bluuebunny/crossref_metadata_2025_split huggingface dataset:
1424The diagnosis of non-adherence in hypertension using a urine biochemical screen is unaffected by drug pharmacokinetics
Authors: Lane D , Alghamdi R , Muscat M , Kaur M S , Davis T , Cole R , Patel P , Tomaszewski M , Gupta P 
Published: October 2019

Abstract

Introduction
Suboptimal drug adherence in hypertension is pandemic and traditional diagnostic tools to detect non-adherence have lacked accuracy and robustness. The inability to identify non-adherence has therefore driven the development of biochemical drug screening by liquid chromatography tandem mass spectrometry (LC- MS/MS) in urine and blood, which are the most accurate metrics presently available. Urinary antihypertensive testing is evidenced to improve non-adherence rates, significantly decrease blood pressure after physician intervention, and be cost effective. The European Society of Cardiology (ESC) and European Society of Hypertension (ESH) 2018 guidelines have recommended the use of biochemical testing for non-adherence diagnosis. However, it has been argued that the variable pharmacokinetic parameters of the medication (such as their half-lives and clearance rates) may affect the detection of medications in urine and hence the determination of adherence. We hypothesized that pharmacokinetic parameters do not affect the detection of antihypertensive medications in urine.

Aim
This study compared the pharmacokinetic parameters of the most commonly prescribed antihypertensive medications against their detection in urine by LC-MS/MS.

Methods
Results of urinary drug screens from 463 hypertensive patients (total prescribed medications N=1709) were collated. An adherence score termed as the C score (number of detected vs. prescribed medication) was generated for each of the 27 common antihypertensive medications. Pharmacokinetic parameters such as bioavailability, plasma concentration, volume of distribution, half-life, plasma clearance and urinary excretion values for each drug were obtained from published literature. Partial linear correlation was conducted between the C score of all the medications and each pharmacokinetic parameter studied.

Results
40% of patients were non-adherent. The average number of prescribed medications was high (N=3.7, SD: 1.5), and the average number of drugs detected was lower (N=2.5, SD: 1.6). Amlodipine was the most prescribed (N=224), and clonidine was the least (N=10). The half-lives ranged from 0.87 to 39 hours for bumetanide and amlodipine respectively. The urinary excretion percentage varied from <1% for nifedipine, and 94% for benfroflumethiazide. No significant correlation was found between any drug C score and their respective pharmacokinetic variables such as the medication half-lives (figure1).
Half-life versus adherence score

Conclusion
This study reports no significant correlation between drug pharmacokinetics and adherence. To the best of our knowledge this is the first study of its kind. Urinary biochemical testing by LC-MS/MS for non-adherence remains a valid tool for diagnosis although further detailed pharmacokinetic studies are needed to confirm this finding.

Acknowledgement/Funding
None
1441LRP5 and PCSK9 in inflammatory cells immunomodulation
Authors: Borrell M , Crespo J , Badimon L 
Published: October 2019

Abstract

Background
Atherosclerosis, the leading cause of cardiovascular diseases, is driven by high blood cholesterol levels and chronic inflammation. The disruption of the hepatic interaction between Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) and Low-Density Lipoprotein Receptor (LDLR) downregulates blood cholesterol levels and reduces cardiovascular events. Recent data suggest that other members of the LDLR superfamily may be targets of PCSK9.

Purpose
The aim of this work is to determine if LDLR-related protein 5 (LRP5) is a PCSK9 target, and to study the role of PCSK9 and LRP5 in foam cell formation and hence, in the mechanism of lipid accumulation and atherosclerotic plaque formation.

Methods
Intracellular protein and lipid localization, cholesteryl esters (CE) accumulation; quantification of structural and inflammatory proteins expression and immunoprecipitation analyses were performed in primary cultures of human inflammatory cells (monocytes and macrophages) silenced for LRP5 or PCSK9 and challenged with modified LDLs.

