bluuebunny/crossref_metadata_2025 huggingface dataset:
217Metabolomic profile of patients with new onset heart failure; more microvascular dysfunction in patients with preserved ejection fraction compared to reduced ejection fraction - the PREFERS Study
Authors: Hage C , Lofgren L , Michopoulos F , Nilsson R , Davidsson P , Ekstrom M , Eriksson M J , Lynga P , Persson B , Wallen H , Gan L M , Persson H , Linde C
Published: October 2019

Background

Heart failure with preserved (HFpEF) and reduced (HFrEF) ejection fraction are both associated with metabolic derangements which may have different pathophysiological implications

Purpose

To identify metabolites and pathways differentially altered with the potential to differentiate HFpEF from HFrEF.

Methods

In the PREFERS Stockholm study (Preserved and Reduced Ejection Fraction Epidemiological Regional Study) 121 endogenous plasma metabolites were assessed by targeted mass spectrometry. Partial Least Squares Discriminant Analysis (PLS-DA) was used to identify metabolites differentially altered in new onset HF divided into HFpEF (EF ≥50%, n=46) versus HFrEF (ÈF<40%, n=75) patients. Multivariable logistic regression was used to assess independent associations between HF group and selected metabolites, including sex, age and eGFR as co-variates.

Results

Compared to HFrEF, HFpEF patients were older; 77 vs 65 years (p<0.001), more often female 54% vs 46% (p=0.004) with hypertension 60% vs 40% (p<0.001) and diabetes 63% vs 37% (p=0.007), and lower NT-proBNP 720 vs 1295 ng/L (p=0.014) and eGFR 63 vs 72 mL/min/1.73 m2 (p<0.001).

HFpEF patients had higher levels of hydroxyproline, cysteine, symmetric dimethyl arginine, alanine, kynurenine and acylcarinitines and lower levels of cAMP, lysoPC, L-carnitine, arginine, cGMP, serine and lactate (Figure). HFpEF was independently associated with reduced levels of cGMP (OR 0.98 [95% CI: 0.97–0.99; p=0.008]), serine (0.97 [0.95–1.00; 0.047]) and cAMP (0.97 [0.94–0.99; 0.009]).

Figure 1

Conclusions

In new onset HF patients, HFpEF was associated with decreased cGMP, cAMP and serine indicating increased oxidative stress, impaired innate immune function and myocardial hypertrophy. HFpEF patients displayed a distinct metabolic profile reflecting increased endothelial dysfunction, hypoxia, inflammation and myocardial fibrosis pointing towards more involvement of microvascular dysfunction compared to HFrEF.

Acknowledgement/Funding

Science for Life Laboratory–Astra Zeneca; Mölndal, Sweden collaborative grant No. 1377
251Revacept, an inhibitor of platelet adhesion in symptomatic carotid stenosis: Results from a phase II study
Authors: Groschel K , Richards T , Weimar C , Neugebauer R , Poli S , Weissenborn K , Imray C , Michalski D , Rashid H , Loftus I , Ritter M , Hauser T.-K , Muench G , Poppert H
Published: October 2019

Revacept is a novel lesion-specific inhibitor for platelet adhesion and thrombus formation. The biological drug is based on the platelet GPVI receptor and prevents collagen-mediated platelet activation from the atherosclerotic plaque. The unique characteristic of Revacept is the specific inhibition of plaque-mediated thrombus formation without alteration of hemostasis.

To test this concept in patients with plaque-mediated thrombosis we investigated patients with symptomatic carotid artery stenosis (at least 50% cf. ECST) with a recent ischemic cerebral stroke or transient ischemic attack (TIA). 150 patients were evenly randomized in blinded fashion to receive placebo, 40mg or 120 mg Revacept by IV infusion. To investigate anti-thrombotic efficacy, we assessed microemboli in the middle cerebral artery by transcranial Doppler (MES) and micro-infarctions in the brain by diffusion-weighted nuclear magnetic resonance (DWI-NMR) imaging. Ischemic complications such as myocardial infarctions and ischemic stroke were clinically followed up to 3 and 12 months. Bleeding complications were thoroughly monitored according to the RE-LY study group criteria. All patients were on standard anti-platelet therapy and underwent guideline conform treatment with carotid endarterectomy (CEA),carotid artery stent implantation or intensified conservative treatment.

The study was conducted in 16 centers in Germany and the UK from May 2013 to September 2018. Due to lost to follow-up investigations the planned patient numbers were slightly exceeded to 158 patients, who were finally included in the study according to intention to treat. Currently data clearance and detailed analysis of unblinded data is going on. 7.6% of patients underwent carotid artery stenting, 11.4% were under intensified conservative treatment and 81.0% were surgically treated with CEA. The safety data of the overall 158 patients which was closely monitored by an independent data safety board are available. In the overall study population (before unblinding for treatment) ischemic strokes and myocardial infarctions were numerically lower compared to previous studies with symptomatic carotid stenosis patients undergoing CEA or stenting (meta analysis from the EVA-3S, SPACE and ICSS study). Despite comparable basal anti-thrombotic therapy addition of Revacept did not increase bleeding complications in the overall study population.

The Revacept CS02 study has successfully achieved the aimed patient recruitment. Safety analysis shows a favorable profile. Bleeding complications in these high-risk patients with recent ischemic stroke were not increased compared to historic data from similar control patients. There is a trend for increased anti-thrombotic and anti-ischemic potency with regard to clinical events. Final data will be presented at the congress.

Acknowledgement/Funding

None
256Heart transplant recipients with cardiac allograft vasculopathy have increased platelet aggregation before and after low-dose aspirin therapy
Authors: Bjerre K P , Clemmensen T S , Berg K , Poulsen S H , Dalby S , Hvas A M , Grove E L , Eiskjaer H
Published: October 2019

Background

Following heart transplantation (HTx), long-term survival is reduced mainly due to development of a specific form of coronary artery disease, coronary allograft vasculopathy (CAV). Using optical coherence tomography to visualize the coronary artery wall, we have recently shown that layered fibrotic plaques resembling organized clots are the dominant plaque component in CAV. Thus, thrombosis is suggested as a possible mechanism contributing to development and progression of CAV. Aspirin is widely used after HTx despite limited evidence and lack of specific guidelines. The antiplatelet effect of aspirin has not been thoroughly examined in HTx-patients.

