bluuebunny/crossref_metadata_2025 huggingface dataset:
5131Unmet need for secondary prevention in individuals from the general population with increased lipoprotein(a): a contemporary population-based study
Authors: Madsen C M , Kamstrup P R , Langsted A , Varbo A , Nordestgaard B G
Published: October 2019

Background

There is strong evidence linking high lipoprotein(a) (Lp(a)) to development of incident cardiovascular disease (CVD), but it is not clear whether Lp(a) is associated with risk of recurrent CVD events in individuals from the general population with preexisting CVD. This is of importance as the first drugs specifically aimed at lowering Lp(a) are currently in development, and these would likely be used primarily in individuals with established CVD for secondary prevention of recurrent CVD events.

Purpose

We tested the hypothesis that high concentrations of Lp(a) are associated with high risk of recurrent CVD in individuals from the general population with preexisting CVD.

Methods

From the Copenhagen General Population Study (CGPS) (2003–2015) of 58,527 individuals with measurements of Lp(a) at baseline, 2,527 aged 20–79 with a history of CVD were studied. The primary endpoint was major adverse cardiovascular event (MACE). We also studied 1,115 individuals with CVD at baseline from the Copenhagen City Heart Study (CCHS) (1991–1994) and the Copenhagen Ischemic Heart Disease Study (CIHDS) (1991–1993).

Results

During a median follow-up of 5 years (range: 0–13, 13,974 person-years), 493 individuals (20%) experienced a MACE in the CGPS. MACE incidence rates per 1,000 person-years were 29 (95% CI: 25–34) for individuals with Lp(a) <10mg/dL (<18nmol/L), 35 (30–41) for 10–49mg/dL (18–104nmol/L), 42 (34–51) for 50–99mg/dL (105–213nmol/L), and 54 (42–70) for ≥100mg/dL (≥214nmol/L) (see Figure). Compared to individuals with Lp(a) <10mg/dL (<18nmol/L), the MACE incidence rate ratios were 1.21 (0.98–1.50) for 10–49mg/dL (18–104nmol/L), 1.43 (1.12–1.82) for 50–99mg/dL (105–213nmol/L), and 1.85 (1.38–2.49) for ≥100mg/dL (≥214nmol/L). Independent confirmation was obtained in individuals from the CCHS and CIHDS with MACE incidence rates per 1,000 person-years of 94 (95 CI: 84–106) for individuals with Lp(a) <10mg/dL (<18nmol/L), 115 (103–129) for 10–49mg/dL (18–104nmol/L), 134 (115–156) for 50–99mg/dL (105–213nmol/L), and 140 (116–169) for ≥100mg/dL (≥214nmol/L).

Conclusion

High concentrations of Lp(a) are associated with high risk of recurrent CVD in individuals from the general population with preexisting CVD. This points to a possible unmet need for secondary prevention in individuals with increased Lp(a), and such individuals could be a target group for upcoming randomized cardiovascular outcome trials.

Acknowledgement/Funding

The Novo Nordisk Foundation, Herlev and Gentofte Hospital, Chief Physician Johan Boserup and Lise Boserup's Fund
5132Effect of PCSK9 inhibitors treatment on acute coronary syndrome and stroke incidence: a metanalysis of currently available clinical trials
Authors: Cordero A , Facila L , Rodriguez-Manero M , Gomez-Martinez M , Bertomeu-Gonzalez V , Martinez R , Seijas S , Valle A , Moreno-Arribas J , Agra-Bermejo R , Martin Toro M , Bertomeu Martinez V , Gonzalez Juanatey J R
Published: October 2019

Background

Proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors have demonstrated to induce large reductions in low-density lipoprotein cholesterol (LDLc) and major cardiovascular events but none of the studies was statistically powered to demonstrate reductions in specific endpoints rather than a combined end-point of major cardiovascular events.

Methods

We performed an intention-to-treat meta-analysis in line with recommendations from the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement using currently available studies involving PCSK9 inhibitors. The endpoint assessed were acute coronary syndrome (ACS) and stroke.

Results

We included 81,544 patients, 41,147 treated with a PSCK9 inhibitors: 17,179 with evolocumab; 13,718 with bococizumab and 10,250 with alirocumab (table 1). A total of 1,316 ACS were registered in the treatment group vs. 1,608 in controls, resulting in 18.0% reduction associated with PCSK9 treatment (figure 1). This result was reproduced exactly in the EBCT althougt a non-significant heterogeneity was detected (p=0.052). Metaregression analyses did not demonstrate the implication of the study (p=0.45), study drugs (p=0.26), age (p=0.89), hypertension (p=0.81) or diabetes (p=0.81) on such result.

Results on stroke incidence are presented in figure 2. PCSK9 inhibitors treatment resulted in a 24% reduction of stroke when all studies were analyzed together; heterogeneity was statistically significant (p=0.021) but it was not observed in the EBCT analysis where PCSK9 inhibitors were associated with 24% stroke incidence reduction.

Conclusions

The meta-analysis of currently available studies demonstrates that PCSK9 inhibitors treatment reduces the incidence of ACS by 18% and stroke by 24%.
5201Intra-cardiac thrombus in patients undergoing ventricular tachycardia ablation. a computed tomographic scan study
Authors: Sacher F , Roumegou P , Duchateau J , Derval N , Denis A , Pambrun T , Escande W , Takigawa M , Lam A , Andre C , Chauvel R , Hocini M , Haissaguerre M , Jais P , Cochet H
Published: October 2019

Background

Embolic event is one of the complications of VT ablation. This may be due to the presence of intra-cardiac thrombus before ablation. However, there is no clear consensus on how to rule out thrombus before the procedure.

Objective

We sought to examine the prevalence and risk factors of intra-cardiac thrombus with cardiac computed tomographic (CT) scan in patients undergoing scar-related VT ablation.

