bluuebunny/crossref_metadata_2025 huggingface dataset:
P671Impacts of echocardiography-defined pulmonary hypertension on clinical outcome in patients with multiple myeloma
Authors: Bae S A , Yoon H J , Kim K H , Kim H Y , Park H J , Cho J Y , Jeong M H , Park J C
Published: October 2019

Background

Pulmonary hypertension (PH) is a rarely reported complication of multiple myeloma (MM). PH of MM is usually mild to moderate and can be secondary to a variety of conditions, including left ventricular dysfunction, diastolic dysfunction, chronic heart failure, treatment-related toxicity, thrombophilic condition and precapillary involvement. However, only few reports regarding PH in MM incidence and prognosis exist up to now.

Purpose

The purpose of this study was to investigate the risk factors of transthoracic echocardiography-defined PH and its impact on clinical outcome in patients with MM.

Methods

A total of 277 MM patients was included and divided into 2 groups–those non-pulmonary hypertension (PH) or those with PH, based on the results of the transthoracic echocardiography (TTE); PH group (n=143, 60.9±9.2 years, 68 males) versus non-PH group (n=134, 55.9±11.5 years, 72 males). We analyzed propensity score matching and multiple imputation method were used to deal with the missing data in echocardiographic characteristics.

Results

During the follow-up period (median 618 days), all-cause death occurred in 79 (28.5%) patients and 41 patients (14.8%) died from cardiovascular causes (including acute decompensated heart failure, fatal MI, sudden cardiac arrest). In the Kaplan-Meier survival analysis of crude population and propensity-matched population, cumulative overall survival and cardiovascular death (CVD)-free survival were significantly lower in the PH group than in the non-PH group (p<0.001). In propensity-matched population, estimated pulmonary artery pressure >35mmHg in TTE, congestive heart failure, and DM were significant independent predictors of all-cause death.

KM curves in MM stratified by PH

Conclusion

This study demonstrates that the presence of PH, congestive heart failure, and DM is an independent prognostic factor for all-cause death in MM patients with MM. These results highlight the risk associated cardiovascular disease in MM patients and emphasize that management strategies that prevent deterioration of cardiac function are essential.
P676Percutaneous coronary intervention and clinical outcomes in patients with lymphoma: a 10-year period United States nationwide inpatient sample (NIS) analysis
Authors: Borovac J A , Kwok C S , Konopleva M , Kim P Y , Palaskas N L , Zaman A , Butler R , Lopez-Mattei J C , Mamas M A
Published: October 2019

Background

Clinical outcomes and characteristics of patients with lymphoma undergoing percutaneous coronary intervention (PCI) are unknown.

Purpose

To describe clinical characteristics and procedural outcomes in patients that underwent PCI and had a concurrent diagnosis of Hodgkin (HL) or non-Hodgkin (NHL) lymphoma and compare risks of complications and in-hospital mortality in lymphoma subtypes to patients without lymphoma.

Methods

A total of 6,413,175 PCI procedures undertaken in the United States between 2004 and 2014 in the Nationwide Inpatient Sample were included in the analysis. Multivariable regression analysis was performed in order to examine the association between lymphoma diagnosis and clinical outcomes post-PCI including complications and in-hospital mortality.

Results

Patients with lymphoma generally had a significantly higher incidence of post-PCI complications and in-hospital mortality compared to patients without lymphoma (Figure 1). Patients with lymphoma were more likely to experience in-hospital mortality (OR 1.34, 95% CI 1.20–1.49), stroke or transient ischemic attack (TIA) (OR 1.59, 95% CI 1.47–1.73), and any in-hospital complication (OR 1.19, 95% CI 1.14–1.25), following PCI. In the lymphoma subtype-analysis, diagnosis of HL was associated with an increased likelihood of in-hospital death (OR 1.31, 95% CI 1.17–1.48), any in-hospital complication (OR 1.20, 95% CI 1.14–1,26), bleeding complications (OR 1.12 95% CI 1.05–1.19) and vascular complications (OR 1.10 95% CI 1.03–1.17) while these risks were not significantly associated with NHL diagnosis. Finally, both types of lymphoma were associated with an increased likelihood of stroke/TIA following PCI, with this effect being twice greater for HL than NHL diagnosis (OR 1.66, 95% CI 1.52–1.81 and OR 1.33, 95% CI 1.06–1.66, respectively) (Table 1).

Table 1. ORs for clinical outcomes Variable HL vs. No Lymphoma NHL vs. No Lymphoma Bleeding complications 1.12 (1.05–1.19) 1.07 (0.89–1.27) Vascular complications 1.10 (1.03–1.17) 1.13 (0.92–1.27) Cardiac complications 0.94 (0.85–1.03) 0.86 (0.68–1.11) Post-procedural stroke/TIA 1.66 (1.52–1.81) 1.33 (1.06–1.66) Any complication 1.20 (1.14–1.26) 1.04 (0.91–1.18) In-hospital mortality 1.31 (1.17–1.48) 0.89 (0.65–1.21) HL, Hodgkin's Lymphoma; NHL, non-Hodgkin's Lymphoma; TIA, Transient Ischemic Attack.

Figure 1. Type of lymphoma and outcomes

Conclusions

While the incidence of lymphoma in the observed PCI cohort was low, a diagnosis of lymphoma was associated with an adverse prognosis following PCI, primarily in patients with a diagnosis of HL.
P683Cardiovascular adverse events associated with BRAF and MEK inhibitors
Authors: Mincu R I , Mahabadi A A , Michel L , Mrotzek S M , Schadendorf D , Rassaf T , Totzeck M
Published: October 2019

Background

Cardiovascular adverse events (CVAE) following treatment with B-Raf proto-oncogene serine/threonine kinase inhibitors and mitogen-activated protein kinase (BRAF/MEK) inhibitors in patients with melanoma remain incompletely characterized. We conducted the first detailed meta-analysis focused on BRAF/MEK inhibitor-associated CVAE.