Purpose

To investigate baseline platelet aggregation and the antiplatelet effect of aspirin in HTx-patients with and without CAV.

Methods

We included 68 HTx-patients (median 8.6 years from HTx). In 66 patients taking 75 mg aspirin for a minimum of 7 days, platelet aggregation was measured in whole blood using impedance aggregometry with the following agonists: Adenosine diphosphate (ADP) stimulating ADP-receptors and arachidonic acid (AA) for monitoring of aspirin treatment. Aspirin compliance was confirmed by measuring serum-thromboxane B2. Platelet aggregation prior to aspirin therapy was measured in 59 patients as it was not considered clinically safe to interrupt ongoing aspirin treatment for one week prior to blood sampling in 9 patients mainly due to previous coronary stenting. CAV burden was determined by coronary angiography and echocardiography based on international classification. Patients were divided into two groups; no CAV (n=37) and CAV (n=29).

Results

In HTx-patients not treated with aspirin, we found significantly increased ADP-induced platelet aggregation in patients with CAV vs. patients without CAV (904 (95% CI 813–995) vs. 786 (95% CI 728–843) AU*min, P=0.02). Baseline AA-induced aggregation was also higher in patients with CAV vs. patients without CAV, though non-significant (994 (95% CI 907–1081) vs. 905 (95% CI 839–972) AU*min, P=0.10). Even though aspirin reduced AA-induced platelet aggregation in both groups, patients with CAV had significantly increased AA-induced platelet aggregation compared with patients without CAV on aspirin treatment (380 (95% CI 295–465) vs. 286 (95% CI 239–334) AU*min, P=0.04) (Fig. 1).

Conclusions

HTx-patients with CAV have increased platelet aggregation before and after aspirin treatment compared with HTx-patients without CAV. Aspirin monotherapy may not provide sufficient platelet inhibition in HTx-patients with CAV.

Acknowledgement/Funding

Aarhus University (PhD-salary)
257Ticagrelor decreases concentrations of prothrombotic extracellular vesicles compared to clopidogrel
Authors: Gasecka A , Nieuwland R , Budnik M , Dignat-George F , Eyileten C , Harrison P , Kaplon-Cieslicka A , Lacroix R , Opolski G , Van Der Pol E , Postula M , Leroyer A , Siljander P , Sturk A , Filipiak K
Published: October 2019

Introduction

The platelet P2Y12 antagonist ticagrelor reduces all-cause and cardiovascular mortality in patients after acute myocardial infarction (AMI) compared to clopidogrel, but the underlying mechanism is unknown. Because activated platelets release prothrombotic extracellular vesicles (EVs) exposing P-selectin, fibrinogen and phosphatidylserine (PS), we hypothesized that ticagrelor inhibits the release of EVs compared to clopidogrel.

Purpose

To compare the effects of ticagrelor and clopidogrel on the concentrations of platelet EVs in relation to platelet reactivity, and on the concentrations of EVs from other P2Y12-exposing cells (leukocytes, endothelial cells).

Methods

After the percutaneous coronary intervention, patients with first AMI (n=60, age 64.5±10.8 years, 68% male) were randomized in 1:1 ratio to antiplatelet therapy with ticagrelor or clopidogrel. Venous blood was collected from fasting patients at randomisation, 48 hours after randomisation, and 6 months following the index hospitalization with informed consent. Flow cytometry (Apogee A60 Micro) was used to determine plasma concentrations of EVs labelled with antibodies for activated platelets (CD61, CD62p; PEVs), fibrinogen, phosphatidylserine (PS), leukocytes (CD45; LEVs) and endothelial cells (CD146; EEVs). To maximize the reliability, the analysis of the 1,224 flow cytometry data files was performed with software enabling automatic flow rate stabilization, diameter and refractive index determination, size distribution fitting, fluorescent gate determination, and statistics reporting (MATLAB R2018a). To differentiate between EVs and small platelets, only particles <700 nm were included. Platelet reactivity was assessed by impedance aggregometry (Multiplate Analyzer) using the ASPI test (arachidonic acid, 0.5 mM) and the ADP test (adenosine diphosphate, 6.5 μM).

Results

Concentrations of PEVs exposing P-selectin, fibrinogen and PS were lower after 6 months of therapy with ticagrelor compared to clopidogrel, and decreased over time (p=0.034; p=0.021; p=0.018, respectively). Concentrations of LEVs were lower both after 72 hours and after 6 months of therapy with ticagrelor compared to clopidogrel (p=0.018; p<0.001, respectively). There was a trend towards higher concentrations of EEVs both after 72 hours and after 6 months of therapy with ticagrelor, compared to clopidogrel. There were no correlations between the concentrations of PEVs and platelet reactivity.

Conclusions

Ticagrelor decreases concentrations of prothrombotic EVs, compared to clopidogrel, suggesting that the clinical benefits of ticagrelor may be at least partly explained by inhibition of EV release from activated platelets. Further research is warranted to link this effect with clinical outcomes.

Acknowledgement/Funding

Medical University of Warsaw (1WR/PM2/18)
259Higher risk of myocardial infarction in the first year following 5-fluorouracil treatment
Authors: Shanmuganathan J W D , Kragholm K H K , Tayal B T , Poulsen L P , El-Galaly T C E G , Fosbol E L F , Gislason G G , Kober L K , Sogaard P S , Torp-Pedersen C T T P , Freeman P F
Published: October 2019

Abstract

Background

5-fluorouracil (5-FU) is the third most commonly used chemotherapeutic agent in the treatment of solid malignancies across the world. The most common manifestation of cardiotoxicity associated with 5-FU is chest pain, presenting as atypical chest pain, angina on exertion or rest and acute coronary syndromes including myocardial infarction and in worse case even death.