Results
We first show that LRP5 is needed for macrophage lipid uptake since LRP5-silenced macrophages have less intracellular CE accumulation. In LDL treated macrophages internalization of LRP5-bound LDL starts after 30 minutes of incubation and lasts up to 24hours. The SREBP-2 promoter is not involved in LRP5 regulation but it does regulate macrophage PCSK9 expression. Immunoprecipitation experiments show that LRP5 forms a complex with PCSK9 in lipid-loaded macrophages. Finally we studied the role of PCSK9 and LRP5 in the inflammatory response by TLR4/NFkB signaling pathway. We show decreased TLR4 protein expression levels and decreased nuclear translocation of NFκB in PCSK9 silenced-inflammatory cells after lipid loading indicating a downregulation of the proinflammatory pathway TLR4/NFκB. Increased gene expression is observed in TNF-α and IL1β after lipid-loading that is abolished in PCSK9-silenced macrophages. Furthermore release of the proinflammatory cytokines TNF-α and IL1β is decreased in PCSK9-silenced macrophages. LRP5 protein expression is increased in lipid-loaded macrophages independent of the presence or absence of PCSK9.

Conclusions
These results demonstrate that, in human macrophages, LRP5 is internalized with lipids. Furthermore, PCSK9 and LRP5 can form a complex in the cytoplasm of lipid-loaded macrophages opening the possibility that PCSK9 induces lysosomal LRP5 degradation in a similar manner than it does with LDLR. Finally we also show that PCSK9 gene interference decreases inflammation and supports a role for PCSK9 as an inflammatory mediator in atherosclerosis.

Acknowledgement/Funding
CN16/11/00411-LB; TERCEL RD16/0011/018-LB; FIS2016-02014 -MBP; SEC2015 to MBP
1445Physical activity and long-term mortality risk in Israeli older adults with and without cardiovascular disease
Authors: Gerber Y , Shaked O , Cohen G , Goshen A , Shimony T , Shohat T 
Published: October 2019

Abstract

Background
Physical activity (PA) is a known protective factor among both general population and cardiovascular disease (CVD) patients. Yet, only a few cohort studies assessed the role of PA among older adult populations, characterized by high CVD prevalence rates.

Objectives
To evaluate the association between PA levels and all-cause mortality among Israeli older adults, and to assess whether it differs by baseline CVD status.

Methods
Participants were drawn from the National Health and Nutrition Survey of Older Adults Aged 65+ (“Mabat-Zahav”), conducted by the Israel Center for Disease Control between July 2005 and December 2006. Clinical, behavioral, and psychosocial data were collected via interview at study entry; a detailed PA questionnaire was also administered, through which participants were classified as sufficiently-active, insufficiently-active, and inactive, according to the American College of Sports Medicine classification. Mortality data (last follow-up, December 2016) were obtained from the Israeli Ministry of Health. Inverse probability weighted Cox proportional hazards models, based on propensity score, were constructed to assess the adjusted association between PA categories and mortality.

Results
Of the 1799 participants (mean [SD] age, 74.6 [6.2] years; 647 [36%] with a history of CVD), 559 (31%) were sufficiently-active, 506 (28%) were insufficiently-active and 734 (41%) were inactive. During a mean follow-up period of 9.0 years, 684 participants (38%) died. PA and mortality demonstrated an inverse dose-response relationship in both CVD and non-CVD groups, with no CVD-by-PA interaction detected on multiplicative-scale (P=0.70) or additive-scale (P=0.58). Notably, inactive non-CVD subjects had comparable risk to CVD patients who were sufficiently active (Figure).
Physical activity and mortality

Conclusions
In a nationally-based cohort of subjects aged 65 years and over, PA was inversely associated with mortality risk. CVD patients who preformed sufficient PA had a comparable mortality risk to inactive subjects free of CVD. These findings illustrate the importance of PA in the older adult population.
2139Left atrial dysfunction assessed by strain correlates with symptoms and severity of aortic stenosis
Authors: Santoro C , Pardo A , Hinojar R , Garcia A , Salido L , Gonzalez-Gomez A , Jimenez-Nacher J J , Marco Del Castillo A , Abellas M , Hernandez-Antolin R , Zamorano J L , Fernandez-Golfin C 
Published: October 2019

Abstract

Background
Aortic stenosis (AS) results in high pressure afterload causing detrimental effect especially on the left chambers. Structural and functional changes of the left ventricle (LV) usually corresponds to concomitant remodelling of the left atrium (LA). However, how this pressure afterload specifically affects LA function and whether the study of LA function could help in stratifying patients with different degree of AS it is not known.