Purpose

To determine the type and risk of BRAF/MEK inhibitor-associated CVAE.

Methods

We systematically searched Pubmed, Cochrane, and Web of Science for keywords “vemurafenib”, “dabrafenib”, “encorafenib”, “trametinib”, “binimetinib”, “cobinimetinib” through November 30, 2018. We selected randomized controlled trails (RCT) reporting on CVAE in melanoma patients under BRAF/MEK inhibitors. The selected endpoints were: decrease in left ventricular ejection fraction (LVEF), pulmonary embolism, atrial fibrillation, arterial hypertension, myocardial infarction, heart failure, pericarditis, and QTc interval prolongation. All-grade and high-grade (grade 3 or higher) CVAE were recorded.

Results

9 RCTs including 4,616 patients with melanoma were selected. The treatment with BRAF/MEK inhibitors was associated with an increased risk in a decrease in LVEF, pulmonary embolism, atrial fibrillation, and arterial hypertension. The relative risks (RR) of myocardial infarction, heart failure, pericarditis, and QTc prolongation were similar between the BRAF/MEK inhibitors group and control group (Figure). These results were consistent for high-grade CVAE. The subgroup analysis showed that the combination therapy with BRAF/MEK inhibitors resulted in a higher risk of a decrease in LVEF, pulmonary embolism, and arterial hypertension, while the risk for atrial fibrillation was increased in BRAF inhibitors monotherapy group compared to controls. There was no significant difference between melanoma patients with mean age below and above 55 years old, except for the increased risk of atrial fibrillation in the older population group. The endpoints were similar between studies with mean follow-up times under and over 24 months.

RR of cardiovascular adverse events

Conclusions

The therapy with BRAF and MEK inhibitors is associated with a higher risk of CVAE. This study increases the awareness on CVAE under these therapies and help to balance between beneficial melanoma treatment options and increased cardiovascular morbidity and mortality.
P702Anti-thrombin nanoparticles for reduce vascular damage and promote functional recovery in acute ischemic kidney injury well after reperfusion
Authors: Pan H , Grabau R , Vargas I , Baldwin M , Cara B , Stephenson D , Lindon A , Chalfant C , Wickline S
Published: October 2019

Introduction

We have shown previously that pretreatment of acute ischemic kidney injury (AKI) in mice prior to reperfusion with anti-thrombin perfluorocarbon nanoparticles (PFC NP) limits damage to endothelium and hastens functional recovery. However, whether such treatments are effective after AKI is established is not known. We hypothesized that thrombin would continue to exert deleterious clotting and molecular signaling effects in AKI well after reperfusion that would respond to sustained local inhibition with long acting anti-thrombin nanoparticles.

Methods

23 C57Bl6 mice underwent bilateral kidney ischemia for 17 min, followed by 2 hours reperfusion and i.v. injection of anti-thrombin PPACK (D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone)-conjugated PFC NP (∼ 13,000 PPACK per PFC NP), or plain PFC NP (control: no drug). At 24 hours BUN was measured, and mice were euthanized for kidney histological assessment (H&E), protein expression (western blot) and eicosanoid mediators of inflammation (LC-MS/MS: AB SCIEX 5500 QTRAP).

Results

BUN at 24 hours after AKI was 63.29±9.09 vs 110.96±6.21 (P<0.002), for treated versus untreated mice, respectively, a 43% improvement. Western blots (Figure) indicated 40% reduction of canonical NF-kB signaling pathway protein p65 (p<0.01) and 2.2 fold increases in Bcl-xL: Bax ratio (P<0.01). Vascular damage, as indicated by glomerular and mesangial hemorrhage (Figure), was reduced, as was tubular cell swelling and edema. Levels of inflammatory procoagulant eicosanoids (e.g., PGE1, TBX2, PGA2, 15-HETE, 5-HETE, etc.) generally were higher in renal medulla than in cortex, and were suppressed by PPACK PFC NP.

Discussion

Continued inhibition of thrombin in AKI with locally-acting PPACK PFC NP preserved vascular integrity, limited renal hemorrhage, mitigated inflammation and tubular cell death, and accelerated functional recovery even when administered 2 hours after reperfusion. Because these PPACK PFC NP do not prolong bleeding times or coagulation parameters beyond ∼30–60 min after injection, yet maintain prolonged local surveillance against activated thrombin, they represent a potentially useful therapeutic strategy for established AKI after an ischemic insult.

Acknowledgement/Funding

DK102691
P705Step by step diagnosis and management of statin intolerance: position paper from an international lipid expert panel
Authors: Penson P , Toth P , Mikhailidis D , Ezhov M , Fras Z , Mitchenko O , Pella D , Sahebkar A , Rysz J , Reiner Z , Jozwiak J , Mazidi M , Banach M
Published: October 2019

Background

Statin intolerance is a clinical syndrome whereby adverse effects associated with statin therapy (most commonly muscle symptoms) result in the discontinuation of therapy. Statin discontinuation is associated with increased risk of adverse cardiac outcomes. Many patients who initially experience adverse effects are able to tolerate statin therapy to some extent. Careful stepwise diagnosis and management of individuals who experience adverse effects is essential to enable optimal reduction of cardiovascular risk.

Purpose

In this Position Paper of the International Lipid Expert Panel (ILEP), we present a step by step approach to the diagnosis and practical management of statin intolerance resulting from muscle symptoms, and other adverse effects with demonstrated statin causality.

Methods

Relevant clinical evidence and international clinical guidelines were discussed and assimilated by ILEP members. Consensus was used to formulate recommendations for the diagnosis and management of statin intolerance.