Nevertheless, a widespread appreciation of 5-FU related cardiotoxicity including myocardial infarction is poorly understood.

Purpose

This study aims to examine risk of myocardial infarction in patients treated with 5-FU compared to age- and sex-matched population controls.

Methods and results

Methods: Individuals treated with 5-FU between 2004 and 2014 in the Danish National Patient Register were identified and risk set matching was used to find background population controls matched on age and sex in a 1:5 ratio. Furthermore, two years follow-up time were added with total 13 years. Neither

5-FU patients nor controls had prior ischemic disease. Aalen-Johansen and Kaplan-Meier estimates were used to report the cumulative incidence of myocardial infarction and all-cause mortality, respectively.

A multivariable Shared Frailty Cox regression analysis (adjusted for patient age, sex, hypertension, hypercholesterolemia, diabetes, chronic obstructive pulmonary disease, chronic kidney disease, heart failure and atrial fibrillation as well as selected anti-anginal medications including nitrates, beta- and calcium-blockers) was used to determine the association between 5-FU treatment and the one-year risk of myocardial infarction.

Results

A total of 9,012 5-FU patients and 45,060 controls formed the study population. Differences in comorbid conditions (diabetes, chronic obstructive pulmonary disease, chronic kidney disease, heart failure and atrial fibrillation) and selected anti-anginal medications (nitrates, beta- and calcium-blockers) were non-significant (all P>0.05). The one-year cumulative incidence of myocardial infarction is significantly higher for 5-FU patients at 0.8% versus 0.6% among population controls (Figure 1A), with a competing risk of death of 25.1% versus 1.2%. The risk diminishes beyond one year and becomes lower for 5-FU patients with time (Figure 1A), along with an increasing all-cause mortality (Figure 1B). The unadjusted and adjusted hazard ratio for the one-year risk of myocardial infarction were 1.38 [95% CI 1.07–1.78] and 1.54 [95% CI 1.19–1.99].

Conclusions

Although the one-year risk of myocardial infarction is higher among 5-FU patients compared with population controls, the absolute risk is small and becomes insignificant beyond one year of follow-up.
264The long noncoding RNA H19 modulates cardiac remodeling after infarction
Authors: Choong O K , Chen C Y , Lin J H , Lin P J , Zhang J H , Kamp T J , Hsieh P C H
Published: October 2019

Noncoding RNAs account for 80% of human transcripts, but functional studies on noncoding RNAs are relatively few and limited. Long noncoding RNAs (lncRNAs) are known to have an important role in cardiac development, and lately, high-throughput RNA sequencing has been extensively utilized to profile and explore the transcriptome landscape of lncRNAs in failing hearts. These studies have revealed that lncRNAs are mostly dysregulated in failing hearts and their expression signature can discriminate failing hearts of different etiologies.

H19 is abundantly expressed in failing human hearts and its polymorphism was shown to possess a significant correlation with the risk of coronary artery diseases. In our study using murine hearts, we discovered that H19 was significantly up regulated in the heart after ischemic injury, with predominant expression in cardiac fibroblasts. This finding piqued our interest to further investigate the function of H19 in the heart.

We demonstrated that ectopic overexpression of H19 using the AAV approach led to severe cardiac fibrosis in mouse hearts following myocardial infarction. In light of this finding, we generated H19 knockout mice to further investigate the functionality of H19 and we found that cardiac fibrosis was attenuated in these mice. Altogether, these findings suggested that H19 is a fibrosis regulator during cardiac remodeling process after infarction. Due to the multiple regulatory roles of lncRNAs, we then took advantage of chromatin isolation by RNA purification (ChIRP) to identify the H19-interacting protein, YB-1. Surprisingly, mice with YB-1 knockdown displayed severe cardiac fibrosis even without injury. Furthermore, we demonstrated that YB-1 is a transcriptional suppressor of collagen 1A1. Knockout of H19 in YB-1 knockdown partially suppressed Col1a1 expression, which suggests a negative regulatory role of H19 on YB-1 towards the expression of Col1a1.

Taking into account all of these findings, we concluded that H19 mediates collagen expression in fibroblasts through the inhibition of YB-1 activity during cardiac remodeling.
266Loss of pumilio 1 phosphorylation turns off the regulation of miRNA-221 on gene p27kip1 in the heart
Authors: Zhou Y Z , Richards A M R , Wang P P W
Published: October 2019

Background

MicroRNAs regulate gene expression post-transcriptionally via complementary sequence pairing of mRNA 3'UTR and miRNA seed region. MiR-221 downregulates p27kip1 Cyclin-dependent kinase inhibitor 1B (p27), a cell cycle inhibitor, through direct targeting. The down-regulation of p27 caused by miR-221 upregulation induces cancer cell proliferation and has been reported to be closely associated with human cancer metastasis. This regulation is dependent on the existence of pumilio 1 (PUM1). Meanwhile miR-221 mimics protect cardiac myocytes against ischemic injury. It is a potential therapeutic target for cardioprotection. We investigated whether miR-221 targeted p27 in the heart.

Purpose

To test the hypothesis that the regulation of miR-221 on p27 is abolished in the heart due to lack of RNA binding protein (RBP) PMU1 phosphorylation but not due to p27 3'UTR shortening.

Methods

Primary cardiac fibroblasts (cFB) were isolated and cultured under normoxia and hypoxia. After transfections of miR-221 mimics and mimic control (MC), cell proliferation was assessed by cell number, CCk-8 and Ki67 staining. In vivo rats undergoing left coronary artery ligation (MI) and Sham were treated with intravenous miR-221 mimics. Cells or cardiac tissue were collected to measure p27 and PUM1 by RT-qPCR and Western blot (WB). Full length p27 (coding plus 3'UTR sequence) and 3'UTR p27 sequence were quantified using specific primers. The ratio of 3'UTR/Full length was compared to indicate changes between groups. The ratios of 3'UTR/Full length were compared to indicate changes between groups.