Methods

In absence of contra-indication, all patients undergoing scar-related VT ablation at our institution underwent contrast-enhanced cardiac CT within one week before ablation. 324 consecutive patients (292 male, 59±16 yo) have been included in this study. The etiology was ischemic cardiomyopathy (CMP) (n=191), arrhythmogenic right ventricular CMP (ARVC) (n=37), congenital CMP (n=11) or other CMP (n=85). LVEF was <40% in 154 patients (48%).

Results

Intra-cardiac thrombus was diagnosed in 29 (9%) patients: in the left atrium (n=8), in the right atrium (n=1), in the left ventricle (n=15), in the right ventricle (n=3), in right and left atrium (n=1), and in left atrium and right ventricle (n=1). Moreover in 2, a bilateral pulmonary embolism was identified. The population with thrombus was older (65±12 vs 58±16 years, p=0,005), with more permanent atrial fibrillation (AF) (28% vs 8%; p=0.005). Patients with left ventricular (LV) aneurysm were at higher risk of thrombus 50% vs 3% (p<0.001). The average CHADSVASC score was similar for both groups (2,5 vs 2,1; p=0.179). After matching for age and sex, only ischemic CMP and LV aneurysm were risk factors for thrombus. Because of arrhythmic storm, ablation was performed by epicardial approach only, in 5 patients with intra-ventricular thrombus and by retroaortic approach only, in 2 patients with LAA thrombus. No embolic event occurred during these procedures.

Conclusion

CT scans help eliminating intra-cardiac thrombus before VT ablation procedure. A high proportion of thrombus (9%) was identified. Whereas LV thrombus should systematically be ruled out before scar related VT ablation, in patients with AF, a LAA thrombus should also be eliminated as well as RV thrombus in patients with ARVC.

Acknowledgement/Funding

ANR-10-IAHU-04
5202Zero- or near-zero fluoroscopy radiofrequency catheter ablation for aortic sinus cusp idiopathic ventricular arrhythmias
Authors: Stec S , Styczkiewicz K , Sledz J , Chrabaszcz M , Ludwik B
Published: October 2019

Background

Complete elimination of fluoroscopy during radiofrequency catheter ablation (RFCA) of idiopathic ventricular arrhythmias (IVA) originating from aortic sinus cusp (ASC) may be challenging, requires confirmation of coronary arteries ostia and could be associated with potential risk of collateral damage and severe complications.

Purpose

To validate the implementation, feasibility, learning curve, safety and efficacy of zero-fluoroscopy (ZF) approach in centers using near-zero fluoroscopy (NOX) approach for RFCA of idiopathic premature ventricular complexes/ventricular tachycardias (PVCs/VTs) from ASC.

Methods

From 2012 to 2018, we prospectively enrolled 106 consecutive patients (age: 49±19, males: 58%, children: 7%, 108 PVC/VT focuses from ASC, PVCs/24h: 23808±22006) with ASC-IVA. Patients were unselected and referred for ZF or NOX approach using three dimensional electroanatomic system- 3D EAM without intracardiac or transesophageal echocardiography. The choice of ZF and NOX was based on the first operator experience and from 2014 three experienced operators and three fellows performed ZF as an intention-to-treat approach. The peri-procedural, short-term outcome as well as learning curve of ZF in ASC were evaluated with documentation of reasons for cross-over to NOX approach.

Results

Out of 108 focuses there were majority of left coronary cusps and left/right junctions sites of origin [other rare locations: right coronary cusp (n=7); non-coronary cusp, n=6)]. On intention-to-treat 61/76 (80%) cases were completed without fluoroscopy in ZF-approach. Additionally, 30/30 (100%) cases were completed with NOX. The main reasons for fluoroscopy use in ZF approach (conversion to NOX) were: the need for elective valsalvography plus coronary angiography (n=6), urgent coronary angiography due to validation of transient uncomplicated coronary spasms and ST elevation (n=2), catheter stability checking (n=2), femoral access site confirmation (n=1) and navigation problem (n=1). No significant differences were found in the acute and short-term success rates between ZF and NOX (90% vs 88%, P=NS) and no major complications occurred. The procedure time, fluoroscopy time and ablation time were 66.8±26.9; 3.6±7.2 and 7.3±5.5 min, respectively. The gathering experience of ZF approach, computer-assisted ECG analysis and 3D-EAM reconstruction of aortic root and coronary artery ostia resulted in significant reduction of NOX approach between early and late period [median (n=53): 2012–2016 vs 2017–2018, 40/53 (76%) vs 5/53 (8%), p<0.001].

Conclusion

ZF can be completed in majority of patients with ASC-IVA especially after appropriate training and operators' experience with NOX. ZF approach guided by 3D-EAM is feasible, safe, and effective for treatment of ASC-IVA with importance of training and preprocedural imaging for exclusion of coronary anomalies or validation of coronary arteries ostia by 3D-EAM.
5220Maternal high-fat diet exaggerates the development of diet-induced insulin resistance in adult offspring by enhancing pyroptosis through augmented gasdermin D-mediated pore formation
Authors: Wada N , Yamada H , Motoyama S , Saburi M , Sugimoto T , Miyawaki D , Kubota H , Wakana N , Matoba S
Published: October 2019

Background

Maternal high-fat diet (HFD) has been shown to promote the development of insulin resistance (IR) in adult offspring; however, the underlying mechanisms remain unclear.

