-cause death was observed with initial triple vs initial double therapy (hazard ratio 0.59, 95% CI 0.32–1.09, p=0.087; Figure). Two patients died in the initial triple vs 9 in the initial double therapy group (hazard ratio 0.23, 95% CI 0.05–1.04). Adverse events were consistent with the known safety profiles of the study drugs.

Conclusions

In TRITON, assessments at wk 26 showed marked improvements in both treatment arms, with no difference between groups. Exploratory analysis indicated a signal for improved long-term outcome with initial triple versus initial double therapy.

Funding Acknowledgement

Type of funding source: Other. Main funding source(s): Actelion Pharmaceuticals Ltd.
Prognostic impact of neurohormonal inhibition in pulmonary arterial hypertension
Authors: Scagliola R , Rota I , Cheli M , Brunelli C , Balbi M , Ameri P
Published: November 2020

Background

Experimental evidence points towards a hyperactivity of the sympathetic nervous system and renin-angiotensin-aldosterone system in the pathobiology of pulmonary arterial hypertension (PAH), raising the hypothesis that blockade of neurohormonal axis may have favorable effects in this context.

Purpose

To assess the use and prognostic impact of neurohormonal inhibitors (NEUi) in a single centre cohort of subjects with PAH.

Methods

We analysed retrospectively collected data from our register of right heart catheterizations (RHC) performed consecutively from January 1st 2005 until October 31st 2018. We selected patients with PAH and complete information about demographics, biochemical data and drug therapy at the time of RHC. Patients on beta-blocker, angiotensin-converting enzyme inhibitor (ACEi), angiotensin receptor blocker (ARB) or mineralocorticoid receptor antagonist (MRA) at the time of RHC were classified as NEUi users. Comparisons between NEUi recipients and non-recipients were drawn by chi-square or t-test, as appropriate. Death from any cause was assessed by Kaplan-Meier analysis.

Results

Complete data were available for 57 PAH patients. Mean pulmonary artery pressure, pulmonary artery wedge pressure, diastolic pressure gradient, pulmonary vascular resistance and cardiac index were 45.0±14.9 mmHg, 10.9±3.5 mmHg, 16.0±10.2 mmHg, 8.8±5.1 Wood units and 2.5±0.8 l/min/m2 respectively. Twenty-seven subjects (47.4%) were taking at least one NEUi when RHC was performed: 12 (21.1%) were on beta-blocker, 15 (26.3%) on ACEi/ARB and 6 (10.5%) on MRA. NEUi users were significantly older (67.6±11.9 vs. 58.3±15.2 years, p=0.039), had a higher body mass index (25.9±4.4 vs. 23.6±3.5, p=0.029), more frequently systemic arterial hypertension (74.1% vs. 40.0%, p=0.020), smoking habit (51.9% vs. 20.0%, p=0.025) and lower estimated glomerular filtration rate (58.7±22.7 vs. 73.7±24.7 ml/min/1.73 m2, p=0.022) than non-users. Moreover, 5 NEUi users (18.5%), but no NEUi non-users, had a history of coronary artery disease. Hemodynamic parameters were similar in NEUi recipients and non-recipients (p=NS). Seven patients (25.9%) died in the NEUi users group vs. 17 (56.7%) in the non-users one (p=0.038). Kaplan-Meier analysis confirmed that subjects not taking NEUi were more likely to die over the course of follow-up (Log-Rank p=0.020) (Figure 1).

Conclusions

Our data identify a subset of atypical PAH patients, with pre-capillary pulmonary hypertension and a comorbidity profile for left heart disease (LHD), in whom NEUi have shown to improve survival. A prognostic benefit of NEUi, due to their effects on cardiovascular comorbidities in this kind of patients, has been speculated. Future prospective studies are needed to identify the most appropriate treatment strategies for atypical forms of PAH, with subtle and probably covert LHD.

Figure 1. Kaplan-Meier survival curves

Funding Acknowledgement

Type of funding source: None
Identification of predictors of response to initial oral combination therapy in WHO-functional class II or III PAH patients: a post-hoc analysis of the AMBITION study
Authors: Hatano M , Abe K , Takahashi T , Tunmer G , Koike G
Published: November 2020

Background

AMBITION Study (NCT01178073) provided the first long-term clinical evidence for initial combination therapy with ambrisentan and tadalafil (COMB) compared with monotherapy of either agent (MONO), and the results contributed to the ESC/ERS guidelines recommending initial combination therapy in PAH patients with low and intermediate risk. However, predictors of response to initial oral combination therapy to identify PAH patients who benefit most from it have not been assessed.

Purpose

To identify potential predictors of response to initial combination therapy with ambrisentan and tadalafil (COMB) in PAH patients with WHO-FC II or III in the AMBITION study.

Methods

We examined 302 COMB patients from the modified intention to treat (mITT) population enrolled in the AMBITION study (n=605). The mITT population includes PAH patients with risk factors related to heart failure with preserved ejection fraction (Ex-PAS) who were excluded from the primary analysis set (PAS). A responder (i.e. event-free subject) was defined as not having a clinical failure event. Univariate and multivariate analyses were performed to identify the factors associated with responders. Multivariate logistic regression analysis was used to determine independent risk for each factor that showed a significant difference between cohorts by interactive backward selection. Odds ratio (OR), 95% confidence intervals (CIs) and p-values are presented.

