bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation between different LDL-R mutations and response to ab-PCSK9 therapy in a group of patient with genetic diagnosis of Familial Hypercholesterolemia. Preliminary report
Authors: Buonaiuto A , Gentile M , Calcaterra I.L , Giacobbe C , Tripaldella M , Forte F , Iannuzzo G , Di Minno M.N.D , Fortunato G , Rubba P.O.F 
Published: November 2020

Abstract

Introduction
Familial hypercholesterolemia (FH) is an autosomal dominant disease that leads to premature cardiovascular disease (CAD). The availability of ab-PCSK9 has changed the approach to therapy.

Purpose
To evaluate the relationship between different types of mutations in LDLR gene and response to ab-PCSK9.

Methods
73 FH patients, 33 women and 40 men (53.9±13. yrs), in primary prevention (N=46) and secondary prevention (N=27), were recruited. This sample included patients with mutations in LDLR gene: heterozygotes for missense mutations (N=31), for null mutations (N=31), compound heterozygotes or homozygotes (N=11). At baseline, the whole sample had a maximally tolerated lipid lowering therapy (MT-LLT) without ab-PCSK9; 16 patients had MT-LLTs intolerance. After 160 days with ab-PCSK9 therapy we evaluated the achievement of a goal (LDL-C&lt;70 mg/dL in primary prevention without Diabetes Mellitus, LDL-C&lt;55 mg/dL).

Results
After 160 days of therapy with ab-PCSK9 (45 patients on Alirocumab, 28 patients on Evolocumab) and MT-LLT, 29/73 patients (39.7%) of the whole sample achieve the goal of LDL-C. Of them 14/29 (48.2%) were in primary prevention, 15/29 (51.7%) in secondary prevention, no difference in achievement of the goal. We then evaluated the percent of patients achieving the goal of LDL-C:
15/31 (48.3%) patients with missense mutation and 14/31 (45.1%) patients with null mutation, no significant difference among groups;
0/11 compound heterozygotes or homozygotes;
3/16 (18.7%) MT-LLTs intolerance.
The other main cardiovascular risk factors did not influence of the achievement the goal of LDL cholesterol.

Conclusions
Lack of correlation between type of mutation in heterozygous FH patients and ab-PCSK9 therapy response; response was significantly poorest in patients with compound heterozygosis or homozygosis mutation as compared to heterozygotes; the intolerance to MT-LLT was significant in the achievement of the goal of LDL-C.
Different between guideline 2016 vs 2019

Funding Acknowledgement
Type of funding source: None
Safety and efficacy of low-dose rivaroxaban in Asian patients with atrial fibrillation and chronic kidney disease
Authors: Liu L , Tseng Y.J , Lin P.L , Chiou W.R , Lee Y.H 
Published: November 2020

Abstract

Background
Low-dose rivaroxaban (10mg/day) has been commonly used in Asia for patients with atrial fibrillation (AF). However, its effectiveness and safety, particularly in patients with chronic kidney disease (CKD), is limited. Moreover, inappropriate low-dose rivaroxaban is frequently prescribed. We aimed to evaluate the effectiveness and safety of low-dose rivaroxaban in patients with or without CKD, compared to that of the standard dose in real-world practice.

Methods
3122 patients with AF treated with rivaroxaban between October 2012 and December 2016 were included in this retrospective multicenter study. We compared the different doses of rivaroxaban stratified according to renal function in this cohort. Bleeding events and major adverse cardiovascular events (MACE) including CV death, MI, stroke, and thromboembolism were recorded.

Results
1218 (39%) patients received standard-dose rivaroxaban (20mg/day). 1147 (36.7%) patients with eGFR&gt;50 mL/min/1.73m2 and 757 (24.3%) patients with eGFR&lt;50 mL/min/1.73m2 received low-dose rivaroxaban (10mg/day). The patients who received low-dose rivaroxaban were older, more likely to be female, and with more comorbidities. After adjustment, the use of low-dose rivaroxaban was significantly associated with increased risks of MACE in the patients without CKD compared to the patients with CKD (HR: 1.75; 95% CI: 1.07 to 2.89). Also, the risk of bleeding was highest in CKD patients despite low-dose rivaroxaban treatment. There was no difference in bleeding between the standard-dose and low-dose of rivaroxaban in patients without CKD (HR: 1.29; 95% CI: 0.8 to 2.08).

Conclusions
The use of inappropriate low-dose rivaroxaban in patients without CKD increased MACE significantly, compared to low-dose rivaroxaban in CKD patients. In addition, the risk of bleeding was strongly associated with CKD, not with the dose of rivaroxaban.
Cumulative Event Rates

Funding Acknowledgement
Type of funding source: None
Meta-analysis comparing the efficacy and safety of direct acting oral anticoagulants to warfarin in patients with atrial fibrillation with and without diabetes
Authors: Shetty S , Malik H 
Published: November 2020

Abstract

Background
Direct-acting oral anticoagulants (DOACs) are now the preferred choice over warfarin in patients with atrial fibrillation (AF). The comparative efficacy and safety of DOACs over warfarin in patients with and without diabetes mellitus (DM) has not been fully evaluated.

Purpose
To evaluate the efficacy and safety of DOACs compared to warfarin in patients with non-valvular atrial fibrillation with and without DM.

Methods
A comprehensive review of the literature was performed to identify RCTs with data on DOACs compared to warfarin in the subgroups of DM and nonN-DM. Our outcome of interest were stroke/systemic embolization (SSE) and major bleeding. A random-effects meta-analysis was performed. We further performed a network meta-analysis to assess the most effective of all the therapies for the above mentioned subgroups.