Approach and results

Eight-week-old female wild-type mice (C57BL/6) were fed a HFD or normal diet (ND) one week prior to mating, and received during pregnancy and lactation. Eight-week-old male offspring of both groups were fed a HFD for 8 weeks. Offspring of HFD-fed dams (O-HFD) showed significantly enhanced IR compared with offspring of ND-fed dams (O-ND). There was no difference in body weight, epidydimal white adipose tissue (eWAT) weight, and cumulative caloric intake between the 2 groups. However, eWAT adipocyte size was significantly increased in O-HFD, accompanied by the abundant crown-like structures. Flow cytometric analysis revealed an increased percentage of M1, but not M2, macrophages. Serum and eWAT concentrations of IL-1β, but not TNF-α, were significantly higher in O-HFD than O-ND (3.7-fold and 2.0-fold, respectively, P<0.05). Treatment with NLRP3 inflammasome inhibitor MCC950 completely abrogated the enhanced IR in O-HFD to a similar extent of that in O-ND, although IR was modestly, but not significantly, ameliorated in O-ND even after MCC950 treatment. Consistent with in vivo findings, in vitro polarization of bone marrow-derived macrophages (BMDMs) did not show any difference in TNF-α mRNA expression after conventional stimulation. In contrast, palmitate acid (PA)-mediated metabolic activation of BMDMs following LPS priming showed a significantly higher concentration of IL-1β in culture supernatants from O-HFD (45%, P<0.05). However, protein expression levels of NLRP-3, ASC, and procaspase-1 after LPS priming were equivalent between the 2 groups. Consistently, intracellular flow cytometric analysis of caspase-1 activity after PA activation did not show any difference, which was compatible with the finding that ex vivo caspase-1 activity of eWAT assessed by fluorescent image of IVIS revealed no difference between the 2 groups. To further examine the mechanism of augmented IL-1β release in BMDM of O-HFD, we examined the cleavage of caspase substrate gasdermin D (GSDMD) and subsequent pore formation. Protein and gene expression levels of GSDM-D after LPS priming were significantly higher in O-HFD (50% and 381%, respectively, P<0.05). At 2 hrs after PA stimulation following LPS priming, cleaved GSDM-D was significantly increased in O-HFD (80%, P<0.01). Consistently, percentage of pore formation assessed by ethidium bromide staining was significantly higher in O-HFD (60%, P<0.05), while LDH release could not be observed.

Conclusions

Our findings demonstrate that maternal HFD exaggerates diet-induced insulin resistance in adult offspring by enhancing pyroptosis through augmented GSDM-D-mediated pore formation.
5221Knockout of purinergic receptor Y13 (P2Y13) results in an improved outcome in metabolic syndrome in mice
Authors: Merz J , Rofa K , Dimanski D , Ahmed I , Hoppe N , Bode C , Zirlik A , Stachon P
Published: October 2019

Background

Metabolic syndrome clusters the main risk factors for cardiovascular diseases and endocrine dysfunction. Novel studies show that the important underlying mechanism is a long term inflammation of adipose tissue with a gradual shift from the anti-inflammatory M2 towards the pro-inflammatory M1 macrophages (pathognomonic). Massive hypertrophy induces adipocyte death, which releases DAMPs like nucleotides recognized by purinergic receptors orchestrating ongoing inflammatory process. Interestingly, we found Gi coupled P2Y13R only expressed on M1 macrophages, not in M0 (unstimulated) and M2 macrophages.

Nevertheless, the role of P2Y13R in the immune system and especially macrophages is currently unknown. Given its pivotal role in central metabolic processes (P2Y13R has been described in insulin secretory signalling) together with its unique expression in its pathognomonic inflammatory macrophage subtype makes it an interesting candidate to investigate its role in metabolic syndrome.

Purpose

Due to the unique expression of P2Y13R on M1 macrophages we hypothesise an improved outcome in a high-fat diet induced metabolic syndrome by interfering with the P2Y13 signalling cascade.

Methods

BMDM differentiation to macrophages using M-CSF and subsequent stimulation with medium (M0), LPS and IFNγ (M1) or IL4 (M2); Expression of P2Rs quantified using Taqman qPCR.

Male C57Bl6/J wild-type (WT) and P2Y13-deficient (KO) mice were fed with a high-fat diet (HFD) for 20 weeks; On week 15 we performed the ITT, on week 16 the GTT. Metabolic performance was monitored by metabolic caging.

Results

We observed a unique expression of P2Y13R on M1 macrophages. Adult P2Y13-deficient mice showed a higher O2 consumption compared to adult C57Bl6/J wild-type mice (AUC of O2 consumption 2nd day= KO: 61620±2261mL/kg vs WT: 53830±916.1mL/kg, p=0.0331). Although both P2Y13−/− mice and WT littermates consumed comparable amount of food (daily food intake per mouse → KO: 3.97±0.25g vs WT: 3.76±0.18g), P2Y13 deficient animals showed significantly decelerated weight gain (e.g. on week 15 → KO: 142±2% (n=10) vs WT: 198±5% (n=10), p<0.0001). Obese P2Y13−/− animals outperformed obese WT littermates in a peritoneal glucose tolerance test (2h after glucose injection → KO: 272.9±21.0 mg/dL (n=10) vs WT: 532.6±21.2 (n=10) mg/dL, p<0.0001). There was no difference in the cell amount of stromal vascular fraction cells.

Conclusion

Global P2Y13 deficiency leads to an improved outcome in metabolic syndrome with an increased protection against developing an insulin resistance as shown through an improved glucose tolerance and basal glucose levels, a decelerated weight gain despite comparable food consumption and a better metabolic turnover. Observing these beneficial metabolic improvements, we hypothesise that antagonization of P2Y13R could be a promising therapeutic target in the field of metabolic syndrome.
5941Improvement of cardiac output after transcatheter repair of severe tricuspid regurgitation impacts all-cause mortality
Authors: Stocker T J , Orban M , Braun D , Hertell H , Englmaier A , Roesler D , Reithmayer T , Nabauer M , Massberg S , Hausleiter J
Published: October 2019

Background

Severe tricuspid regurgitation (TR) impairs right-ventricular forward stroke volume and left-ventricular preload leading to a reduction of cardiac output (CO). Transcatheter tricuspid valve repair (TTVR) is a novel experimental treatment strategy for TR and an alternative to surgery in fragile patients. The clinical impact of improved CO after TTVR on the prognosis of chronic heart failure patients is currently unknown.