Results

MiR-221 mimics significantly downregulated the expression of p27 mRNA and protein in cFB in both normoxia and hypoxia. P27 downregulation led to cFB proliferation, which could be abrogated by p27 overexpression. miR-221 mimic treatment increased cardiac miR-221 by ∼2–5 fold in Sham and ∼15 fold in MI. Whilst p27 expression was not affected in either Sham or MI hearts. Simultaneously α-SMA+ cells, an indication of cFB number and activation, were reduced by miR-221 mimic in Sham and MI heart. The ratios of p27 3'UTR/full length did not vary significantly between cultured cFB and heart (Sham and MI), indicating the 3'UTR length did not vary between cFB and the whole heart. PUM1 mRNA expression was stable in cFB and the heart. However, phosphorylated PUM1 was highly expressed in cFB but completely diminished in Sham and MI hearts.

Conclusion

MiR-221 downregulated p27 in primary cFB and induced cell proliferation in vitro. miR-221 could not regulate cardiac p27 expression nor increase cFB proliferation in vivo. MiR-221 induced p27 regulation was correlated with the presence or absence of phosphorylated PUM1. For the first time, we demonstrated that loss of phosphorylated PUM1 turns off the regulation of miRNA-221 on gene p27 in the heart. The mechanism of PUM1 phosphorylation warrant future investigation.
280The impact of epicardial collateral use on the outcomes of retrograde chronic total occlusion percutaneous coronary intervention
Authors: Karacsonyi J , Karmpaliotis D , Alaswad K , Jaffer F A , Yeh R W , Martinez-Parachini J R , Tajti P , Kandzari D E , Krestyaninov O , Jaber W , Choi J , Rangan B V , Ungi I , Banerjee S , Brilakis E S
Published: October 2019

Background

The impact of the type of collateral vessel used on the outcomes of retrograde chronic total occlusion (CTO) percutaneous coronary intervention (PCI) has received limited study.

Methods

We reviewed the baseline clinical and angiographic characteristics and procedural outcomes of 1,501 retrograde CTO PCIs performed in 1494 patients between 2012 and 2019 at 26 centres.

Purpose

We sought to examine the impact of the type of collateral vessel used on the outcomes of retrograde CTO PCI.

Results

Mean patient age was 65.0±10 years and 86% were men. Septal collaterals or bypass grafts were used in 66%, epicardial collaterals in 34% of lesions. Compared with cases in which only septal collaterals and bypass grafts were used, use of epicardial collaterals were associated with larger vessel diameter (3.0 [2.5; 3.0] vs. 3.0 [2.5, 3.2] mm, p=0.005), more moderate/severe tortuosity (55% vs. 42%, p<0.0001), more moderate/severe calcification (73% vs. 65%, p=0.002), and higher Japan chronic total occlusion score (3.34±1.02 vs. 3.11±1.07, p<0.0001). Epicardial collateral use was associated with lower technical (76.3% vs. 80.6%, p=0.053) and procedural (71.9% vs. 77.8%, p=0.011) success rates, but similar incidence of major cardiac adverse events (4.72% vs. 4.56%, p=0.889). Epicardial collaterals were associated with more perforations (10.63% vs. 7.30%, p=0.028). Epicardial collateral use was associated with longer fluoroscopy time (82 [64, 104] 76 [(55, 102] p=0.0003) and higher contrast volume (300 [221; 414] ml vs. 270 [200; 370] ml, p<0.0001).

Conclusion

In a contemporary, multicenter registry epicardial collaterals were used in approximately one-third of retrograde CTO PCIs. Use of epicardial collaterals was associated with lower success but similar major complication rates.

Acknowledgement/Funding

Minneapolis Heart Institute Foundation
286Predictors of atrial fibrillation in patients with embolic stroke of undetermined source: an analysis of the RE-SPECT ESUS trial
Authors: Granger C B , Sacco R L , Easton J D , Meyerhoff J , Cronin L , Kleine E , Grauer C , Bahit M C , Brueckmann M , Diener H.-C
Published: October 2019

Background

A proportion of patients with embolic stroke of undetermined source (ESUS) may have silent atrial fibrillation (AF) or develop AF after the initial evaluation. Better understanding of risk for identification is critical to implement optimal monitoring strategies with the goal of preventing recurrent stroke. The RE-SPECT ESUS trial provides an opportunity to assess predictors for developing AF and associated recurrent stroke.

Methods

RE-SPECT ESUS was a randomized, controlled trial (564 sites, 42 countries) assessing dabigatran versus aspirin for the prevention of recurrent stroke in patients with ESUS. Of 5390 patients enrolled and followed for a median of 19 months, 403 (7.5%) were found to develop AF reported as an adverse event or using cardiac monitoring per standard clinical care. Univariable and multivariable regression analyses for predictors of AF were conducted.

Results

In a multivariable analysis, clinical predictors for developing AF were: older age, history of heart failure, lower heart rate, hypertension, higher body mass index, and being from Western Europe (Table). Using several published predictive models, including HAVOC, C2HEST, AS5F, ARIC, and CHA2DS2-VASc, high scores were associated with increased rates of AF. In patients who developed AF, recurrent stroke occurred in 7.0% per year, versus 4.2% per year in patients who did not develop AF (hazard ratio 1.75; 95% CI 1.30–2.35, p=0.0002).

Conclusion

Besides age as the most important variable, several other factors, including lower heart rate, higher body mass index, and hypertension, are independent predictors of AF after ESUS. Understanding who is at higher risk of developing AF may help identify patients requiring more intense, long-term cardiac monitoring.

