bluuebunny/crossref_metadata_2025_split huggingface dataset:
P1521In a 36-week placebo-controlled phase 2 trial in patients with non-alcoholic steatohepatitis (NASH), treatment with MGL-3196 (resmetirom) significantly reduces atherogenic lipoprotein particles
Authors: Taub R , Frias J P , Baum S J , Hsia S , Harrison S 
Published: October 2019

Abstract

Background
MGL-3196 is a liver-directed, orally active, highly selective thyroid hormone receptor-β agonist being developed for the treatment of non-alcoholic steatohepatitis (NASH). In a 36-week Phase 2 NASH study, MGL-3196 treatment compared with placebo (PbO) resulted in significant reductions in hepatic fat, liver enzymes, NASH on liver biopsy, and atherogenic lipids including low-density lipoprotein cholesterol (LDL-C) and triglycerides. Most NASH patients die of cardiovascular disease (CVD), and, in NASH patients, CV risk correlates better with LDL particle than LDL-C levels.

Purpose
To determine the effects of MGL-3196 on lipoprotein particle concentrations in patients with NASH.

Methods
MGL-3196–05 (NCT02912260) is a 36-week multicenter, randomized, double-blind, placebo controlled study of NASH patients assessed with serial liver imaging and liver biopsies. Patients received 2:1 MGL-3196 80 mg (blinded ± 20 mg dose adjustment possible at Week 4 based on Week 2 pharmacokinetic data) or placebo once daily, for 36 weeks. Lipoprotein particle concentrations were assessed in fasting blood samples at baseline and Week (Wk) 36.

Results
As shown (Table), MGL-3196 significantly reduced the level of lipoprotein particles, with greater reductions in patients with baseline (BL) LDL-C ≥100 mg/dL and the patient group with higher MGL-3196 exposures (High exp).
Lipoprotein particles Particles (by NMR) (nmol/L) Time Point Placebo, n=34 MGL-3196 (all), n=73 MGL-3196 BL LDL-C ≥100 mg/dL, n=44; High Exp, n=25 (PbO BL ≥100 mg/dL, n=23 mean data not shown) Total LDL, mean (SD) BL 1234 (276) 1275 (328) 1443 (290) 1407 (267) Wk 36 1251 (323) 1045 (264) 1155 (248) 1090 (216) % change from BL vs PbO (SE), p value −19.6 (4.2), <0.0001 −19.8 (5.6), 0.0008 −22.8 (6.3), 0.0006 Small LDL, mean (SD) BL 746 (295) 835 (294) 887 (329) 916 (314) Wk 36 749 (343) 641 (207) 641 (234) 618 (149) % change from BL vs PbO (SE), p value −27.7 (8.9), 0.002 −34.3 (13.1), 0.01 −39.4 (14.7), 0.009 Total VLDL and Chylomicron, mean (SD) BL 56.8 (23.9) 55.9 (22.9) 61.4 (24.5) 66.0 (24.8) Wk 36 58.8 (24.4) 46.0 (21.1) 47.6 (22.9) 47.4 (23.1) % change from BL vs PbO (SE), p value −22.7 (6.9), 0.001 −27.2 (7.5), 0.0006 −34.7 (8.3), <0.0001 Large VLDL and Chylomicron, mean (SD) BL 6.3 (4.3) 8.7 (5.8) 8.9 (6.1) 10.2 (6.8) Wk 36 7.2 (4.5) 6.6 (3.9) 6.7 (4.1) 7.2 (4.7) % change from BL vs PBO (SE), p value −52.5 (11.8), <0.0001 −65.6 (15.5), <0.0001 −71.3 (17.4), 0.0001 BL, baseline; High exp, high MGL-3196 exposure based on % increase from baseline in sex hormone binding globulin, BL LDL-C ≥100, a prespecified group.

Conclusions
MGL-3196 significantly reduced atherogenic lipoprotein particles, particularly in NASH patients with greater BL hypercholesterolemia. These findings are consistent with a potentially beneficial effect of MGL-3196 on the CV risk profile in NASH patients.
P1523Comparative long-term outcomes among men and women after percutaneous coronary intervention
Authors: Procopi N , Zeitouni M , Kerneis M , Hammoudi N , Berman E , Barthelemy O , Choussat R , Guedeney P , Braik N , Silvain J , Le Feuvre C , Helft G 
Published: October 2019

Abstract

Background
Comparative long-term outcomes among women and men treated with percutaneous intervention (PCI) are unknown.