Purpose

This study has been designed to analyze the impact of TTVR on CO and the association to post-interventional hospitalization for congestive heart failure (CHF) and all-cause mortality.

Methods

Between February 2017 and October 2018 we prospectively enrolled 70 patients suffering from chronic heart failure (median age 78 years; 54% female; 90% NYHA III or IV; median NT-pro-BNP of 3,540 ng/ml) due to severe TR (all ≥ grade 3 of 4). All patients underwent TTVR with isolated intervention to the tricuspid valve (n=41) or combined mitral and tricuspid intervention due to concomitant mitral regurgitation (n=29). Invasive CO was measured shortly before TTVR under general anesthesia using transpulmonary thermodilution. For a more physiologic assessment, non-invasive CO was measured using the inert gas rebreathing technique (Innocor, Innovision, Glamsbjerg, Denmark). Non-invasive CO was assessed 2 weeks prior TTVR (baseline), at the day of discharge from the hospital (post-procedural) and after a median of 193 days (interquartile range, IQR 53 to 360 days; follow-up).

Results

Invasive CO significantly correlated to non-invasive assessment of CO at baseline (Pearsons correlation coefficient r=0.36, p<0.01). Baseline median non-invasive CO (3.3 l/min, IQR 2.4 to 4.2 l/min) improved with TTVR in the post-procedural analysis (4.0 l/min, IQR 2.8 to 5.1 l/min, p<0.001). At follow-up, median non-invasive CO improved by 0.5 l/min (IQR 0.0 to 1.6 l/min). CO changed ≤0.5 l/min in 37 patients (low ΔCO) and >0.5 l/min in 33 patients (high ΔCO). Hospitalization for CHF was significantly lower with high ΔCO (18%), when compared to low ΔCO (54%; p<0.01). Furthermore, all-cause mortality was significantly reduced in the high ΔCO-group (3%), when compared to the low ΔCO-group (43%; p<0.001). Significant differences in mortality were also observed in the subgroup of patients with isolated tricuspid intervention (10% vs. 45%, p=0.016).

Conclusion

Successful TTVR with maintenance of improved CO impacts patient prognosis and is associated to a reduced rate of hospitalization and all-cause mortality.
5942Clinical outcomes and prognostic implications of effective regurgitant orifice area. Defining severe mitral regurgitation
Authors: Monteagudo Ruiz J M , Gonzalez Gomez A , Hinojar Baydes R , Casas Rojo E , Garcia Martin A , Moya Mur J L , Aquila I , Jimenez Nacher J J , Barrios V , Ruiz Leira S , Marco Del Castillo A , Pardo Sanz A , Zamorano Gomez J L , Fernandez Golfin C
Published: October 2019

Background

Previous studies showed that the effective regurgitant orifice area (EROA) is a strong predictor of clinical outcomes. However, there is controversy over the optimal threshold that identifies patients at high-risk, especially in secondary mitral regurgitation (MR).

Purpose

To determine the optimal EROA threshold that identifies a subgroup patients with an increased risk of cardiac death and hospitalization for heart failure (HF), in both, primary and secondary MR.

Methods

A total of 6022 consecutive transthoracic echocardiograpic studies were analysed. Patients with significant MR were prospectively included. The EROA was calculated by the PISA method. Each patient was followed up for three years. Cox regression was performed to study predictors of the combined end-point. ROC curve analysis was performed to determine the optimal cut-off values of EROA.

Results

Significant primary MR was found in 115 patients (62%), whereas significant secondary MR was described in 71 studies (38%). In primary MR, the optimal threshold of EROA for predicting the combined end-point was 45mm2 (Sn=85.7%; Sp=82.2%). After adjusting for NYHA class, ejection fraction and chronic kidney disease, an EROA ≥45mm2 was strongly associated with cardiac death and admissions due to HF (HR 15.65, 95% CI 4.34–56.47, p<0.001). Regarding secondary MR, the optimal cut-off value was 21mm2 (Sn=75.0%; Sp=61.8%) and the adjusted HR was 2.57 (95% CI 1.03–6.37, p=0.042).

Sensitivity and specificity curves

Conclusions

Our study demonstrates that an EROA of at least 45mm2 in primary MR or of at least 21mm2 in secondary MR is independently associated with a significantly increased risk of cardiac death and hospitalization for HF.
5943Mechanistic insights of papillary muscle dyssynchrony mediated function mitral regurgitation and modulation by cardiac resynchronization
Authors: Spinka G , Bartko P , Arfsten H , Heitzinger G , Pavo N , Strunk G , Gwechenberger M , Hengstenberg C , Binder T , Huelsmann M , Goliasch G
Published: October 2019

Abstract

Background

Mechanistic features of functional mitral regurgitation (FMR) include papillary muscle displacement due to left ventricular remodeling. Intraventricular conduction delay might further augment this condition by introducing interpapillary muscle dyssynchrony.

Objectives

To define this mechanism as a major contributing factor in FMR and prove the reversibility of FMR by interpapillary muscle resynchronization.

Methods

We enrolled 269 chronic HFrEF patients with conduction delay and comprehensively assessed dyssynchrony by complementary echocardiographic techniques. Opposing wall delay, calculated by speckle tracking, was determined as the time difference between peak longitudinal strain of the mid-anterior and inferior wall from a 2-chamber view. Furthermore, opposing wall delay was assessed as the time difference between peak strain values from tissue Doppler velocity-coded data of the mid-inferior septal and mid-lateral wall segments.