Acknowledgement/Funding

Funded by Boehringer Ingelheim
298Change in respiratory muscle strength predicts clinical events in patients with chronic heart failure
Authors: Hamazaki N , Masuda T , Kamiya K , Matsuzawa R , Nozaki K , Ichikawa T , Tabata M , Maekawa E , Noda C , Yamaoka-Tojo M , Matsunaga A , Ako J
Published: October 2019

Background

Respiratory muscle weakness, frequently observed in patients with chronic heart failure (CHF), has been documented as a predictor for poor prognosis. Several studies have reported that respiratory muscle training increases respiratory muscle strength and consequently improves exercise tolerance and quality of life in these patients. However, the relationship between the change in respiratory muscle strength and prognosis is still unclear.

Purpose

We aimed to investigate whether the change in respiratory muscle strength following cardiac rehabilitation predicts the incidence of clinical events in CHF patients.

Methods

We studied 348 patients with CHF who were hospitalized because of decompensated heart failure and received 5-month cardiac rehabilitation during hospitalization and after hospital discharge. Clinical characteristics including aetiology of heart failure, comorbidity conditions, medications, blood examination and echocardiographic variables were obtained from clinical records. We also measured maximal inspiratory pressure (PImax) as respiratory muscle strength at hospital discharge and 5 months later. The change of PImax (ΔPImax) between the 5-month observation period was examined. We followed up the patients after the observation period and investigated the incidence of all-cause mortality or all-cause unplanned readmission. In statistical analysis, patients were divided into two groups based on the median value of ΔPImax. We compared the event-free survival rate between the two groups using the Kaplan-Meier method with a log-rank test. We also performed the Cox proportional hazard model to clarify whether the ΔPImax was an independent predictor for the incidence of clinical events.

Results

Over a median follow-up of 1.6 years, 121 patients (34.8%) died or readmitted, and their rate of incidence was 21.7/100 person-years. The higher ΔPImax was associated significantly with a higher rate of event-free survival (Log-rank: 8.085, P=0.004, Figure 1). In univariate Cox proportional hazard model, ΔPImax was a significant predictor for the all-cause mortality/readmission (unadjusted hazard ratio for PImax increase of 10 cmH2O: 0.842, 95% CI: 0.763 - 0.931, P=0.001). Even after adjustment for clinical confounding factors including baseline PImax, ΔPImax remained significant and independent predictor for the all-cause mortality/readmission (adjusted hazard ratio for PImax increase of 10 cmH2O: 0.862, 95% CI: 0.763 - 0.974, P=0.017, Figure 2).

Conclusion

This study is the first to demonstrate that the change in respiratory muscle strength following cardiac rehabilitation independently predicts the incidence of clinical events in patients with CHF. The increase in PImax of 10 cmH2O was associated significantly with a 14% decrease in the rate of all-cause mortality or readmission.

Acknowledgement/Funding

JSPS KAKENHI JP16K16442
404Impact of cardiovascular risk factors for the development of cardiovascular disease: Results from MORGAM and BiomarCaRE consortia
Authors: Magnussen C
Published: October 2019

Background

Knowledge about the impact of modifiable risk factors for cardiovascular disease (CVD) onset is essential to improve CVD prevention.

Purpose

We estimated population-attributable fractions (PAFs) of body-mass-index (BMI), systolic blood pressure (SBP), diabetes, blood lipids (non-high-density lipoprotein cholesterol; non-HDL-C) and daily smoking for CVD.

Methods

Harmonized data from MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Biomarkers for Cardiovascular Risk Assessment in Europe (BiomaCaRE) consortia were used to calculate hazard ratios (HRs; 95% CI) and PAFs for incident CVD (myocardial infarction or coronary death, unstable angina, cardiac revascularization, ischemic stroke). PAFs for single risk factors or any combination of them were estimated using methods by Laaksonen 2011.

Results

We included 150,190 participants (77,801 men and 72,389 women) without CVD at baseline. Strongest associations were seen for SBP ≥160 mmHg (HR 1.79, 1.67–1.92 men; HR 1.93, 1.75–2.14 women), diabetes (HR 2.02, 1.86–2.20 men; HR 2.29, 2.06–2.55 women), non-HDL-C ≥220 mg/dL (HR 3.11, 2.49–3.88 men; HR 2.27, 1.68–3.05 women), daily smoking (HR 1.82, 1.73–1,90 men; HR 2.16, 2.0–2.33 women). Table 1 provides PAFs for incident CVD. Overall PAFs for men and women were 73.7% (67.7–79.1) and 73.3% (64.9–80.9).

Table 1. PAFs (%) for 5-year incident CVD Risk factor/category PAFs (95% CI), men PAFs (95% CI), women Underweight 0.1 (−0.1, 0.3) 0.2 (−0.1, 0.6) Pre-obesity 6.6 (4.3, 8.9) 4.3 (1.5, 6.9) Obesity 3.9 (2.7, 5.3) 8.0 (5.3, 10.5) SBP 130 to <140 mmHg 2.8 (1.7, 4.0) 2.7 (1.3, 4.0) SBP 140 to <160 mmHg 9.7 (8.1, 11.3) 9.3 (6.7, 11.6) SBP ≥160 mmHg 11.3 (9.7, 12.8) 18.9 (16.2, 21.8) Diabetes 5.2 (4.5, 6.2) 7.8 (6.5, 9.4) non-HDL-C 100 to <145 mg/dL 4.3 (1.8, 6.4) 3.3 (0.5, 6.5) non-HDL-C 145 to <185 mg/dL 13.9 (9.8, 17.5) 11.3 (6.0, 16.2) non-HDL-C 185 to <220 mg/dL 15.8 (12.8, 18.4) 12.8 (8.8, 17.0) non-HDL-C ≥220 mg/dL 16.7 (14.6, 18.5) 17.0 (12.5, 21.1) Daily smoking 16.5 (15.0, 18.3) 12.3 (10.7, 13.7) The N CVD events/N used was 8,302/77,801 for men and 4,071/72,389 for women.