Results

Consensus resulted in the adoption of three parts to the recommendation. 1) diagnosis of Statin Intolerance; 2) advice for management of all patients with statin intolerance; 3) specific advice for patients who have partial (rather than complete) statin intolerance. Patients with partial statin intolerance are likely to make up the vast majority (even 95%) of statin-intolerant individuals. Each part of the recommendation consists of a four-step process and has an associated acronym to aid memory (see attached recommendations). We adopted the Banach and Mikhailidis four-step approach to diagnosis and we developed novel recommendations for management.

Summary of the ILEP SI recommendations.

Conclusions

We present recommendations, which will enable clinicians to distinguish between rare, severe adverse effects; true statin intolerance, and symptoms incorrectly attributed to statin therapy. In each case we summarize guidelines, clinical evidence and expert opinion pertaining to the optimal management of cardiovascular disease in these patients.

Acknowledgement/Funding

None
P708Identification of 26 novel loci that confer susceptibility to early-onset coronary artery disease in a Japanese population
Authors: Oguri M , Kato K , Horibe H , Fujimaki T , Sakuma J , Takeuchi I , Murohara T , Yasukochi Y , Yamada Y
Published: October 2019

Background

Early-onset coronary artery disease (CAD) has a strong genetic component. Although genome-wide association studies have identified various genes and loci significantly associated with CAD mainly in European ancestry populations, genetic variants that contribute to susceptibility to this condition in Japanese individuals remain to be identified definitively.

Purpose

The purpose of the study was to identify genetic variants that confer susceptibility to early-onset CAD in Japanese. We have now performed exome-wide association studies (EWASs) in subjects with early-onset CAD and controls.

Methods

A total of 7256 individuals aged ≤65 years was enrolled in the study. The EWAS was conducted with 1482 subjects with CAD and 5774 controls. Genotyping of single nucleotide polymorphisms (SNPs) was performed with Illumina Human Exome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. The relation of allele frequencies for 31,465 SNPs that passed quality control to CAD was examined with Fisher's exact test. To compensate for multiple comparisons of allele frequencies with CAD, we applied a false discovery rate (FDR) of <0.05 for statistical significance of association.

Results

The relation of allele frequencies for 31,465 SNPs to CAD with the use of Fisher's exact test showed that 170 SNPs were significantly (FDR <0.05) associated with CAD. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of hypertension, diabetes mellitus, and dyslipidemia revealed that 162 SNPs were significantly (P<0.05) related to CAD. A stepwise forward selection procedure was performed to examine the effects of genotypes for the 162 SNPs on CAD. The 54 SNPs were significant (P<0.05) and independent [coefficient of determination (R2), 0.0008 to 0.0297] determinants of CAD. These SNPs together accounted for 15.5% of the cause of CAD. After examination of results from previous genome-wide association studies and linkage disequilibrium of the identified SNPs, we newly identified 21 genes (RNF2, YEATS2, USP45, ITGB8, TNS3, FAM170B-AS1, PRKG1, BTRC, MKI67, STIM1, OR52E4, KIAA1551, MON2, PLUT, LINC00354, TRPM1, ADAT1, KRT27, LIPE, GFY, EIF3L) and five chromosomal regions (2p13, 4q31.2, 5q12, 13q34, 20q13.2) that were significantly associated with CAD. Gene ontology analysis showed that various biological functions were predicted in the 18 genes identified in the present study. The network analysis revealed that the 18 genes had potential direct or indirect interactions with the 30 genes previously shown to be associated with CAD or with the 228 genes identified in previous genome-wide association studies of CAD.

Conclusion

We have newly identified 26 loci that confer susceptibility to CAD. Determination of genotypes for the SNPs at these loci may prove informative for assessment of the genetic risk for CAD in Japanese.
P715Deletion of fibroblast activation protein decreases experimental atherosclerotic plaque formation and vulnerability
Authors: Stein S , Weber J , Nusser-Stein S , Pahla J , Zhang H , Oppi S , Staels B , Gorrell M D , Luscher T F , Matter C M
Published: October 2019

Background

Fibroblast activation protein (FAP) is a serine protease that is upregulated in sites of tissue remodeling, including arthritis, tumors and atherosclerosis. We have reported that FAP degrades type I collagen in human thin-cap fibroatheromata; its expression is enhanced in advanced human plaques and induced by inflammation. However, the role of endogenous FAP in atherosclerosis remains unknown.

Purpose

To investigate the effects of constitutive Fap loss-of-function on atherosclerotic plaque formation and vulnerability.

Methods and results

Male 8-week-old Apoe−/− Fap+/+ and Apoe−/− Fap−/− mice were fed a high-cholesterol diet (1.25% chol) for 12 weeks. En face analyses of thoracoabdominal aortae using Oil Red O (ORO) revealed decreased plaques in Apoe−/− Fap−/− mice (5.7±0.5%; n=21) compared to Apoe−/− Fap+/+ mice (10.7±0.7%; n=24; p<0.0001). In parallel, ORO analyses of serial aortic root cross sections showed diminished plaques in Fap-deficient mice (18.4±3.4% vs 27.6±2.1%). As a surrogate of plaque vulnerability, fibrous cap thickness was increased in Apoe−/− Fap−/− mice (65±6 mm vs 35±3 mm; p<0.01), whereas necrotic core size, plaque macrophages (CD68) and T cells (CD3) accumulation, as well as VCAM1 expression did not differ. These changes were independent of plasma triglycerides, total and LDL-cholesterol levels. Plasma of Fap-deficient mice showed decreased FAP activity compared to Fap wildtype controls. Notably, second harmonics generation in cross sections of aortic root plaques showed that the deposition and density of fibrillar collagens was enhanced in Fap-deficient (25.5±4.4%) compared to control plaques (13.8±2.5%; p<0.05). Consistently, Fap deletion led to an accumulation of uncleaved pre-COL3A1, a proteolytic target of FAP.