Results

Patients with severe FMR had markedly increased interpapillary longitudinal dyssynchrony (160ms [IQR 120–200]) compared to those with moderate (70ms [IQR 40–110]), no, or mild FMR (60ms [IQR 30–100]; P<0.001). Increased interpapillary muscle dyssynchrony was correlated with effective regurgitant orifice area (P<0.001; Figure A), regurgitant volume (P<0.001, Figure B) and vena contracta width (P<0.001, Figure C). Restoration of longitudinal papillary muscle synchronicity by cardiac resynchronization therapy (CRT) was correlated with FMR regression, as reflected by the reduction in regurgitant volume (P<0.001) and vena contracta width (P<0.001). Conversely, the improvement of FMR was associated with improved interpapillary radial (P=0.006) and longitudinal (P<0.001) dyssynchrony. The improvement of dyssynchrony-mediated FMR signified a better prognosis compared to no improvement in FMR during the 8-year follow-up period even after comprehensive adjustment by a bootstrap-selected confounder model (adj. HR of 0.41; 95% CI 0.18–0.91; P=0.028; Figure D). The results remained virtually unchanged after adjustment for left bundle branch block.

Figure 1. Dyssynchrony-FMR-CRT

Conclusion

Intraventricular dyssynchrony introduces unequal contraction by papillary muscle bearing walls, which has an adverse effect on FMR. CRT can effectively restore interpapillary balance and thus create a less tented leaflet configuration, resulting in a clinically meaningful reduction of FMR. The restoration of papillary muscle synchronicity in dyssynchrony-mediated FMR translates into a significantly better prognosis.
5944Mortality advantage of mitraclip in patients with heart failure and mitral regurgitation: an updated meta-analysis
Authors: Ashukem M , Bhavi Pandya M D , Verma Diva Ratyan M D
Published: October 2019

Background

In patients with symptomatic mitral regurgitation who are high risk for surgery, transcatheter mitral-valve repair has been shown to be safe and improve clinical outcomes. However, its impact on survival has shown conflicting results in recent trials.

Methods

PubMed, EMBASE and Google Scholar databases were queried for all trials about MitraClip compared with optimal medical therapy

Results

This meta-analysis of 9 trials including 3199 patients, found that patients treated with

MitraClip compared to optimal medical therapy had similar 30-day mortality (OR 0.64, 95% CI 0.32- 1.28) while at 12-months MitraClip was associated with significantly lower all-cause mortality (OR 0.46, 95% CI 0.33- 0.65). Absolute risk reduction was 13.9% and number needed to treat to save 1 life at 12 months was 7.2.

Figure 1

Conclusions

In this meta-analysis, transcatheter mitral valve repair with MitraClip was associated with significantly lower mortality at 12 months of follow up
5963Automated quantification of epicardial adipose tissue from non-contrast CT on multi-center and multi-vendor data using deep learning
Authors: Commandeur F , Goeller M , Razipour A , Cadet S , Hell M M , Kwiecinski J , Chen X , Chang H J , Marwan M , Achenbach S , Berman D S , Slomka P J , Tamarappoo B K , Dey D
Published: October 2019

Background

Epicardial adipose tissue (EAT), a metabolically active visceral fat depot surrounding the coronary arteries, has been shown to promote the development of atherosclerosis in underlying coronary vasculature.

Purpose

We evaluate the performance of deep learning (DL), a sub-group of machine learning algorithms, for robust and fully automated quantification of EAT on multi-center cardiac CT data.

Methods

In this study, 850 non-contrast calcium scoring CT scans, from multiple cohorts, scanners and protocols, with manual measurements of EAT from 3 different readers were considered. The DL method was based on a convolutional neural network trained to reproduce the expert measurement. DL global performance was first assessed using all the scans, and then compared to inter-observer variability on a subset of 141 scans. Finally, automated EAT progression was compared to manual measurement using baseline and follow-up serial scans available for 70 subjects. The proposed model was validated using 10-fold cross validation.

Results

Automated quantification was performed in 1.57±0.49 seconds compared to 15 minutes for manual measurement. DL provided high agreement with expert manual quantification for all scans (R=0.974, p<0.001) with no significant bias (0.53 cm3, p=0.13). EAT volume was higher in patients with hypertension (+18.02 cm3, p<0.001, N=442), with diabetes (+18.33 cm3, p<0.001, N=75) and with hypercholesterolemia (+7.33 cm3, p=0.039, N=508). Manual EAT volumes measured by two experienced readers on 141 scans were highly correlated (R=0.984, p<0.001) but presented a significant difference of 4.35 cm3 (p<0.001). On these 141 scans, DL quantifications were highly correlated to both experts' measurements (R=0.973, p<0.001; R=0.979, p<0.001) with significant and non-significant bias for readers 1 and 2 (5.19 cm3, p<0.001; 0.84 cm3, p=0.26), respectively. In 70 subjects, EAT progression quantified by DL correlated strongly with EAT progression measured by the expert reader (R=0.905, p<0.001) with no significant bias (0.64 cm3, p=0.43), and was related to increased non-calcified plaque burden quantified from coronary CT angiography (5.7% vs 1.8%, p=0.026).

Automated vs. manual EAT volume

Conclusion

Deep learning allows rapid, robust and fully automated quantification of EAT from calcium scoring CT. It performs as an expert reader and can be implemented for routine cardiovascular risk assessment.

Acknowledgement/Funding

1R01HL133616/01EX1012B/Adelson Medical Research Foundation
5970Morbidity and mortality in patients precluded for transvenous pacemaker implantation: experience with the Micra transcatheter pacemaker
Authors: Garg A , Koneru J N , Fagan D , Stromberg K , El-Chami M F , Piccini J P , Roberts P R , Soejima K , Cheng A , Ellenbogen K A
Published: October 2019

Background

The Micra transcatheter pacemaker has proven to be a safe and effective alternative to transvenous pacemakers (TVPs). However, the safety profile after Micra implantation in patients deemed poor candidates for TVPs is poorly understood.

Purpose

To evaluate the safety and all-cause mortality outcomes in Micra recipients stratified by whether or not they were precluded for therapy with TVP.