Conclusion

Uncontrolled risk factors, especially non-HDL-C and SBP in the highest category, daily smoking and diabetes had the highest impact for incident CVD. All risk factors combined accounted for a PAF of 73%. Targeting risk factors would lead to a substantial reduction of CVD onset.

Acknowledgement/Funding

BiomarCaRE: EU Seventh Framework Programme (FP7/2007-2013), No. HEALTH-F2-2011-278913. MORGAM: EU FP 7 CHANCES (HEALTH-F3-2010-242244).
406Phenotyping acute decompensated heart failure by intrarenal venous flow and right ventricle-pulmonary circulation uncoupling
Authors: Labate V , Vella A , Carenini M , Losito M , Caracciolo M M , Rovida M , Bandera F , Guazzi M
Published: October 2019

Background

Intrarenal venous blood flow (IRVF) has recently been used to assess renal haemodynamics in heart failure (HF).Different IRVF patterns have been described, with discontinuous IRVF related to a worse outcome compared to the continuous one.

Purpose

We aimed at studying the interaction between IRVF and the right heart dynamics thorough the study of right ventricular (RV) to pulmonary circulation (PC) coupling in acute decompensated (AD) HF patients.

Methods

92 ADHF patients underwent a transthoracic echocardiography followed by renal ultrasonography and laboratory tests. The IRVF was evaluated by Venous Impedance Index (VII)

Results

Dividing the population according to the different IRVF patterns allowed to phenotype the HF population. Patients with the worst IRVF pattern (monophasic) showed significantly higher prevalence of pulmonary hypertension and RV dysfunction with a lower TAPSE/PASP ratio. Patients with continuous IRVF pattern showed normal pulmonary pressures and RV function with a higher TAPSE/PASP ratio. A strong logarithmic correlation between VII and TAPSE/PASP ratio was observed (R2=0,5406).

At multivariate linear regression analysis, RV to PC uncoupling was identified as independent determinant of VII. TAPSE/PASP was inversely associated with VII (−0.55±0.16, p=0.0011). LVEF was not associated with VII (p=0.08).

No difference in renal function laboratory test was found while NT-proBNP was significantly higher in the IRVF monophasic group.

Patients characteristics Total (92) Continuous (32) Pulsatile (19) Biphasic (15) Monophasic (26) P value VII 0.49±0.36 0.11±0.06 0.38±0.12 0.74±0.05 0.95±0.02 <0.0001 LVEF (%) 43.9±16.1 51.4±13.4 41.6±15 43±15.3 34±16.3 0.002 TAPSE (mm) 16.7±5.5 20.1±5.1 13.9±2.7 17±6.5 13.7±4.3 <0.0001 PASP (mmHg) 41.6±14.5 30.9±6.9 42.9±9.3 52.6±12.6 50.3±16.3 <0.0001 TAPSE/PASP 0.46±0.26 0.69±0.24 0.33±0.08 0.34±0.14 0.29±0.11 <0.0001 Creatinine (mg/dL) 1.25±0.52 1.25±0.59 1.17±0.49 1.26±0.52 1.31±0.48 0.6 GFR (ml/min/1.73sqm) 58.9±2.2 59.6±22.9 60.2±17.8 61.6±23.5 55.4±16.9 0.7 NT-proBNP (ng/L) 5511±7764 2231±2463 6365±10318 7257±8173 7509±8380 0.004 VII = Venous impedance index; LVEF = left ventricle ejection fraction; TAPSE = Tricuspid annular plane systolic excursion; PASP = Pulmonary artery systolic pressure; IVC = Inferior vena cava; GFR = Glomerular filtration rate.

Conclusions

The identified correlation between RV to PC uncoupling and the IRVF pattern provides new evidence regarding the pathophysiological mechanisms of cardio-renal syndrome paving the way to interventions with proven effectiveness on the RV to reverse the unfavorable kidney hemodynamics and failure.
429Impairment in arterial-ventricular coupling and its prognostic value in patients with decompensated heart failure
Authors: Lukina O , Soloveva A , Troitskaya E , Soseliya N , Meray I , Villevalde S , Kobalava Z
Published: October 2019

Objective

The interaction of the left ventricle (LV) with the arterial system, termed ventricular-arterial coupling (VAC), is a central determinant of cardiovascular performance and cardiac energetics. Heart failure (HF) modify the structure and function of LV. The aim of the study was to assess VAC parameters and their prognostic value in patients with different phenotypes of decompensated HF.

Methods

Parameters of VAC were assessed by 2-dimentional echocardiography in 355 patients admitted with decompensated HF (198 male, 72±11 years (M±SD), arterial hypertension 94%, previous myocardial infarction 42%, HF with preserved ejection fraction (HFpEF) 36%, reduced EF (HFrEF) 44%, mid-range EF (HFmrEF) 20%, diabetes 40%, NTproBNP 3763 (1801; 5486) pg/ml, eGFR 51 (41; 64) ml/min/1.73 m2) on the admission. VAC was expressed as the ratio arterial elastance (Ea)/ end-systolic LV elastance (Ees) and was considered optimal at range of 0.6–1.2. Patients received standard therapy (334 (94%) beta-blockers, 312 (88%) iv diuretics, 170 (48%) – iv nitrates, 280 (79%) and 57 (16%) ACEI and ARB, 270 (76%) MRA). Hospital length of stay was 10 (8; 12) days. P<0.05 was considered statistically significant.

Results

The median values of Ea, Ees and VAC were 2.2 (1.7; 2.9) mmHg/ml, 1.8 (1.0; 3.0) mmHg/ml and 1.32 (0.75; 2.21). Impairment of VAC was revealed in 63% of patients: VAC >1.2 – in 55% (predominantly patients with HFrEF), VAC<0.6 – in 8% of patients (all with HFpEF). Normal VAC was observed in 78% of patients with HFpEF, 42% of patients with HFmrEF and only in 1% with HFrEF. There was significant correlation between VAC and levels of NTproBNP (r=0.35), hematocrit (r=−0.29), hemoglobin (r=−0.26), systolic pulmonary artery pressure (sPAP) (r=0.18), diameters of left atrium (r=0.32) and right ventricle (RV) (r=0.32).