Conclusions

Constitutive Fap deletion decreases experimental atherosclerosis and features of plaque vulnerability. Thus, inhibition of FAP expression or activity may be a promising therapeutic target in atherosclerosis.

Acknowledgement/Funding

Swiss National Science Foundation, Swiss Heart Foundation
P740Repeated social defeat exaggerates fibrin-rich clot formation in FeCl3-induced arterial thrombosis mice model by enhancing NETs formation
Authors: Sugimoto T , Yamada H , Kubota H , Miyawaki D , Motoyama S , Wada N , Saburi M , Wakana N , Matoba S
Published: October 2019

Background and objective

Depression is an independent risk factor of cardiovascular disease (CVD). We have recently shown that repeated social defeat (RSD) precipitates depressive-like behaviorsin apoE−/− mice and exaggerates atherosclerosis development by enhancing neutrophil extracellular traps (NETs) formation (BBRC 2018; 500:490). Here, we investigated the impact of RSD on arterial thrombosis.

Methods and results

Eight-week-old male WT mice were exposed to RSDby housing with a larger CD-1 mouse in a shared home cage. They were subjected to vigorous physical contact daily for 10 consecutive days. Control mice were housed in the same gage without physical contact. After social interaction testto confirm depressive-like behaviors, defeated mice (19 of 31) and control mice (12 of 14) were underwent arterial injury at 10 wks of age. A filter paper saturated with 10% FeCl3was applied on the adventitial surface of left carotid artery for 3 min and analyzed 3 hrs later. The volume of thrombi calculated by summing8–15 frozen cross-sectional images, each separated by 200 μm, was comparable between the 2 groups. However, fibrinogen/fibrin-positive areas in immunofluorescent images were significantly increased in defeated mice (27.8% vs. 48.8%, Control vs. Defeat, P<0.01).The numberof Ly-6G-positive cells in thrombi was markedly higher in defeated mice (144/mm2 vs. 878/mm2, Control vs. Defeat, P<0.05). Further, Ly-6G-positive cells were almost accumulated at the inner surface of injured artery, which were co-localized with neutrophil elastase, Cit-H3, and CD41-positive staining. Treatment with DNase Icompletely diminished the exaggerated fibrin-rich clot formation in defeated miceto a similar extent of control mice (25.7% vs. 22.3%, Control vs. Defeat, P= NS), while the volume of thrombi and number of Ly-6G-positive cells in thrombi were comparable between the 2 groups even afterDNase I treatment. Platelet aggregations induced by ADP or collagen were comparable between the 2 groups, suggesting that NETs formation primarily contributes to the exaggerated fibrin-rich clot formation in defeated mice.

Conclusions

Our findings demonstrate for the first time that repeated social defeat enhances fibrin-rich clot formation after arterial injury by enhancing NETs formation, suggesting that NETosis could be a new therapeutic target in depression-related CVD development.
P748Afterload-induced TRIF-dependent signaling promotes fibrosis but not cardiomyocyte hypertrophy
Authors: Bettink S I , Kazakov A , Koerbel C , Boehm M , Scheller B , Schirmer S H
Published: October 2019

Background

Pressure overload dependent cardiac remodeling is characterized by a continuous functional loss of cardiomyocytes, cardiomyocyte hypertrophy, cell death and fibrosis. The relevance of the MyD88- and NFκB-independent inflammatory TRIF (TIR-domain-containing adapter protein inducing IFN-β) signaling pathway in myocardial hypertrophy is incompletely understood.

Methods and results

The murine model of afterload induced myocardial hypertrophy (trans-aortic constriction, TAC) was used to investigate the time dependent chemokine expression in C57Bl/6J Wild type (WT) mice after intervention. Myd88- as well as TRIF-dependent chemokines reached their expression maximum at d7 post intervention. This time point was determined for further investigations on TRIF knockout-mice (TRIF−/−) compared to WT mice. While left ventricular (LV) mRNA-expression of TNFalpha and IL6 was upregulated in TRIF−/− mice, CXCL10, CXCL11, RANTES and pathway molecule IRF3 remained unchanged. In the stage of established hypertrophy (35 days after TAC) cytokine levels returned to baseline in WT as well as in TRIF−/− mice.

Cellular hypertrophy (increase in cardiomyocyte size) as well as echocardiographic determined increase of LV mass was similar in TRIF−/− and WT mice at d7 as well as at d35 after TAC. Additionally at d7 and d35 the fractional shortening function didn't show any differences between the groups after TAC.

On the other hand LV interstitial fibrosis (determined by collagen content) was significantly less distinct in TRIF−/− mice (1.4±0.2%) than in WT mice (2.3±0.3%, (p<0.01 TRIF−/− vs. WT) at d7 following TAC. According to that TGFbeta protein expression was more pronounced in WT (318±85% of sham-operated controls) than in TRIF−/− mice (111±15% of sham-operated controls; p<0.05 TRIF−/− vs. WT). These differences in fibrosis and TGFbeta remained at d35. Even the hydroxyproline concentration was higher in LV tissue of the WT mice than in the TRIF−/− mice d35 after TAC (WT: 93.4±7.7μM, TRIF−/− 54.8±9.0μM, p<0.5 TRIF−/− vs. WT). The expression of TGFbeta signaling pathway associated SMAD proteins (SMAD 3, pSMAD3, SMAD4) was up to two fold higher in WT mice than in TRIF−/− mice. Additionally expression of antifibrotic miR29b was more pronounced in TRIF−/− mice (2.34±0.71) than in WT mice (0.98±0.08) after TAC d7.