Objective
To describe and compare mortality and predictors of poor outcomes among men and women who underwent PCI.

Methods
Consecutive men and women admitted for PCI between 2008 and 2011 were prospectively included and followed-up in this cohort study. Major adverse cardiovascular and cerebrovascular events (MACCE) and causes of death were collected through consultations, calls and death certificate. The primary endpoint was all-cause mortality according to gender. Secondary endpoints were cardiovascular death, non-cardiovascular death and MACCEs. Last detailed cardiovascular and vital status were collected in January 2019.

Results
A total of 3524 patients including 2720 men (77.1%) and 804 women (22.8%) were followed-up for a median time of 7.0 years (IQ1: 5.4; IQ 3: 7.2). The follow-up rate was 97.6%. Women were older at baseline (70±13.1 vs. 64.6±12), smoked less often (18.9% vs. 30.4%) but suffered more frequently of hypertension (67.9% vs. 58.1%) and chronic kidney disease (42.6% vs. 22.7%). All-cause death occurred for 30.3% (n=1070) and MACCE for 40.9% (n=1443) of patients in the cohort. In unadjusted analyses, women had a higher risk of all-cause mortality (35% vs 29%, HR = 1.25, 95% CI [1.09–1.43], p=0.0015) and cardiovascular mortality (61% vs. 57%, HR = 1.31, 95% CI [1.10–1.56]) but there was no difference on occurrence of MACCE (HR = 1.079, 95% CI = [0.9271–1.221]). After adjustments for baseline cardiovascular risk factors, presentation and severity of coronary disease, women and men shared a similar risk of mortality along time (adHR = 0.90, 95% CI [0.77–1.05]).
Survival curves in women vs. men

Conclusions
In this long-term follow-up, women had a higher risk of all-cause and cardiovascular mortality after PCI in unadjusted analyses. However, gender was not independently associated with mortality after adjustment for cardiovascular risk factors.
P1536Does free thyroxine (fT4) predict risk of atherosclerotic cardiovascular disease (ASCVD)?
Authors: Anderson J L , Jacobs V , May H T , Bair T L , Benowitz B A , Lappe D L , Muhlestein J B , Knowlton K U 
Published: October 2019

Abstract

Background
Thyroid hormones are associated with arrhythmic risk, but their relationship to ASCVD is unclear. The Rotterdam Study* reported associations of higher fT4 and lower thyroid stimulating hormone (TSH) levels with ASCVD, including within the euthyroid range. Free T3 (fT3) was not assessed.

Methods
We tested whether fT4, fT3, and TSH levels were associated with ASCVD in Intermountain Healthcare. All patients >18 y old with an fT4 level in the electronic medical record database were included. The hormone reference ranges were divided into quartiles (Q), and associations with prevalent and incident ASCVD were assessed by multivariable regression and trend tests.

Results
A total of 212,202 patients (age = 64.4±11.2 y; 66.6% women) were included and followed for 6.1±4.4 y. Of these, 8.3%, 86.6%, and 5.1% had fT4 levels below, within, and above the reference range. CAD was prevalent in 18.9% of fT4 Q1 patients. The adjusted odds ratio (OR) for coronary artery disease (CAD) increased through (Q4/Q1 OR=1.36) and beyond (High/Q1 OR=1.71) the normal range, p-trend<0.001 (Table). Smaller incremental risks were noted for fT3 (Q4/Q1 OR=1.13; High/Q1 OR=1.25). The frequencies of incident MI (Q1=2.5%) and stroke (Q1=5.4%) were low and did not show a concentration-related risk gradient. Incident all-cause death (Q1=24.3%) increased slightly for Q4 and high fT4 (OR=1.05, 1.06) but not fT3; death also increased with low fT4 (OR=1.28). TSH showed no consistent gradient within the normal range for prevalent or incident events; however, mortality increased with both high and low TSH.
Thyroid Hormone Levels and Prevalent CAD Prevalent CAD (adjusted OR) Low Normal Q1 Normal Q2 Normal Q3 Normal Q4 High fT4 (n=212,202) OR=1.08, p=0.02 OR=1.00 referent OR=1.11, p<0.001 OR=1.21, p<0.001 OR=1.36, p<0.001 OR=1.71, p<0.001 fT3 (n=30,200) OR=1.12, p<0.001 OR=1.00 referent OR=0.98, p=0.61 OR=1.02, p=0.53 OR=1.13, p<0.001 OR=1.25, p<0.001 TSH (n=183,227) OR=1.39, p<0.001 OR=1.00 referent OR=0.93, p=0.42 OR=0.88, p=0.15 OR=0.92, p=0.35 OR=1.73, p<0.001 Reference Q 1–4 are: fT4: 0.75–0.90; 0.91–1.01; 2.02–1.14; 1.15–1.50 ng/dL; TSH: 0.54–1.30; 1.31–2.04; 2.05–3.68; 3.69–6.80 uIU/mL; fT3: 2.40–2.60; 2.70–2.80; 2.90–3.10; 3.20–4.20 pg/dL.