Purpose
We aim to evaluate the differences in LA and LV function according different degree of AS by standard and speckle tracking echocardiographic.

Methods
From January 2016 to May 2018 we recruited 135 patients referring to our echo-lab with diagnosis of AS (mean age 79.5±4.4; 60/55% female). We divided this population according to AS severity in patients with moderate AS, severe asymptomatic and severe symptomatic AS and matched with 35 control group with no aortic stenosis (n=45, mean age: 77.6±4.5). All patients underwent standard and 2-dimensional speckle tracking echocardiography computing global longitudinal strain (GLS) of LV and peak atrial strain of LA (PALS).

Results
In all patients PALS was a good predictor of E/e' ratio after correction for LV EF and age (p<0.001, β: −0.48). LVEF and GLS progressively decreased together with worsening of AS degree, as well as parameters of geometry and function of LA (Table1). By excluding patients with LV dysfunction the reduction gradient of parameters of LA geometry and function was still present. However, when severe symptomatic with asymptomatic severe AS are compared, no difference in E/e' ratio was found while both GLS and PALS were significantly reduced (both p<0.0001).
Variables Overall population (180) Control (45) Moderate AS (45) Severe asympt AS (45) Severe sympt. AS (45) p LVEF 65.0±11.1 67.7±5.6 69.4±8.5 66.1±10.7 59.5±13.5 0.0001 GLS −20.4±4.1 −23.1±2.4 −21.5±2.9 −21.4±3.2 −17.1±4.3 0.0001 LA vol index 41.6±21.5 28.2±10.4 40.1±19.7 39.8±16.7 52.3±24.9 0.0001 LA strain 23.6±10.9 30.8±10.3 27.8±9.2 24.4±9.7 15.2±7.1 0.0001 LA reservoir 46.4±15.9 51.9±11.5 53.0±15.0 48.3±14.1 37.2±16.1 0.0001 Ee' ratio 14.8±7.0 9.6±2.7 13.7±6.3 15.4±6.2 19.3±7.2 0.0001

Conclusions
LA function seems to progressively decrease according to the degree of AS, independently from LV function. Significant difference was found between parameters of LA remodelling and dysfunction between symptomatic and asymptomatic AS patients. The assessment of LA function by strain may help stratify the patients with AS, identifying those who need intensive medical/surgical treatment.
2204Predicting the trajectory of depression following an acute coronary syndrome: the role of resilience
Authors: Smith J H C , Toukhsati S , Francis A J P , Stavropoulos V , Hare D L 
Published: October 2019

Abstract

Background
Depression is common in patients following an Acute Coronary Syndrome (ACS) substantially increases the risk of future events and mortality. Post-ACS depression typically resembles one of four longitudinal trajectories: chronic; absent; recovered, or delayed depression. Early identification of a patient's post-ACS depression trajectory will improve risk stratification, treatment implementation and risk management.

Purpose
To explore whether stable psychosocial traits, such as resilience, predict the trajectory of depression one month and 6 months following an ACS admission.

Method
Consecutive adult ACS patients (STEMI/NSTEMI) admitted to a large general hospital completed the Cardiac Depression Scale (CDS) and the Sense of Coherence scale during their admission, then one and six months following discharge.

Results
132 ACS in-patients (males = 111; mean age = 63.13±13.47) satisfied enrolment criteria. Unconditional linear latent growth modelling identified a 3-class model for the trajectory of depression post-ACS (increasing depression; consistent non-depressed; decreasing non-depressed). For the increasing depression class, resilience at baseline was significant and negative compared to the consistent class, b=−0.06, Wald chi square (1) = 4.42, p=0.036 and the decreasing class, b=−0.09, Wald chi square (1) = 7.20, p=0.007.