Conclusion

In afterload induced hypertrophy TRIF-dependent signaling doesn't influence cardiomyocyte hypertrophy. But TRIF plays an important role in the regulation of fibrosis in pressure overload dependent remodeling. Through the modulation of the TGF-beta signaling pathway and antifibrotic microRNAs TRIF signaling is involved in the development of interstitial fibrosis. Especially in the early stage of the cardiac remodeling.

Acknowledgement/Funding

KFO196
P749Dynamic of cardiac magnetic resonance imaging parameters in patients with non-ischemic cardiomyopathies after endomyocardial stem cell transplantation
Authors: Kurlianskaya A , Polonetsky O , Denisevich T , Shatova O , Osmolovskaya T , Isaikina Y , Salauyou D
Published: October 2019

Background

Autologous mesenchymal stem cell (MSC) transplantation can be considered as an alternative method of end-staged chronical heart failure treatment in patients with Non-ischemic Cardiomyopathies (NICMP). About 2/3 NICMP are determined by previous myocarditis, transformed in inflammatory cardiomyopathy (ICM), while only 1/3 of NICMP cases are associated with idiopathic dilated cardiomyopathy (DCM). Application of MSC therapy in different groups of NICMP patients is not sufficiently studied.

Purpose

The purpose of the study was to compare cardiac magnetic resonance imaging (cMRI) parameters in the left ventricle (LV) segments of myocardium in patients with DCM and ICM before and after autologous MSC transplantation.

Methods

The study covered 15 patients with DCM (mean age 45.8±3.1 years; 4 females, 11 males; LV ejection fraction (EF) <40%) and 15 patients with ICM (mean age 46.0±3.6 years; 5 females, 10 males; LV EF <40%). All patients underwent cMRI, endomyocardial injections of 0.2 ml autologous MSC culture (CD105+, CD90+, CD73+ cells) into akinetic and hypokinetic myocardial segments. In total we have analysed 228 segments of NICMP patients.

Results

In patients with ICM we found significant decrease in extracellular volume (ECV) within 6 months after primary examination (from 32 [28; 36]% to 27 [25; 30]%, p=0,007). As a result, ICM patients had lower ECV than DCM patients 6 months after MSC transplantation 27 [26; 29] % and 31 [29; 32]% respectively (p=0,001). Patients with ICM demonstrated an increase in LV systolic myocardial segment thickness (SMST) 6 months after MSC injections (5.91 [5.74; 6.15] mm – baseline vs. 6.67 [6.60; 6.82] mm – 6 months later, p≤0,010) with a bigger increase 12 months after MSC injection (9.58 [9.47; 9.73] mm, p≤0,010). In ICM patients LV SMST was significantly higher than in DCM patients 12 months after MSC transplantation (9.58 [9.47; 9.73] mm vs. 7.38 [7.29; 7.61] mm, p=0.032). ICM patients showed an increase in LV ejection fraction (EF) within 6 months after MSC therapy (from 20 [17; 24]% to 27 [17; 32]%, p=0.043).

Conclusions

Endomyocardial MSC transplantation showed better results in ICM patients compared to DCM patients. It led to a significant decrease in ECV within 12 months in contrast to DCM patients. ICM patients also demonstrated significant increase of LV SMST and LV EF within 6 months after MSC therapy.
P773Initiation of sacubitril/valsartan and optimisation of evidence-based heart failure therapies after hospitalisation for acute decompensated heart failure: An analysis of the TRANSITION study
Authors: Wachter R , Pascual-Figal D , Belohlavek J , Straburzynska-Migaj E , Witte K K , Fonseca C , Cavusoglu Y , Pouleur A C , Goncalvesova E , Lonn E , Noe A , Schwende H , Bao W , Butylin D , Senni M
Published: October 2019

Background

Optimisation of chronic heart failure (HF) therapy remains the key strategy to improve outcomes after hospitalisation for acute decompensated HF (ADHF) with reduced ejection fraction (HFrEF). Initiation and uptitration of disease-modifying therapies is challenging in this vulnerable patient population. We aimed to describe the patterns of treatment optimisation including sacubitril/valsartan (S/V) in the TRANSITION study.

Methods

TRANSITION (NCT02661217) was a randomised, open-label study comparing S/V initiation pre- vs. post-discharge (1–14 days) in patients admitted for ADHF after haemodynamic stabilisation. The primary endpoint was the proportion of patients achieving 97/103 mg S/V twice daily (bid) at 10 weeks post-randomisation. Up-titration of S/V was as per label. Information on dose of S/V and on the use of concomitant HF medication was collected at each study visit up to week 26.

Results

A total of 493 patients received at least one dose of S/V in the pre-discharge arm and 489 patients in the post-discharge arm. One month after randomisation, 45% of patients in the pre-d/c arm vs. 44% in the post-discharge arm used 24/26 mg bid starting dose and 42% vs. 40% were on 49/51 mg S/V bid, respectively. At week 10, 47% of patients had achieved the target dose in the pre-discharge arm vs. 51% in the post-discharge arm. At the end of the follow-up at 26 weeks, the proportion of patients on S/V target dose further increased to 53% in the pre-discharge and 61% in the post-discharge arm (Figure 1). At week 10, the mean dose of S/V was 132 mg in the pre-discharge arm and 136 mg in the post-discharge arm, and at week 26, it was 140 mg and 147 mg, respectively.

Before hospital admission, 52% and 54% of the patients received a beta-blocker (BB) in the pre-discharge and post-discharge group, respectively, and 42% in both arms received a mineralcorticoid receptor antagonist (MRA). At time of discharge, 68% and 71%% of the patients received a BB and 68% and 65% an MRA, in the pre-discharge and post-discharge groups, respectively. These proportions remained stable to week 10 and week 26.

Uptitration of sacubitril/valsartan

Conclusions

In the vulnerable post-ADHF population, initiation of S/V and up-titration to target dose was feasible within 10 weeks in half of the patients alongside with a 20% increase in the use of other disease-modifying medications that remained stable through the end of the 6-month follow-up.