Methods

Micra patients from the Micra Transcatheter Pacing (IDE) Study, Continued Access (CA) study, and Post-Approval Registry (PAR) were divided into groups based upon whether or not the implanting physician considered the patient to be precluded from receiving a transvenous pacing system. All-cause mortality was compared between the Micra patient groups and patients receiving a single-chamber transvenous pacing system (SC-TVP) since 2010 from the Medtronic product surveillance registry using univariate and multivariate Cox models.

Results

Among 2,819 patients who underwent a Micra implant attempt, the overall major complication rate through 24 months was 3.5%. In these patients, 548 were deemed precluded from TVP implantation. Prior device infection or bacteremia (38.9%), venous access issues (36.1%) and thrombosis (10.2%) were amongst the most common causes of preclusion for TVP implantation. These patients were younger (71.7 vs. 76.7 years), more frequently on hemodialysis (26.3% vs. 2.5%), and more often had a prior CIED implanted (38.4% vs. 4.4%) than non-precluded patients. Over an average follow-up of 13.5±11.1 months, all-cause mortality was significantly higher in precluded Micra patients compared with SC-TVP patients (HR: 2.16, 95% CI: 1.54–3.2, P<0.001) (Figure 1). However, there was no significant difference in all-cause mortality when comparing non-precluded Micra patients and SC-TVP patients (HR: 1.12, 95% CI: 0.86–1.44, P=0.401). Acute all-cause death (within 1 month) among Micra patients was 2.74% and 1.32% in the precluded and non-precluded TVP groups, respectively. The procedure-related death rate was 0.55% for the TVP precluded group and 0.13% for the not precluded group (P=0.092). The major complication rate through 24-months was similar between the two Micra groups (4.0% vs 3.4%, P=0.630).

All-cause mortality for Micra and SC-TVP

Conclusion

The overall safety profile of Micra remains is in line with previously reported data. All-cause mortality risk (both acute and long term) appears to be higher in patients who were precluded from receiving TVP.

Acknowledgement/Funding

Supported by Medtronic
6089Increased vascular endothelial growth factor signalling following loss of endothelial endoglin leads to peripheral arteriovenous shunting and high output heart failure
Authors: Tual-Chalot S , Garcia-Collado M , Redgrave R E , Singh E , Davison B , Luli S , Jin Y , Wang Y , Lawrie A , Jakobsson L , Arthur H M
Published: October 2019

Background

Endoglin is a co-receptor for TGFbeta/BMP9/10 signalling and ENG mutations lead to the vascular disorder hereditary haemorrhagic telangiectasia type I (HHT). Endoglin is also required for normal vascular development and angiogenesis, but little is known about endoglin's role in quiescent adult vascular endothelium.

Purpose

The goal of this present study is to determine how endoglin maintains vessel calibre in adult life to prevent AVM formation and thereby protect heart function.

Methods

To investigate this role, tamoxifen was administered to adult Cdh5(PAC)-CreERT2; Engfl/fl mice to generate endothelial-specific depletion of endoglin (Eng-iKOe). Cardiac magnetic resonance imaging, myography, vascular casting, microsphere injection, immunohistology, qPCR and aortic telemetry were used to evaluate cardiovascular changes after endoglin knockdown.

Results

Endothelial-specific loss of endoglin leads to an enlarged heart and cardiomyocyte hypertrophy within 5 weeks, progressing to high output heart failure (HOHF). In vivo aortic telemetry revealed significant loss of aortic pressure within a few days of endoglin depletion. Increased cardiac size and reduced cardiac afterload were confirmed by ventricular pressure loop analysis. As HOHF could result from arteriovenous malformations (AVMs), and these are found primarily in mucocutaneous and pulmonary tissues in HHT, we systematically screened for AVMs using microspheres and vascular casting. Although AVMs were absent in the majority of tissues, they were observed in the pelvic region and may account for the rapid increase in cardiac output. The pelvic cartilaginous symphysis is a noncapsulated cartilage with a naturally high endogenous expression of vascular endothelial growth factor (VEGF). Development of pelvic AVMs in this region of high VEGF expression occurred because loss of endoglin in endothelial cells leads to increased sensitivity to VEGF and a hyper-proliferative response. Finally, we found that inhibition of VEGFR2 was protective against AVMs development, enlargement of the heart and dilatation of the ventricles.

Conclusion

Our results showed the essential role of endoglin in the maintenance of adult cardio-vasculature through crosstalk with the VEGF signalling pathway.

Acknowledgement/Funding

British Heart Foundation, Cure HHT, The Swedish Research Council, The Cardiovascular Programme at Karolinska Institutet, The Swedish Cancer Society
6091Chronic heart failure is associated with inflammatory deterioration of the bone marrow vascular niche
Authors: Hoffmann J , Abplanalp W , Rasper T , Fischer A , Assmus B , Wild P , Koeck T , Zeiher A M , Dimmeler S
Published: October 2019

Introduction

Inflammation plays a crucial role in many aspects of cardiovascular disease. Particularly, acquired mutations of hematopoietic stem cells (HSC) leading to clonal expansion of inflammatory cells (CHIP) are increased with age and are associated with an enhanced risk of cardiovascular disease. The bone marrow (BM) vascular niche plays a crucial role in maintenance and regulation of HSC functions. Previous studies in mice showed the reduction of a specific Endomucin-high (H-type) endothelial cells (EC) subpopulation by aging. However, the impact of cardiovascular disease is unclear. Therefore, we aimed to investigate the effects of age and heart failure (HF) on the vascular BM cell composition in mice and humans.