Conclusions
Patients who reported lower levels of resilience during an ACS admission were significantly more likely to experience initially high levels of depressive symptoms (CDS ≥85) that exceeded the clinically relevant cut-off (CDS ≥95) at 6 months post-discharge. This study suggests that screening for resilience and depression will improve risk stratification for persistent and delayed depression post-ACS.
2212Body mass index and its association to cardiovascular outcomes in patients with stable coronary heart disease - experiences from the STABILITY study
Authors: Held C , Hadziosmanovic N , Hagstrom E , Hochman J S , Stewart R A H , White H D , Wallentin L 
Published: October 2019

Abstract

Background
Obesity, assessed as body mass index (BMI), is an established risk factor for development of coronary heart disease (CHD). However, in patients with heart failure and atrial fibrillation there is an “obesity paradox” with better prognosis among obese patients. The association between BMI and cardiovascular outcomes in patients with stable CHD is unclear.

Methods
The prospective STABILITY trial included 15,828 patients with stable CHD with a follow-up of 3–5 years (median 3.7) on optimal secondary preventive treatment. BMI and waist circumference were measured at baseline (n=15,785). All cardiovascular outcomes were centrally adjudicated. Associations between obesity indices and outcomes were evaluated by multivariable Cox regression analyses with adjustments for age, sex, study treatment, and clinical risk factors.

Results
Mean age was 64 years and 19% were females. In total, 3250 (20.9%) patients had BMI <25, 6628 (42.8%), BMI >25 and <30 and 5614 (36.3%), BMI >30. Underweight (BMI <18.5) was seen in 79 patients. Most risk markers (diabetes, hypertension, and levels of inflammatory biomarkers and triglycerides) showed a graded association with higher BMI. The frequency of smoking and levels of HDL, GDF-15 and NT-proBNP were higher at lower BMI. Lower BMI was associated with an increased risk of MACE, total and CV death, and heart failure (Figure). Higher BMI was associated with increased risk of the same outcomes and also with MI. BMI was not associated with the risk of stroke. There was no interaction with age, sex, diabetes or type of MI (type 1 vs type 2–5). Associations between waist circumference and outcomes were weaker and not significant in the fully adjusted model.
Figure 1

Conclusion
In patients with stable CHD on optimal secondary prevention BMI had a U-shaped association with the risk of MACE, death, and heart failure and a linear association with the risk of MI. The lowest risk for MACE was seen for BMI between 25 and 30, considered as overweight. The findings do not support current recommendations to achieve an ideal BMI of 20–25 for weight adjustments in patients with CHD.

Acknowledgement/Funding
The original STABILITY study was funded by GlaxoSmithKline
2226The randomised study of epicardial application of hydrogel with amiodarone for prevention of postoperative atrial fibrillation in patients after coronary artery bypass grafting
Authors: Bockeria O , Shvartz V A , Kanametov T 
Published: October 2019

Abstract

The purpose of our study was to evaluate safety and efficacy of local epicardial application of amiodarone - releasing hydrogel in the prevention of postoperative atrial fibrillation (AF) in patients undergoing coronary artery bypass grafting (CABG).

Material and methods
We present an open prospective randomised study, in which 60 patients (47 male), mean age of 62±8,5 were included. Baseline clinical, laboratory and instrumental characteristics were similar in all patients. Patients didn't have any arrhythmic complains or previously registered AF. All patients underwent elective CABG and were randomised into two groups: Group #1 (n=30) - had the amiodarone-releasing hydrogel application before chest closure, and Group #2 (n=30) regular CABG surgery, no local application. We used 60 mg of amiodarone in hydrogel. This dose was experimentally determined during previously performed animal study. Heart rhythm control was monitored continuously during first 5 postoperative days and occasionally (mornings and evenings) the remaining days before the discharge. The local ethics committee approved this study design.