Acknowledgement/Funding

The TRANSITION study was funded by Novartis
P776Use of sacubitril-valsartan in an extensive long term follow up cohort in real life
Authors: Galvan Ruiz M , Singh M , Fernandez De Sanmamed M , Groba Marco M , Perez Nogales E , Medina Gil J M , Martin Lorenzo P , Quevedo Nelson V , Mendoza Lemes H , Pena Ortega P , Rua-Figueroa Erausquin D , Medina Suarez J M , Caballero Dorta E , Garcia Quintana A
Published: October 2019

Background

Most clinical data regarding the use of sacubitril-valsartan (SV) in patients with heart failure with reduce EF (HFrEF) come from clinical trials, while observational studies in real life are scarce.

Purpose

To analyse the efficacy, safety and tolerability of SV in patients with HFrEF in real life.

Methods

An analysis of the SAVE-RLife (SV Evidence in Real Life) study was performed. This is an observational and ambispective study that included all patients with HFrEF who started SV between SEP2016 and DEC2018.

Results

A total of 291 patients were included in the study with a median follow-up of 326 (169; 523). Mean age 66.16±11.8, 71 were women (24.4%), 209 patients started treatment at office (71.8%) and 82 during the admission (28.2%). The main aetiologies were ischemic heart disease (51.5%) and idiopathic dilated cardiomyopathy (35.4%). Comorbidities included: 71.5% hypertensive, 55.3% dyslipidemic, 37.1% AF and 44% T2DM. Baseline treatment included 85.9% beta-blockers, 87.2% ACEI or ARA-II, 65.6% MRA and 17.5% iSGLT2. After treatment start with SV, baseline and follow-up analytical parameters such as GFR, K+ levels and NT-BNP, and echo parameters of LV reverse remodeling were evaluated (Table 1).

Improvement of the functional NYHA class (Figure 1) and reduction in the incidence of hospital admission or visits to emergency room (ER) were observed. Side effects were 16.2% acute renal failure, 9.3% symptomatic hypotension, 9.7% asymptomatic hypotension and 15.9% hyperkalemia. In 31 patients (11%) the drug was discontinued, one patient due to angioedema. 7.9% of patients died during follow-up, 7 of them due to HF (2.4%).

Table 1 Before SV After SV P value Analytical data GFR (ml/min) 70.25±24.95 68.27±24.62 0.008 Serum K+(mEq/L) 4.53±0.50 4.71±0.456 <0.001 NT-proBNP (pg/ml) 2201 (846; 4664) 1146 (436; 2564) <0.001 Echocardiographic data LVEF (%) (n=84) 30.60±7.16 38.30±12.22 <0.001 LVED (mm) (n=72) 65.22±7.82 60.81±8.37 <0.001 PAPs (mmHg) (n=48) 44.48±13.03 37.52±12.25 0.002 MR (grade 1–4) (n=71) 1.83±0.91 1.38±0.90 <0.001 Clinical outcomes HF Hospital/ER Admission the year before (mean± SD) 0.79±1.09 0.41±0.963 <0.001

Predictors of clinical improvement

Conclusions

SV has shown to improve morbidity and mortality in patients with HFrEF by improving functional class, decreasing NT-proBNP levels and reducing admissions due to HF, without significant side effects. In our study SV improved LVEF and reverse remodeling echocardiographic parameters too.
P778Valsartan reduces level of soluble ST2 and left ventricle remodeling in patients with dual chamber pacemaker
Authors: Radzik E , Pigon K T , Banasik G B , Tomasik A T , Jachec W J , Romuk E R , Birkner E B , Kawecki D K , Wojciechowska C W , Kalarus Z K , Gasior M G , Kozielska E K
Published: October 2019

Introduction

Permanent right ventricle pacing leads to left ventricle remodeling, its systolic dysfunction and symptomatic heart failure in the long run. Valsartan is well known for its preventive anti-remodeling function in the post infarction heart remodeling.

Objectives

To assess the effect of valsartan on left ventricle remodeling in patients with second and third degree atrioventricular block with first-time implantation of dual chamber pacemaker.

Methods

This was a randomized, double-blind, placebo controlled single center study. One hundred eligible patients were assigned in a 1:1:1 fashion to receive placebo, valsartan 80mg or 160mg once daily, respectively. Echocardiographic assessment of left ventricle geometry, its systolic and diastolic function was performed at baseline and at twelve months. One patient from placebo group suffered stroke. We present the baseline date for 100 enrolled patients and follow-up data for 88 patients who have completed the study. Data in valsartan arms are pooled in one group. Concentration of soluble ST2 was measured in duplicates with Aspect Reader (Critical Diagnostics).

Results

Results are presented in table. Data are presented as mean and standard deviation.

Table 1 Placebo (n=28) Valsartan (n=60) ANOVA Baseline 12 mths Baseline 12 mths sST2, ng/mL 36.0±16.0 39.4±15.3 35.1±15.2 19.9±6.5 0.01 LVEF, % 60±8 55±9 60±8 58±8 0.01 LVEDD, mm 48±5 50±4 48±6 49±5 NS LVESD, mm 29±4 32±5 29±5 31±4 NS LVEDV, mL 79±12 84±13 80±12 81±13 NS LVESV, mL 32±5 38±7 31±5 34±6 0.01 E/A 0.94±0.12 0.92±0.13 0.94±0.15 0.95±0.15 NS DecT, ms 211±38 226±43 223±45 218±37 0.01 IVRT, ms 98±14 108±17 101±17 99±18 0.01

Conclusion

Valsartan has protective effect of left ventricle remodeling and function. It may be useful in prevention of pacing induced heart failure. Decrease in soluble ST2 concentration may help explain the alternative mechanism for protective role of valsartan. (NCT01805804)
P780Superiority of long-acting to short-acting loop diuretics in the treatment of heart failure with preserved ejection fraction: a sub-analysis of the CURE-HF Registry
Authors: Suzuki S , Motoki H , Kanzaki Y , Maruyama T , Hashizume N , Kozuka A , Yahikozawa K , Kuwahara K
Published: October 2019

Introduction

Long-acting loop diuretics have a possibility of better prognosis compared to short-acting loop diuretics in patients with heart failure with preserved ejection fraction (HFpEF).