Conclusions
Consistent with the Rotterdam Study, we found an increase in prevalent CAD with increasing fT4 levels within and beyond the normal range and, uniquely, a more modest relationship with fT3. We could not confirm a normal-range relationship between hormone levels and incident events or between TSH and prevalent disease. The relationship of fT4 levels to ASCVD is intriguing, is deserving of further study, and may have important implications for ASCVD prevention.
*A Bano, et-al. Circ Res 2017; 121:1397–1400
P1569The Impact of Multidisciplinary Cardio-Oncology Program on the Cardiovascular Outcomes in Breast Cancer Patients
Authors: Wei-Ting C , Feng Y H , Kuo Y H , Chen W Y , Huang C T , Wu H C , Wang W C , Liao C T , Chen Z C 
Published: October 2019

Abstract

Background
Chemo- and target therapies may induce myocardial dysfunction and lead to poor prognoses. Early detection of minor myocardial dysfunction is important for the prevention of subsequent cardiotoxicity. Cardio-oncology is a multidisciplinary field focusing on managing and preventing cardiovascular complications in cancer patients. However, whether Cardio-oncology program truly makes difference in cardiovascular outcomes remains unknown. Herein, we are sharing our experiences in our Medical Center.

Methods
Since 2014 till 2017, we recruited 154 patients with newly diagnosed breast cancer preparing for Epirubicin therapy. Echocardiography, biomarkers, six minute walking distance and cardiovascular adverse events including new onset of hypertension, stroke, myocardial infarction (MI) and mortality were recorded at baseline, three months, six months and one year. Any functional decline was reported to oncologists for the consideration of changing regimens. Otherwise, cardiologists would be consulted for cardiovascular educations and therapies. The echocardiographic and clinical records of 450 breast patients receiving Epirubicin therapy during 2010 to 2013 were also collected as comparison.

Results
Compared with the ratio of 20% patients receiving echocardiography prior to 2014, the ratio increased to 100% since Cardio-Oncology program started. Also, the drop of left ventricular ejection fraction (LVEF) from 25% attenuated to 5%. Before Cardio-Oncology Program, there were 1.7% of new onset hypertension, 0.8% of MI, 0.8% of stroke and 16.8% of mortality. Conversely, after the program, there were only 0.6% of new onset hypertension while no other cardiovascular complications were reported. Furthermore, compared with previous reports of the effectiveness of Cardio-Oncology Program, our result also displayed a superior impact on the cardiovascular outcomes.

Conclusions
Collectively, through a comprehensive monitoring and an early intervention of myocardial dysfunction post chemotherapies, Cardio-Oncology Program truly decreased the cardiovascular complications in breast cancer patients.

Acknowledgement/Funding
Chi-Mei Medical Center
P1574Predictors of mortality in hospitalized atrial fibrillation patients with cancer
Authors: Malik A H , Shetty S , Malik S 
Published: October 2019

Abstract

Background
Recent reports indicate an important interplay between Atrial fibrillation (AF) and cancer. There is little information regarding the outcomes of these patients. Hence, we performed a study to identify predictors of in-hospital mortality to help guide goals of care discussions.