Results
The incidence of postoperative AF occurrence was significantly lower in Group #1: AF was registered in 3.3% cases versus 37% of patients from Group #2 (p<0.001). There was slight increase of PQ interval duration in Group #1 - 0.14 sec (0.12; 0.16), which however was significantly higher then in Group #2 - 0.12 (0.12; 0.14), (p<0.01). QRS and QT intervals were similar in both groups without significant difference.
There were no complications associated with the application procedure neither during postoperative period, such as AV block, infection or life-threatening situations.
According to 5 days ECG monitoring, the average heart rate in the Group #1 was 59 (52; 60) beats per min versus 69 beats per min (65; 75) in Group #2 (p<0.001). Temporary atrial or atrio-ventricular pacing used for correction of the heart rate if required in both groups. By the time of discharge none of the patients required permanent cardiac pacing. The length of stay in Group #1 was significantly shorter: 6 (6; 7) days versus 8 (8; 9) days (p<0,001).
Among all studied parameters, amiodarone-releasing hydrogel application and older age were statistically significant in postoperative AF occurrence (p<0.01). According to the Cox regression model amiodarone-releasing hydrogel application decreases the incidence of postoperative AF by 18,9 folds. The older age instead increases the incidence of postoperative AF by 1,2 folds.

Conclusions
The local epicardial amiodarone (60 mg) application in hydrogel before chest closure is a safe procedure. This approach showed it's effectiveness in AF prevention in patient undergoing elective CABG.
2230Results from the CAMI1 Study: selective CRP apheresis as a new treatment option in acute myocardial infarction
Authors: Garlichs C , Torzewski J , Sheriff A , Pfluecke C , Darius H , Lehrke S , Horstkotte J , Heigl F , Ince H , Mitzner S , Nordbeck P , Butter C , Zaenker M , Ries W 
Published: October 2019

Abstract

Background
Inflammation is increasingly recognized as an important pathogenic feature in cardiovascular disease. In patients with STEMI, C-reactive protein (CRP), the prototype human acute phase protein, is a marker of poor prognosis and independently predicts 30-day mortality. In STEMI, CRP may indeed be intimately involved in myocardial damage by activating the complement system in the ischemic tissue. In animal experiments, CRP removal after STEMI reduces infarct size and results in a significantly better left ventricular ejection fraction (LVEF). Recently, in the multi-center matched-control pilot study on CRP apheresis in Acute Myocardial Infarction (CAMI1), a newly designed CRP adsorber has been demonstrated to efficiently and selectively lower CRP plasma levels in humans. Here, we present preliminary data of the ongoing trial.

Methods
Up to the present day, 67 STEMI patients were enrolled in the study following complete coronary revascularization. 32 patients received CRP apheresis, whereas 35 patients treated by standard protocols served as controls. CRP apheresis started 24±12 h and 48±12 h after onset of symptoms. In case of a rapid increase in CRP plasma levels following the 2nd session, a 3rd session was carried out another 24 h later. In each apheresis session, 6000 ml plasma was treated via peripheral venous access. Primary study endpoint was myocardial infarction size as determined by Cardiac Magnetic Resonance Imaging (MRI) 5±3 days after STEMI.

Results
Apheresis sessions were well tolerated with no relevant side effects. Peak CRP plasma levels after STEMI ranged from 12 mg/l to 279 mg/l. The peak CRP level after AMI can be calculated precisely with at 2–3 CRP quantifications during the first 24 h after the onset of symptoms. The regression coefficient for this analysis is 0.95. This mathematical step allows for the comparison of the CRP-apheresis group and the controls on the basis of their individual CRP peak levels. The statistical evaluation shows that the apheresis patients no longer correlate with the control with regard to the endpoints infarct size, LVEF, longitudinal strain and circumferential strain. They perform significantly better at all endpoints. The CRP apheresis reduced the development of myocardial damage.

Conclusions
Here, an unequivocal association between infarct size and CRP is demonstrated for the first time. CRP apheresis following STEMI is feasible and safe. Our preliminary results in a small cohort show a significant beneficial effect of CRP apheresis on myocardial infarction size and wall motion. Selective CRP apheresis may emerge as a new therapeutic approach in the treatment of acute myocardial infarction.