Purpose

To investigate the effect of long- and short-acting loop diuretics in patients with HFpEF.

Methods

From the Clue of Risk Stratification in Patients With Heart Failure Registry (CURE-HF Registry), we enrolled 301 consecutive patients with HFpEF (median age, 84 years; 55% female). Long-acting loop diuretics (azosemide) were administrated in 127 patients, and short-acting loop diuretics (furosemide) in 174 patients. We constructed Cox models for MACE (defined as a composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, and heart failure [HF] hospitalization).

Results

During a median follow-up of 317 [174–734] days, the primary endpoint occurred in 129 patients (42.8%). On multivariate inverse probability of treatment weighted (IPTW) Cox modeling, patients treated with long-acting loop diuretics had a significantly lower incidence of adverse events than those treated with short-acting loop diuretics (hazard ratio [HR], 0.39; 95% confidence interval [CI] 0.23–0.67; P=0.001). Furthermore, on multivariate IPTW Cox modeling for the secondary endpoints, all-cause mortality (HR, 0.50; 95% CI, 0.20–0.80; P=0.01) and unplanned hospitalization for decompensated HF (HR, 0.50; 95% CI, 0.28–0.89; P=0.018) were also reduced in patients treated with long-acting loop diuretics.

Conclusions

Long-acting loop diuretics reduced the risk of MACE compared to short-acting diuretics in patients with HFpEF.
P781Resveratrol improves cardiac function and exerts an anti-inflammatory effect in systolic heart failure patients
Authors: Halmosi R , Gal R , Deres L , Horvath O , Marton Z S , Sumegi B , Toth K , Habon T
Published: October 2019

Introduction

The positive effects of resveratrol on heart failure have already been evaluated in several experimental animal models, however, in a human clinical trial it was not yet confirmed. The aim of our study was to assess the effect of resveratrol supplementation on left ventricular structure and function in patients with heart failure with reduced ejection fraction (HFrEF).

Methods and materials

60 HFrEF patients (age: 66.7±11.04 years, 17 women and 43 men) were enrolled into our study. They were randomized into two groups, in the first group (n=30) daily 2x50 mg resveratrol was administered orally and placebo was given in the other group (n=30). 56% of the enrolled patients had ischemic HFrEF. During the whole study period, patients were taken the optimal medical therapy of HFrEF (ACEI/ARB, BB, MRA) in the same dose as before the randomization. On the day of randomization and 3 months later echocardiography, six minutes walking test (6MWT) and quality of life questionnaire (QoL) test were performed. Besides the routine lab tests, the levels of biomarkers (NT-proBNP, galectin-3) and inflammatory cytokines (IL-1, IL-6) were also measured.

Results

After the 3-month-long follow-up period left ventricular ejection fraction improved significantly in the resveratrol group comparing to the placebo group (p<0.001). The function of the right ventricle (RV) improved (p<0.05), moreover the RV dimensions, as well as atrial volumes decreased significantly in the resveratrol group (p<0.05). In the case of 6MWT (p<0.05) and QoL test (p<0.05) a significant improvement could be observed in the resveratrol group versus the placebo group (p<0.05). Lab test analysis showed that resveratrol supplementation reduced significantly the total cholesterol level (p<0,05) and LDL-C level (p<0,05) and had no overt effect on other metabolic parameters. NT-proBNP level increased significantly in the placebo group (p<0.05) by the end of the trial, however, in the resveratrol group we could see a slight improving tendency (NS). In the case of Galectin-3, no significant changes could be seen.

Conclusions

Our results revealed that resveratrol supplementation in systolic heart failure patients adding to the standard medical therapy resulted in an improvement of echocardiographic parameters, functional status and decreased the level of inflammatory cytokines.

Acknowledgement/Funding

GINOP-2.3.2-15-2016-00048
P795Long-term prognostic value of the combination of plasma volume status and pulmonary-systemic pressure ratio in patients admitted with acute decompensated heart failure
Authors: Yamada T , Morita T , Furukawa Y , Tamaki S , Kawasaki M , Kikuchi A , Kawai T , Seo M , Nakamura J , Abe M , Yamamoto K , Kayama K , Kawahira M , Tanabe K , Fukunami M
Published: October 2019

Background

Plasma volume (PV) expansion plays an essential role in heart failure and PV status provides prognostic information in patients (pts) with acute decompensated heart failure (ADHF). On the other hand, concomitant presence of pulmonary hypertension in heart failure is associated with increased adverse events and may be related to interventricular uncoupling and impaired cardiac efficiency. It has recently been shown that an increased mean pulmonary artery pressure to mean systemic arterial pressure ratio (MPS ratio), a marker of interventricular coupling and efficiency, is associated with worse clinical outcomes in patients with advanced heart failure. However, there is no information available on the long-term prognostic value of the combination of PV status and MPS ratio in pts admitted for ADHF.

Methods

We studied 248 pts admitted for ADHF, who underwent right heart catheterization at the admission and were discharged with survival. PV status and MPS ratio were obtained at the admission. PV status was calculated as the following: Actual PV = (1 − hematocrit) x [a + (b x body weight)] (a=1530 in males and a=864 in females, b=41 in males and b=47.9 in females), Ideal PV = c x body weight (c=39 in males and c=40 in females), and PV status = [(actual PV − ideal PV)/ideal PV] x 100(%). The study endpoint was cardiovascular death (CVD).