Methods and results

Aging mice showed an age-dependent decrease of type H (Emcn-high) BM ECs (p=0.004), whereas the BM frequencies of type L (Emcn-low) ECs did not significantly differ (P=0.18). Importantly, we also observed a marked reduction of type H EC in chronic ischemic mice (P=0.016 vs. sham) indicating that chronic ischemic HF induces similar alterations of the vascular stem cell niche. Importantly, type H ECs were also significantly reduced in ischemic HF patients (n=16) compared with control subjects (n=8; P=0.0003). To gain insights into the mechanisms underlying the changes in the vascular niche, we performed single cells RNA sequencing of human BM ECs. These studies confirmed the decrease in Emcn-expressing ECs in ischemic HF patients, which was accompanied by significantly increased expression of inflammatory genes, including IL1b (P<0.0001 vs. control). Inflammatory EC phenotypes and IL1b expression in HF could be further confirmed at protein level using cytospin immunostainings. Finally, we comprehensively evaluated phenotype-associated differences in the bone marrow plasma proteomes of healthy individuals (n=19) and patients with chronic ischemic (n=22) and non-ischemic (n=19) HF, using proximity extension assays. Here, we identified 182 proteins significantly differentially regulated in CHF versus CTRL. Among the top upregulated proteins the BM environment of patients with CHF showed a striking enrichment of inflammatory and ECM remodeling components.

Conclusions

Our data show for the first time an impact of chronic heart failure on the bone marrow vascular niche in humans. These changes seem to be strongly associated with increased inflammatory response and bone matrix remodeling in CHF. Specifically, the induction of the inflammatory cytokine IL1b may contribute to the disturbed phenotype suggesting that inhibition of IL1b (e.g. by canakinumab) may be used as a novel strategy to prevent or reverse the deterioration of the vascular BM niche.
6097Aminoterminal proB-type natriuretic peptide: a key parameter to optimise therapeutic management of low-flow, low-gradient aortic stenosis
Authors: Annabi M S , Bergler-Klein J , Dahou A , Burwash I G , Ong G , Tastet L , Guzetti E , Orwat S , Baumgartner H , Bartko P E , Mascherbauer J , Mundigler G , Cavalcante J , Pibarot P , Clavel M A
Published: October 2019

Background

B-type natriuretic peptide (BNP) and aminoterminal-proBNP (NT-proBNP) are well established surrogates of LV function impairment. However, data are scarce regarding their prognostic value to risk-stratify patients with classical low-flow, low-gradient aortic stenosis (LFLG-AS, with low left ventricular [LV] ejection fraction).

Methods

The TOPAS study is a prospective observational cohort of 240 patients with aortic valve area <0.6 cm2/m2, mean gradient<40 mmHg and LVEF<50%. True severe AS was adjudicated using flow independent grading schemes.

Results

BNP significantly predicted one-year (area under the receiver operating-characteristic curve [AUC]) 0.62±0.04, p=0.026) but not three-year mortality. After adjustment for the severity of AS, initial treatment (aortic valve replacement [AVR] vs. conservative management [ConsRx]), age, sex and the EuroSCORE (Model#1), BNP-ratio>550 pg/ml had a trend to predict time to death (HR=2.14 [1.00–4.58], p=0.05). In contrast, NT-proBNP ratio significantly predicted both one and three-year mortality (AUC=0.67±0.04 and 0.66±0.05, both p=0.001), and independently predicted time to death (HR=1.39 per 1 unit of Log transformed NT-proBNP [1.11–1.74], p=0.004). In a head-to-head comparison (108 patients with both biomarkers), the AUCs to predict one and thre-year mortality were significantly higher with NT-proBNP versus BNP (p<0.009). NT-proBNP but not BNP independently predicted mortality and significantly improved Model#1 (Likelihood ratio test Chi2=15.95, p<0.001). The category-free net reclassification index of NT-proBNP was 0.71 (p=0.008) versus 0.38 (p=0.15) for BNP. Furthermore, there was a marked survival benefit associated with AVR in patients with NT-proBNP ≥1700 pg/ml (adjusted hazard ratio (aHR) associated to AVR vs conservative management=0.52 [0.31–0.85], p=0.009), while those<1700 pg/ml had excellent one-year survival under ConsRx (only one death [4.5±4.4%] at one year as compared to 23 [37±6.2%] for ConsRx-NTproBNP>1700, aHR=0.11 [0.01–0.83], p=0.033). The survival benefit associated with AVR interacted with NT-proBNP (p<0.001) but not with true or pseudosevere AS (p=0.53 for interaction), suggesting that NT-proBNP might identify moderate AS patients but sufficiently severe valvulo-ventricular disease to justify AVR.

Survival according to NT-proBNP and AVR

Conclusion

NT-proBNP appears to be an excellent biomarker for the clinical purpose of risk-stratifying classical LFLG-AS. A threshold of 1700 pg/ml i.e. close to the diagnostic threshold for heart failure in acute dyspnea, was a strong independent determinant of the survival benefit associated with aortic valve replacement. Our findings suggest that NT-proBNP should be preferred over BNP.

Acknowledgement/Funding

Canadian Institute of Health Research
6099Impact of aortic valve replacement on outcomes of patients with low-flow, low-gradient moderate aortic stenosis
Authors: Annabi M S , Dahou A , Bergler-Klein J , Burwash I G , Orwat S , Baumgartner H , Bartko P E , Mascherbauer J , Mundigler G , Cavalcante J , Ribeiro H B , Rodes-Cabau J , Clavel M A , Pibarot P
Published: October 2019

Background

Aortic valve replacement (AVR) is recommended for patients with low-flow, low-gradient (LFLG) and true-severe aortic stenosis (TSAS). However, there is very few data on the potential benefit of AVR in patients with LFLG pseudo-severe (i.e. moderate) AS (PSAS).

Methods

Consecutive patients with aortic valve area ≤0.6 cm2/m2, mean gradient <40 mmHg were prospectively recruited in a multicenter observational cohort study. The patients were categorized in TSAS vs. PSAS using previously reported thresholds of flow-independent parameters of AS severity (projected valve area at normal flow rate ≤1.0 cm2 and/or aortic valve calcium score by CT >1200 AU in women and >2000 AU in men). To account for between-treatment-group differences, inverse probability-of-treatment weighting was combined to Cox proportional hazards regression.