Methods
The Nationwide Inpatient Sample was used to identify patients with a diagnosis of cancer, who were found to have AF from 2002–2014. Trend rate, patients' and hospital characteristics along with in-hospital complications and predictors of in-hospital mortality were assessed. Backward stepwise elimination technique was used to fit the multivariate regression model.

Results
Over the 13-year study period, 12,410,290 (national estimate) patients with a cancer diagnosis were identified. 1,013,735 had AF, and 10.2% of the AF patients with cancer died while hospitalised. A variety of comorbidities, in-hospital procedures and in-hospital complications increased the odds of in-hospital mortality in these patients. Also, weekend admissions, elective admissions, and rural hospitals in comparison to urban teaching and non-teaching hospitals were associated with higher in-hospital mortality.

Conclusion
Stroke, myocardial infarction, pulmonary embolism, deep venous thrombosis, acute kidney injury, congestive heart failure, sepsis, and cardiogenic shock are most significant predictors of in-hospital mortality in AF patients with cancer.

Acknowledgement/Funding
None
P1580Left atrial volume index predicts improvement in renal function after catheter ablation of atrial fibrillation
Authors: Usuda K , Kato T , Furusho H , Tokuhisa H , Tsuda T , Takashima S , Murai H , Usui S , Takamura M 
Published: October 2019

Abstract

Background
Atrial fibrillation (AF) increased the risk of development of kidney disease. The elimination of AF by catheter ablation is associated with improvement in renal function. However, the mechanism of cardio-renal interaction in AF has not been fully elucidated.

Purpose
We tested the hypothesis that left atrial volume index (LAVI), which is a marker of left atrial mechanical reserve, predicts improvement in renal function after restoring sinus rhythm with catheter ablation of AF.

Methods
We analyzed consecutive patients who underwent catheter ablation of AF from January 2012 to October 2018 and had completed follow-up more than 3 months after catheter ablation. Exclusion criteria were need for hemodialysis and acute hospitalization. Estimated glomerular filtration rate (eGFR) was assessed on admission and at the end of follow-up periods after catheter ablation and the difference was defined as ΔeGFR. Left atrial volume index was derived using the biplane area-length method.

Results
A total of 159 AF patients (paroxysmal 112 [70%], persistent 47 [30%]) were included in this study. The mean age was 65±11 years and 74% were male. During the mean follow-up period of 7.9±3.2 months, 105 patients (66%) were free from atrial tachyarrhythmias and 54 (34%) experienced the recurrence. Baseline eGFR and LAVI were not significantly different between the non-recurrence group and the recurrence group (71.0±17.4 and 75.1±22.8 mL/min/1.73m2; p=0.24, 35.7±12.5 and 37.9±15.0 ml/m2; p=0.34). ΔeGFR in the non-recurrence group was significantly greater compared with the recurrence group (+1.5±1.0 versus −4.3±1.4 mL/min/1.73m2; p=0.001). Baseline LAVI was negatively correlated with ΔeGFR in the non-recurrence group (r=−0.3; p=0.002; Figure), but not in the recurrence group (p=0.1). Multiple regression analysis in the non-recurrence group identified baseline LAVI (β=−0.35, p<0.001), baseline age (β=−0.31, p<0.001) and baseline eGFR (β=−0.59, p<0.001) as independent predictors for eGFR improvement after catheter ablation. In the patients with LAVI <34 ml/m2, age <70 years and eGFR <90 mL/min/1.73m2, the mean ΔeGFR was +6.3±1.9 mL/min/1.73m2.
Figure 1

Conclusions
LAVI, a marker of left atrial mechanical reserve, was an independent predictor of improvement in renal function after restoring sinus rhythm with catheter ablation of AF. This observation suggests that AF-related deterioration of renal function is due at least in part to impaired atrial mechanical function.
P1596Interaction of CaMKII and NaV1.8 modulates cardiac electrophysiology in human heart failure
Authors: Tirilomis P , Ahmad S , Bengel P , Pabel S , Maier L , Hasenfuss G , Dybkova N , Sossalla S T 
Published: October 2019

Abstract

Introduction
In human heart failure, electrical remodeling contributes to the risk of arrhythmia generation. Increased expression of Ca/Calmodulin-dependent protein kinase IIδ (CaMKIIδ) and an enhanced persistent Na current (INaL) have been linked to arrhythmogenesis. CaMKIIδ increases INaL via regulation of sodium channels thereby contributing to arrhythmias through early- and delayed-afterdepolarizations (EADs and DADs). Genome-wide association studies (GWAS) have described the implication of the neuronal sodium channel isoform NaV1.8 (SCN10A) in cardiac electrophysiology showing modulation in cardiac conduction. We showed that the expression of the isoform Nav1.8 is significantly increased in human failing cardiomyocytes and contributes substantially to the enhanced INaL.