Results

During a mean follow-up period of 5.2±4.4 yrs, 62 pts had CVD. PV status (10.0±16.2 vs 5.0±15.3%, p=0.03) and MPS ratio (0.408±0.114 vs 0.347±0.102, p=0.0001) were significantly greater in patients with than without CVD. At multivariate Cox regression analysis, PV status and MPS ratio were significantly associated with CVD, independently of prior heart failure hospitalization, eGFR, and serum sodium level and anemia. Patients with greater PV status (> median value = 4.6%) and MPS ratio (> median value = 0.346) had a significantly higher CVD risk than those with either and none of them (44% vs 22% vs 14%, p<0.0001, respectively).

Conclusions

The combination of PV status and MPS ratio might be useful for stratifying patients at risk for CVD in patients with ADHF.
P798Automated blood pressure measurements: optimal diastolic blood pressure range in treated hypertensives at high cardiovascular risk
Authors: Sobieraj P , Lewandowski J , Sinski M
Published: October 2019

Background/Introduction

Automated office blood pressure measurements (AOBPM) is recommended for the diagnosis of arterial hypertension. Nevertheless, use of automated office blood pressure in monitoring of treated patients with hypertension is limited by the discrepancies between AOBPM, auscultatory and research grade measurements of blood pressure. The treatment targets using AOBPM are not well-determined.

Purpose

This post-hoc analysis is aimed to establish the optimal range for on-treatment diastolic blood pressure (DBP) measured with AOBPM in hypertensive patients without cardiovascular disease but at high risk, who achieved systolic blood pressure treatment goal (SBP).

Methods

Data of 3715 subjects without prior cardiovascular disease treated to achieve SBP goal <120 mm Hg were selected from SPRINT trial database obtained from National Heart, Lung and Blood Institute. Clinical endpoint was defined as myocardial infarction, acute coronary syndrome not resulting in myocardial infarction, stroke, acute decompensated heart failure or death from cardiovascular causes.

On-treatment blood pressure was computed as mean of AOBPM readings in a period from 6th month until to end of the study, which was considered as with a stable blood pressure.

Optimal on-treatment DBP range was established on the basis of hazard ratio plot for clinical endpoint after adjustment for age, sex, SBP, smoking habits and history of chronic kidney disease. The target DBP range was set to be 10 mm Hg wide, what is line with current ESC/ESH guidelines. To evaluate nonlinear relationship between continuous variables and outcome cubic spline methods were used.

Results

Data of 3715 (38.3% female and 61.7% male) subjects aged 67.3±9.2 mm Hg were analysed. Mean on-treatment SBP and DBP were 120.8±8.5 mm Hg and 68.2±8.1 mm Hg, respectively. Lowest hazard risk of primary endpoint was found in on-treatment DBP range 62.8–72.8 mm Hg with a minimum at 67.8 mm Hg (Figure 1). Hazard risk increased linearly toward lower and higher values than selected optimal DBP range.

Figure 1

Conclusion(s)

In treated hypertensives at high cardiovascular risk, but without prior cardiovascular disease who achieved SBP treatment goal, on treatment DBP 62.8–72.8 mm Hg range should be considered when treatment is monitored using AOBPM.
P802Interrelationships of sympathetic nervous system activity with attended and unattended blood pressure levels in essential hypertensive patients
Authors: Manta E , Tsioufis C , Dimitriadis K , Kouremeti M , Kakouri N , Kasiakogias A , Leontsinis I , Vogiatzakis N , Konstantinidis D , Andrikou I , Liatakis I , Tousoulis D
Published: October 2019

Background/Introduction

Measurement of unattended blood pressure (BP) may provide additional information over conventionally attended BP. Moreover, hypertension is related to sympathetic drive while there are scarce data on the diverse links of attended and unattended BP with muscle sympathetic nerve activity (MSNA) in hypertensive patients.

Purpose

The aim of this study was to assess the relation of BP levels in the attended and unattended setting with MSNA in patients with essential hypertension.

Methods

We studied 38 patients with essential hypertension (age: 59±11 years, 20 males, office BP: 142/86±19/11 mmHg, 24-hour BP: 137/80±14/12 mmHg). In all participants sympathetic drive was assessed by MSNA estimations based on established methodology (microneurography). Both unattended BP (patient alone in the room, an oscillometric device programmed to perform 3 BP measurements, at 1-minute intervals, after 5 minutes) and attended BP were measured with the same device, on the same day of MSNA recording, in random order. Patients were divided into the combined attended and unattended hypertensive group when BP≥140/90 mmHg in both attended and unattended BP estimations and to the attended hypertensive group when only attended BP≥140/90 mmHg.

Results

Patients with combined attended and unattended hypertension (n=18) compared to those with attended hypertension (n=20) were older (61±11 vs 57±11 years, p=0.03), whereas did not differ regarding 24-h ambulatory BP levels, glucose levels, renal function and left ventricular mass index (p=NS for all). Moreover, patients with combined attended and unattended hypertension compared to those with attended hypertension were characterized by greater levels of MSNA (41.2±11.6 vs 32.2±10.1 bursts per minute, p=0.031). In all participants, sympathetic nerve traffic as assessed by resting MSNA was related to attended systolic BP (r=0.459, p=0.004), attended diastolic BP (r=0.503, p=0.001), unattended systolic BP (r=0.433, p=0.007) and unattended diastolic BP (r=0.423, p=0.008).

Conclusions

The phenotype of combined attended and unattended hypertension compared to attended hypertension is accompanied by higher sympathetic nervous system activation. Moreover, the close association of MSNA with attended and unattended BP levels in essential hypertension, further supports the key role of sympathetic drive in modulating BP.