Results

Univariate analysis showed that responders tended to be lower age, female, typical PAH (i.e. PAS), absence of coronary artery disease, non-use of oxygen therapy, and have better baseline parameters (i.e., lower NT-proBNP, longer 6-minute walk distance, low Borg index, high SaO2, WHO-FC II). A multivariate logistic regression analysis showed that female gender (OR=2.669, 95% CI: 1.291–5.518, P=0.0081), use of aldosterone antagonist diuretics (OR=2.535, 95% CI: 1.027–6.257, P=0.0436), lower log NT-proBNP (OR=0.704, 95% CI: 0.524–0.944, P=0.0190), and longer 6-minute walk distance (OR=1.006, 95% CI: 1.002–1.010, P=0.0039) were independent predictors of response to initial combination therapy.

Conclusion

These findings suggest that initial combination therapy with ambrisentan and tadalafil is beneficial, especially in less severe typical PAH patients. It also demonstrates that there is a potential contributing factor (i.e. use of aldosterone antagonist diuretics) which is not listed in the risk assessment table of the ESC/ERS guidelines.

Funding Acknowledgement

Type of funding source: Private company. Main funding source(s): AMBITION study was funded by GlaxoSmithKline (GSK; study number 112565; trial registration number: NCT01178073) and Gilead Sciences, Inc. This analysis was funded by both companies.
Pulmonary hypertension and congenital heart disease: medical treatment and risk factors for survival
Authors: Playan Escribano J , Segura De La Cal T , Segovia Cubero J , Rueda Soriano J , Garcia Hernandez F.J , Lopez Meseguer M , Perez Penate G.M , Lara Padron A , Campo Ezquibela A , Sala Llinas E , Mombiela T , Guerra Ramos F.J , Samper G.J , Blanco I , Escribano Subias P
Published: November 2020

Background

Pulmonary arterial hypertension (PAH) is a common comorbidity in congenital heart disease (CHD) and significantly affects prognosis. There are four large clinical groups of CHD-related PAH: Eisenmenger syndrome, PAH associated with non-restrictive shunt, PAH associated with restrictive shunt and postoperative PAH. Our purpose was to study the clinical and prognostic differences among them.

Methods

The REHAP is a Spanish multicentre voluntary registry of patients over 14 years of age, which includes patients with CHD and PAH, starting in 2007. 664 patients were analyzed: Baseline characteristics, functional class, right catheterization data, treatment and survival were compared.

Results

664 patients were analyzed: characteristics are detailed in the table. Patients with Eisenmenger were more frequently treated with oral monotherapy as a first line therapy and received less frequently prostanoids during the follow-up. Patients with Eisenmenger had significantly better prognosis, with the best long-term survival of the 4 groups. In a cox regression model, postoperative PAH has a 1.7 hazard ratio (HR) (reference group: Eisenmenger) after adjustment for age (HR 1.02 p 0,001), functional class (HR NYHA III-IV 2.3 p<0,001), sex (p 0.8) and pulmonary vascular resistance (p 0.7).

Conclusion

The clinical classification of PAH associated with CHD defines both the baseline characteristics and the prognosis of patients. Outcome relates closely to functional class and type of PAH–CHD. Eisenmenger group, which has the most severe hemodynamics, is the one with the best prognosis despite a less aggressive treatment.

Funding Acknowledgement

Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Ferrer, Janssen
The role of asymmetric dimethylarginine (ADMA) in the follow-up of patients with precapillary pulmonary hypertension (PH)
Authors: Shafran I , Probst V , Campean J , Sadushi-Kolici R , Gerges C , Lang I , Skoro-Sajer N
Published: November 2020

Introduction

Asymmetric dimethylarginine (ADMA) interferes with L-arginine in the production of nitric oxide, a key mediator of endothelial cell function. ADMA is elevated in pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) and is associated with unfavorable outcomes.

Aim

To assess the role of ADMA to monitor disease progression of PH patients treated with PAH-specific therapy.

Methods

ADMA was measured by competitive ELISA at baseline (BL) and follow-up (FU). Risk assessment including a clinical assessment, echocardiography, 6-minute walking test, NT-pro-BNP and hemodynamic assessment by right heart catheterization was performed accordingly. Risk was calculated according to the ESC/ERS 2015 guidelines by the SPHAR method.

Results

ADMA samples were collected from 113 patients treated at our institution between 2012 and 2019. 89 (79%) patients had PAH, 15 (13%) were diagnosed with CTEPH and 9 (8%) with group 3 – PH associated with lung disease. 69% were females. 15 (13.3%) patients had a low risk at baseline, 96 (85%) intermediate risk and 2 (1.8%) were high risk patients. 75% received oral medications, 31% received subcutaneous treprostinil. Median baseline ADMA was 0.738umol/l. At BL no significant difference of ADMA plasma levels was found among the different PH types (p=0.063), or between different risk categories (p=0.531).

Change in ADMA plasma levels correlated with change in risk (p=0.002, rs 0.291) and with change in mixed venous saturation (p=0.034, rs −0.205). Change in ADMA plasma levels also correlated with risk at FU (p=0.011, rs 0.240).

Patients categorized as low risk at FU had a median ADMA plasma level decrease of 22%, compared with −3 to 0% ADMA plasma level change in patients with moderate to high risk at FU (p=0.04). Patients who improved their risk category had a median decrease of ADMA plasma level of 23% vs. 2.3% in patients who did not improve (p=0.011). Decrease of ADMA plasma levels was a weak but significant discriminator for improvement of risk in ROC analysis (p=0.032, AUC 0.374).

Conclusion

ADMA plasma levels paralleled the hemodynamic and clinical benefit of PAH-specific treatments in patients with precapillary PH. ADMA could be used as a biomarker for monitoring treatment effects in precapillary PH.

Funding Acknowledgement

Type of funding source: None