Results

Among the 430 patients included in this study, 297 (69%) were classified as TSAS and 274 (57%) underwent AVR. Of note, 21% of the patients treated by AVR were classified as PSAS. In patients managed conservatively (ConsRx), 52% had PSAS and 48% TSAS. During a median follow-up of 28 months [8–60], 198 patients died. The adjusted weighted hazard ratio (awHR) of death associated with AVR as compared to ConsRx was 0.42 [0.24–0.73] (p<0.0001, Figure1-Panel-A). This survival benefit associated with AVR was observed not only in patients with TSAS but also in those with PSAS (awHR: 0.29 [0.12–0.70]; p=0.006, Figure1-Panel-B).

Figure 1

Conclusion

The results of this study suggest that AVR is associated with a survival benefit not only in LFLG patients with TSAS but also in those with PSAS. Randomized trials are needed to confirm the benefit of AVR in patients with moderate AS and depressed LV systolic function.

Acknowledgement/Funding

Canadian Institute of Health Research
6111Optical coherence tomography derived predictors of restenosis after non-stenting coronary intervention with drug-coated balloon
Authors: Nakagama S , Niida T , Matsuda Y , Nakamura T , Sasaoka T , Hatano Y , Umemoto T , Lee T , Yonetsu T , Hirao K
Published: October 2019

Background

One of the limitations of metallic stents including contemporary drug eluting stents lies in the permanent existence of metallic materials within the coronary arteries, which may lead to neoatherosclerosis and a long-term use of dual antiplatelet therapy. Some reports have recently suggested the efficacy and safety of non-stent strategy with drug-coated balloon (DCB) angioplasty in combination with debulking devices for de novo lesions. However, little is known about the potential risk of restenosis after percutaneous coronary intervention (PCI) with DCB.

Purpose

We sought to assess the predictive factors of restenosis by optical coherence tomography (OCT) after PCI with DCB instead of metallic stents.

Methods

We retrospectively investigated 49 de novo lesions in 38 patients treated by DCB without stent implantation in whom OCT was performed immediately after PCI and follow-up angiography was performed at median of 5.6 (3.7–6.9) months. OCT findings after PCI and the incidence of restenosis at follow-up angiography were evaluated. By means of OCT images, medial coronary dissection was defined as a dissection which reached the medial layer of the vessel, and major dissection was defined as a dissection with more than 60 degrees of the circumference of the vessel or more than 3mm in length. Restenosis was defined as more than 50% diameter stenosis evaluated by Quantitative Coronary Angiography.

Results

Restenosis was observed in 13 of 49 lesions (27%). In univariate logistic regression analysis, major dissection and medial dissection at the final OCT were associated with restenosis (Odds ratio [OR] 10.0; 95% confidence interval [CI] 2.5–52.6; p<0.01 and OR 5.8; 95% CI 1.5–25.1; p=0.01, respectively). Lesion preparation prior to DCB were performed with rotational atherectomy (n=9), orbital atherectomy (n=2), directional atherectomy (n=4), excimer laser angioplasty (n=17), scoring balloon angioplasty (n=13), or balloon angioplasty (n=4). OCT-defined major dissection remained a significant predictor for restenosis independent of debulking devices used for the preparation (OR 8.1; 95% CI 1.2–70.2; p=0.03).

Conclusions

Major dissection was associated with restenosis after non-stenting PCI with DCB. Stent implantation should be considered in cases of OCT-defined major dissection.

Acknowledgement/Funding

None
6117Persistent LBBB and AV block with high-burden RV pacing following transcatheter aortic valve replacement are associated with new onset cardiomyopathy
Authors: Ananwattanasuk T , Ghannam M , Lathkar-Pradhan S , Latchamsetty R , Jame S , Jongnarangsin K
Published: October 2019

Background

Left bundle branch block (LBBB) and AV nodal block (AVB) requiring permanent pacemaker implantation occur frequently following transcatheter aortic valve replacement (TAVR) and may be associated with adverse clinical events.

Objectives

The study aims to assess the incidence of new onset cardiomyopathy among patients with normal left ventricular systolic function patients who developed LBBB or persistent AVB with high-burden right ventricular (RV) pacing (>80%) following TAVR procedure.

Methods

Consecutive patients who underwent TAVR procedure from January 2012 to June 2017 at the University of Michigan Health System were included in the retrospective analysis. Those who had a preexisting cardiac implantable electronic device (CIED), prior LBBB, left ventricular ejection fraction (LVEF) <50%, and follow up period less than 1 year were excluded from this analysis. New onset cardiomyopathy was defined by a left ventricular ejection fraction (LVEF) <45% within 1 year after TAVR.

Results

A total of 362 patients were included in the study (mean age 76.9±11.5 years, 56.1% male). Of these, 30 patients (8.3%) developed persistent AVB and required >80% RV pacing (pacing group), 61 patients (16.9%) developed persistent LBBB (LBBB group), and 271 patients (74.9%) did not have LBBB or AVB or required <80% RV pacing (control group). Baseline LVEF was 63.9+6.4% in pacing group (p=0.76) and 64.4+7.4% in LBBB group (p=0.89) compared to 64.3+6.5% in control group. Within 1 year after TAVR, 10/30 patients (33.3%) in pacing group (p<0.01) and 20/61 patients (32.8%) in LBBB (p<0.01) developed new onset cardiomyopathy compared to 9/271 patients (3.3%) in control group. LVEF at 1 year was 53.8+11.9% in pacing group (p<0.01) and 53.7+12.1% in LBBB group (p<0.01) compared to 64.8+7.7% in control group.

Conclusion

Among patients with normal baseline left ventricular systolic function, AV block required high-burden RV pacing and persistent LBBB following TAVR were associated with significantly higher incidence of new onset cardiomyopathy.