In-hospital mortality was 1.5%. After 6 months of follow-up 72 (20.3%) patients were readmitted with decompensated HF and 42 (11.8%) patients died. Patients with vs without worse prognosis had lower Ea (2.1 (1.7; 2.8) vs 2.3 (1.9; 3.0) mmHg/ml, Ees (1.5 (0.7; 2.5) vs 1.9 (1.0; 3.1) mmHg/ml, systolic blood pressure (130 (115; 150) vs 140 (130; 160) mmHg), higher level NTproBNP (4687 (3277; 6220) vs 3396 (1555; 5052) pg/ml), RV diameter (3,3 (3,0; 3,7) vs 3,0 (2,8; 3,5) cm), p<0.05 for all. There was increased risk of re-hospitalizations with decompensated HF and all-cause death in patients with decrease of Ea <2.2 mmHg/ml (OR 2.5, 95% CI 1.39–4.34, p<0.05), increase sPAP >45 mmHg (OR 3.7, 95% CI 1.74–7.45, p<0.05).

Conclusion

Impairment of VAC was revealed in 63% of patients with decompensated HF. Decrease of arterial elastance <2.2 mmHg/ml and increase of sPAP >45 mmHg are associated with risk of all-cause death and decompensated HF re-admissions in 6 month follow-up.
430Non-invasive estimation of right atrial pressure by IVC measurement differently predicts long-term prognoses in acute heart failure patients with reduced and preserved LVEF
Authors: Saito C , Jujo K , Abe T , Kametani M , Arai K , Minami Y , Ashihara K , Hagiwara N
Published: October 2019

Introduction

Inferior vena cava (IVC) measurement by bed-side echocardiography is a non-invasive, reproducible and feasible estimation of right atrial pressure (RAP). However, the effect of left ventricular systolic functions on the clinical efficacy of estimation of RAP using IVC parameters in hospitalized patients with acute heart failure (AHF) has not been fully discussed.

Purpose

We aimed to investigate the prognostic impact of RAP evaluation by IVC measurement in AHF patients, focusing on left ventricular ejection fraction (LVEF).

Methods

This observational study initially included 1,350 consecutive patients who were urgently hospitalized due to AHF. After the exclusion of patients receiving hemodialysis, those died in hospital, and those without full information of echocardiography during the index hospitalization, 507 patients with reduced (<40%; HFrEF) and 482 patients with preserved (≥40%; HFpEF) LVEF who discharged alive were respectively analyzed. In accordance with ESC guidelines, HFrEF and HFpEF patients were respectively divided into three groups depending on maximum IVC diameter and collapse; Normal-RAP group (IVC diameter ≤2.1cm and collapse >50%), High-RAP group (IVC diameter >2.1cm and collapse <50%), and Intermediate-RAP group (others). The endpoints of this study were cardiovascular (CV) death after the discharge, and hospitalization due to heart failure recurrence (HHF).

Results

During the observation period, 70 HFrEF patients (13.8%) and 51 HFpEF patients (10.5%) died by CV cause, and 223 HFrEF patients (43.9%) and 158 HFpEF patients (32.8%) were rehospitalized due to HF. In HFrEF patients, Kaplan-Meier analysis showed a low CV mortality rate only in the Normal-RAP group (Log-rank trend: P=0.001, Figure), but no significant difference in HHF rate among RAP groups (p=0.35, Figure). In multivariate Cox regression analysis, RAP classification was an independent predictor of CV mortality in HFrEF patients (adjusted hazard ratio (AHR) 1.90 [95% confidence interval (CI) 1.12–3.21)), even after the adjustment of diverse covariants. On the other hand, in HFpEF patients, Kaplan-Meier analysis showed the high mortality rate and HHF rate only in the High-RAP group (Log-rank trend: both p<0.001, Figure). Multivariate Cox regression analysis revealed that RAP classification independently predicted both prognoses (CV mortality: AHR 2.23 [95% CI 1.10–4.52]; HHF: AHR 1.34 [95% CI 1.03–1.74]) in HFpEF patients.

Figure 1

Conclusion

Non-invasive and easy classification of AHF patients by maximum IVC size and collapse may predict CV mortality after the discharge in HFrEF and HFpEF; while, it failed in HHF of HFrEF patients.
444Plasma levels of microfibrillar associated protein type 4 (MFAP4) are predictive for aortic dissection in patients with Marfan Syndrome
Authors: Van Andel M M , Wanga S , Yin X , Skroblin P , Koolbergen D R , Groenink M , Zwinderman A H , De Vries C J , Mulder B J M , Mayr M , De Waard V
Published: October 2019

Aim

Marfan syndrome is a disorder with mutations in the fibrillin-1 gene, leading to elastic fiber degradation and increased TGF-beta signaling. The life-threatening feature of Marfan is aneurysm formation with a risk of fatal aortic dissections. In a proteomics screen, we identified MFAP4, a protein involved in fibrillin-1 and elastic fiber formation, to be increased in the Marfan aorta. We aim to study the role of MFAP4 in Marfan aortic disease.

Methods and results

MFAP4 co-localizes in the aorta with elastin and collagen fibers.

In vitro experiments show that MFAP4 expression is upregulated by TGF-beta, which could explain the increased MFAP4 protein levels in the Marfan aorta.