Purpose
We investigated a potential interaction of CaMKIIδ and NaV1.8 and thereby its role in arrhythmia generation and electrophysiology in human and murine failing hearts.

Methods
Cardiomyocytes were isolated from explanted failing hearts and CaMKIIδ transgenic (TG) mice. We performed immunostainings and co-immunoprecipitation (Co-IP) to show interactions of CaMKIIδ and Nav1.8 in isolated cardiomyocytes and homogenates. Whole-cell patch clamp experiments were conducted in isolated human and murine ventricular cardiomyocytes. Additionally, Ca2+ transients were measured using epifluorescence microscopy with the Ca2+ dye fura-2 (10μmol/L) whereas Ca2+ sparks measurements were performed by using confocal microscopy with the Ca2+ dye fluo-4 (10μmol/L). PF-01247324 is a novel specific NaV1.8 inhibitor (orally bioavailable; 1 μmol/L) and autocamtide inhibitory peptide (AIP, 1 μmol/L) was used to inhibit CaMKIIδ.

Results
Co-immunoprecipitation experiments revealed an association of CaMKIIδ and Nav1.8 in human homogenates compared to healthy controls. Furthermore, immunohistochemistry stainings in isolated human cardiomyocytes showed a co-localization of CaMKIIδ and NaV1.8 at the intercalated disc and t-tubules. We observed a significant reduction of INaL integral and proarrhythmic SR-Ca2+ spark frequency (CaSpF) after addition of either PF-01247324 or the CaMKIIδ inhibitor AIP in failing human and murine ventricular cardiomyocytes. When PF-01247324 and AIP were added together, the decrease in INaL integral and CaSpF was comparable to PF-01247324 alone in human failing cardiomyocytes. Inhibition of NaV1.8 did not show an effect on Ca2+ transient amplitude or Ca2+ transient decay at different stimulation frequencies in CaMKIIδ TG cardiomyocytes.

Conclusion
Our results demonstrate the significance of both CaMKIIδ and NaV1.8 in INaL generation and their detrimental interaction. This data suggest that increased CaMKIIδ activity plays a substantial role for the activation of NaV1.8-mediated late sodium current and SR-Ca2+ leak.
P1630Improved outcome by guideline-directed medical therapy in real-world heart failure patients despite low blood pressure and renal dysfunction
Authors: Chen X , Dahlstrom U L F , Pivodic A , Fu M 
Published: October 2019

Abstract

Background
Among patients with heart failure and reduced ejection fraction (HFrEF), angiotensin-converting enzyme inhibitors (ACEI/ARB), β-adrenergic receptor blockers (BB) and aldosterone antagonists (AA) are guideline-directed medical therapy (GDMT) to improve prognosis and well-being. However, low blood pressure (BP) and renal dysfunction are often challenges and barriersof the clinical implementation in real-world.

Purpose
To investigate whether it is beneficial to apply GDMT in real-world patients with HFrEF despite low blood pressure and renal dysfunction.

Methods
This study initially included 51060 HF patients from the Swedish Heart Failure Registry. After the exclusion of patients with ejection fraction ≥40% (53.4%), systolic BP>100mmHg (40.0%), eGFR>45ml/min/1.73m2 (3.3.%) and those died during hospitalization (0.3%), 1386 patients were ultimately enrolled in this study. Patients were grouped into five subgroups (ACEI/ARB+BB+AA, ACEI/ARB+BB, ACEI/ARB+AA, ACEI/ARB and BB). Outcome is all cause mortality.

Results
Among the study patients, 485 (35.0%) were treated with ACEI/ARB+BB+AA, 672 (48.5%) with ACEI/ARB+BB, 41 (3.0%) with ACEI/ARB+AA, 68 (4.9%) with ACEI/ARB and 120 (8.7%) with BB. Patients in ACEI/ARB+BB+AA group were younger (72.9±9.7 vs. 76.1±9.2 vs. 73.9±9.7 vs. 79.5±8.0 vs. 79.3±8.9), with higher BMI (25.4±4.5 vs. 25.5±4.7 vs. 23.7±4.2 vs. 23.4±3.8 vs. 24.7±6.3), more in NYHA I/II (30.8% vs. 33.3% vs. 1.7% vs. 18.9% vs. 24.3%). During the follow-up, all cause mortality was lowest in patients treated with ACEI/ARB+BB+AA (59% vs. 60.4% vs. 75.6% vs. 75% vs. 79.2%). After adjustement for age and gender, when compared with the ACEI/ARB+BB+AA group, the hazard ratio for ACEI/ARB+BB is 1.05 (0.91–1.23), ACEI/ARB+AA 1.16 (0.80–1.68), ACEI/ARB 1.51 (1.11–2.04), and BB 2.36 (1.86–2.98) respectively

Conclusions
In real-world HFrEF patients with low blood pressure and renal dysfunction, full medication of GDMT is associated with improved long-term survival.
P1637Rehospitalisations during 26 weeks of follow up from initiation of sacubitril/valsartan after acute decompensated heart failure: An analysis of the TRANSITION study
Authors: Pascual-Figal D , Witte K K , Wachter R , Belohlavek J , Straburzynska-Migaj E , Fonseca C , Cavusoglu Y , Pouleur A C , Mueller C , Lonn E , Noe A , Schwende H , Bao W , Butylin D , Senni M 
Published: October 2019

Abstract

Background
Patients with acute decompensated heart failure (ADHF) are at high risk of recurrent hospitalisations and death. In-hospital initiation of sacubitril/valsartan (S/V) reduced the risk for HF re-hospitalisation by 44% compared to enalapril in the PIONEER-HF study during the 8-week follow-up period. We aimed to describe the pattern of readmissions and their causes in the TRANSITION study, which randomised participants to pre-discharge or post-discharge initation of S/V.

Methods
TRANSITION (NCT02661217) was a randomised, open-label study comparing S/V initiation pre- vs. post-discharge (1–14 days) in haemodynamically stabilised patients with HF with reduced ejection fraction, admitted for ADHF. The primary endpoint was the proportion of patients achieving 97/103 mg S/V twice daily at 10 weeks post-randomisation. Information on rehospitalisation was collected throughout the study up to 26 weeks.

Results
A total of 493 patients received S/V in the pre-discharge arm and 489 patients in the post-discharge arm. Readmissions due to any cause were reported in 9.7% and 18.1% in the pre-discharge arm vs. 10.6% and 21.3% in the post-discharge arm within 30 days, and 10 weeks respectively. During the 26-weeks follow-up, all-cause readmission was reported in 34.5% of patients in the pre-discharge arm vs. 34.6% in the post-discharge arm. Median time to first rehospitalisation was 67 days in the pre-discharge arm (IQR: 26–110 days) and 50 days (IQR: 23–108 days) in the post-discharge arm. At least one HF hospitalisation was reported in 7.5% of patients in the pre-discharge arm and 7.4% in the post-discharge arm during 10 weeks and in 11.8% and 12.3% of patients, respectively, during 26 weeks of follow-up. Median duration of HF readmission was 7 days (IQR: 4–11 days) in the pre-discharge group and 6.5 days (IQR: 6.5–10 days) in the post-discharge arm. In total 2.6% and 5.5% patients in pre-discharge arm and 3.9% and 7% in the post-discharge arm visited an emergency room during 10 weeks and 26 weeks, respectively.

Conclusions
Initiation of S/V in patients hospitalised for ADHF either before or shortly after discharge, results in comparable rates of all cause and HF rehospitalisations, as well as emergency room visits without hospital admission over the 26 week follow-up period. HF re-hospitalisations rates at 10 weeks in TRANSITION are in line with the 8% in S/V arm reported in PIONEER-HF during the 8-weeks follow-up.

Acknowledgement/Funding
The TRANSITION study was funded by Novartis