In a substudy of 96 Marfan patients from the COMPARE trial, MFAP4 levels correlate with aortic root diameter (r=0.30, p=0.01). Patients previously enrolled in the COMPARE trial were retrospectively analyzed. Cardiovascular events, including aortic dissection, were assessed. Plasma samples were prospectively collected at time of inclusion in the study and analyzed retrospectively on MFAP4. In the 7 years of follow up, 5 Type B dissections occurred, all of them in patients in the upper tertile of plasma MFAP4. High plasma MFAP4 associates with poor dissection-free survival (Figure 1).

Moreover, the aortic distensibility as measure for aortic stiffness and damage, was calculated throughout the aorta from available MRI images of these patients. Interestingly, in the descending thoracic aorta where type B dissections occur, the aortic distensibility is significantly lower (indicating decreased aortic elasticity) in Marfan patients with high plasma MFAP4, thus associating with aortic damage.

Figure 1

Conclusion

MFAP4, a protein involved in extracellular matrix assembly, is elevated in the Marfan aorta. High plasma MFAP4 seems to reflect aortic damage and predicted type B aortic dissections in up to 7 years follow up.
459Direct oral anticoagulants are an effective therapy for left ventricular thrombus formation
Authors: Gama F , Freitas P , Trabulo M , Ferreira A , Andrade M J , Matos D , Strong C , Ribeiras R , Ferreira J , Mendes M
Published: October 2019

Background and aim

Left ventricular thrombus is a frequent complication of myocardial infarction (MI) and heart failure with severely depressed ejection fraction. Once diagnosed, anticoagulation for up to 6-months is recommended, but clinical experience with direct oral anticoagulation (DOAC) is limited to a few case reports. Our aim is to test DOAC LV thrombus resolution efficacy against warfarin.

Methods

Single-centre retrospective cohort study of consecutive patients with recently diagnosed LV thrombus, either after acute myocardial infarction or heart failure with reduced ejection fraction, from January 2009 till December 2018. Thrombus diagnosis and subsequent assessments were performed with echocardiography and complemented with cardiac magnetic resonance, when appropriate. Decisions regarding the type, dose and duration of anticoagulation and any concomitant antiplatelet therapy were left to physician's judgement.

Results

In a population of 66 patients (51 male, mean age 69±12 years), 13 received DOAC therapy, with the remainder receiving vit. K antagonists. One from each group was lost to follow up. The DOAC subgroup had higher prevalence of atrial fibrillation, higher left ventricular end-diastolic volumes and worse wall motion severity score index (WMSI). The duration of anticoagulant therapy, concomitant single or dual antiplatelet therapy and overall follow up were similar between strategies. Thrombus remission was observed in 91.7% (n=11) and 59.6% (n=31) patients within DOAC and warfarin group, respectively. Risk of unsuccessful resolution was reduced by 35% relative to the warfarin group (RR 0.65; 95% CI [0.491–0.862]; p-value 0.035) (figure).

figure

Conclusion

DOAC seems to be an effective alternative to vitamin-K antagonists in patients with LV thrombus.
465Benefit of modern P2Y12-inhibitors on long-term prognosis in patients with ST-elevation myocardial infarction with and without advanced chronic kidney disease
Authors: Schmucker J , Fach A , Osteresch R , Retzlaff T , Michel S , Garstka D , Wienbergen H , Hambrecht R
Published: October 2019

Background

Current guidelines on the management of patients with ST-elevation myocardial infarction (STEMI) recommend the preferred use of the modern P2Y12-inhibitors ticagrelor or prasugrel regardless of the presence of chronic kidney disease (CKD), although patients with advanced stages of CKD were excluded from randomized trials. Aim of the present study was therefore to evaluate the potential benefit of modern P2Y12-inhibitors in patients with and without advanced renal disease at admission.

Methods

All patients admitted with STEMI between 2006–2017 from a large german heart center treated with primary percutaneous coronary intervention (PCI) entered analysis. Initial CKD was estimated with the initial glomerular filtration rate (GFR), calculated with the CKD-EPI-equation, assigning them to the groups G1-G5.

Results

Of 7227 patients with STEMI and primary PCI 2669 (37%) showed no relevant reduction in GFR at admission (≥90 ml/min/1.73 m2, G1), 2976 pts. (41%), a slight reduction (GFR 60–89 ml/min/1.73 m2, G2), 880 pts. (12%) a moderate reduction (GFR 45–59 ml/min/1.73 m2, G3a) and 702 pts. (10%) a moderate to severe reduction (GFR<45 ml/min 1.73 m2, G3b-G5). Pts. with more advanced stages of CKD were on average older (G1: 55±11 years, G2: 66±12 years, G3a: 72±12 years, G3b-G5: 75±11 years, p<0.01) and more likely to be female (G1: 19%, G2: 26%, G3a: 40%, G3b-G5: 48%, p<0.01). Prasugrel/ticagrelor were less often given instead of clopidogrel in patients with advanced CKD (G1: 70%, G2: 45%, G3a: 31%, G3b-G5: 32%, p<0.01). The use of ticagrelor/prasugrel was associated with a reduction in 1-year-MACCE (major adverse cardio- and cerebrovascular events)-rates in patients with no/low-grade-CKD (G1-G2), while no significant reduction in MACCE could be observed for patients with moderate to severe CKD (table). Furthermore, CKD was associated with an elevation in severe bleeding events within 1 year (G1: 1%, G2: 3%, G3a: 5%, G3b-G5: 6%, p<0.01).

Impact of CKD-stage on outcome CKD-stage G1 CKD-stage G2 CKD-stage G3a CKD-stage G3b-G5 1-year-MACCE-rate (%) Ticagrelor/prasugrel 4.5 11.0 27.4 47.3 Clopidogrel 9.9 15.6 26.6 50.4 Significance <0.01 <0.01 0.6 0.7

Conclusions

These data from a large STEMI-registry demonstrate, that modern P2Y12-inhibitors were less often used in patients with CKD and their benefit regarding MACCE disappeared in advanced stages of CKD while bleeding rates increased. These results underline the special role of patients with advanced stage-CKD in STEMI and the necessity of specialized randomized trials for these patients.