Results
Our search identified 4 RCTs with 71,683 randomized patients, of which 22,087 were DM and 49,596 were non-DM. The mean duration of follow up was 2.3 years. Our results showed that the DOACS were associated with lower odds for SSE in diabetics (OR 0.80; 95% CI 0.67–0.95; p-value=0.01) and non-diabetics (OR 0.81; 95% CI 0.71–0.92; p-value&lt;0.01). For major bleeding, DOACs were non-inferior to warfarin in DM (OR 0.94; 95% CI 0.80–1.09; p-value=0.42) and non-DM (OR 0.82; 95% CI 0.62–1.07; p-value=0.15). (Fig 1) Network meta-analysis showed that dabigatran was the most effective for the outcome of SSE irrespective of DM status. However, edoxaban and apixaban were the safest of the DOACs for the outcome of major bleeding (Table 1)

Conclusion
In this meta-analysis of RCT, we found that DOACs are more effective and similarly safe compared to warfarin irrespective of the diabetic status of the patient.

Funding Acknowledgement
Type of funding source: None
Implications of presenting to hospital with AF: the REVIEW AF study
Authors: Gallagher C , Wong C.X , Hendriks J.M , Bednarz J , Elliott A.D , Linz D , Middeldorp M.E , Mahajan R , Lau D.H , Sanders P 
Published: November 2020

Abstract

Background
There is a growing burden of hospitalizations due to atrial fibrillation (AF). The implications of hospitalisation to the individual with AF has not been well characterized.

Purpose
To characterise the consequences of presenting to hospital with AF.

Methods
Individuals presenting to the emergency department (ED) of three hospitals in South Australia from March 2013 to February 2014 with a primary diagnosis of AF were enrolled. Based on coding and individual electronic medical record review all re-presentations over follow up were characterised as: 1) AF related; 2) cardiovascular related (excluding AF); or 3) all other causes. Mortality over follow up was also determined.

Results
The study cohort comprised of 437 individuals with an AF related index presentation. Mean age was 69±15 years and 49.9% were male. Individuals were followed for a mean of 3.7±0.4 years. There were 2304 unplanned presentations over follow up. The percentage of the study cohort who presented to the ED or were admitted to hospital over follow up is detailed in Figure 1. Compared to individuals who did not have a hospital admission for AF over follow up, those who were readmitted for AF were more likely to be hypertensive (63.2% vs 49.3%, p&lt;0.001); and have a higher CHA2DS2-VASc score (3.2±1.8 vs 2.7±1.9, p=0.002) and HAS-BLED score (2.0±1.0 vs 1.5±1.1, p&lt;0.001). A total of 71 individuals (16.2%) died during the follow-up period (annual mortality rate of 3.78%).

Conclusions
A hospital presentation with a primary diagnosis of AF identifies individuals at high risk of repeat hospitalisations and death. Urgent studies are needed to improve management of this high-risk cohort.
Figure 1. Repeat hospital presentations in AF

Funding Acknowledgement
Type of funding source: None
A combined digital and organizational approach dramatically improves access to outpatient care in cardiology
Authors: Jamal F , Boiron F , Tettoni C , Couvert I , Ielissof C , Fasciani S , Zebrowski P.A , Dussardier F , Schloter N , Amaral A 
Published: November 2020

Abstract

We have previously shown that digital preconsultation saves medical time and may improve outcome. But waiting times for a cardiology consultation are still growing mainly due to chronic diseases, aging and a growing demand for prevention.

Purpose
We aimed to evaluate the impact of a combined approach using digital tools and a novel outpatient team organization on access to care, in real life

Methods
We implemented a full digital solution and a dedicated team in a new outpatient cardiology center (Figure). The organization was schematically divided in five parts: (1) digital PRECONSULTATION completed by the patient with an assistant and nurse support if necessary; (2) digital AI-NALYSIS of this data with a trained nurse validation to define the risk level; (3) Medical CONSULTATION either physical or using teleconsultation; (4) RESULTS: directly accessible to the patient and his GP; (5) FOLLOW-UP if relevant mainly based on digital tools and trained nurses. Activity was monitored for 9 months. The following parameters were measured: waiting time (from demand to consultation); medical efficiency (number of consultations/hour of work); patient overall satisfaction

Results
2867 consultations were performed between April and December 2019, with a waiting time of 4.3±1.6 days (compared to a national average of 61 days). Efficiency averaged 2.3 patients/hour. Patient satisfaction averaged 4.84 over 5.
In addition, 160 possible consultations in the emergency room were avoided (mainly mild palpitations and non-cardiac chest pain)

Conclusion
A specific digital platform and a dedicated medical team and organization improved the access to care and the medical efficiency. We believe this is a promising way to decrease the demand burden in the emergency room, to decrease the professional burnout risk and to improve prevention.
Figure 1. A Phygital care path

Funding Acknowledgement
Type of funding source: Private company. Main funding source(s): Cardioparc, Izycardio
Health economic evaluation of screening and treating children with familial hypercholesterolemia early in life: many happy returns on investment?
Authors: Ademi Z , Norman R , Pang J , Liew D , Zoungas S , Sijbrands E , Ference B.A , Wiegman A , Watts G 
Published: November 2020

Abstract

Background
There are no studies that have specifically investigated the cost-effectiveness of cascade screening of children for heterozygous familial hypercholesterolemia (FH) and treatment of affected individuals with statins to prevent coronary heart disease (CHD).

Purpose
This study explores the cost-effectiveness of this strategy from the perspective of the Australian public healthcare system.

Methods
A lifetime Markov model with four health states (Alive without CHD, Alive with CHD, Dead from fatal CHD, and Dead from other causes) was developed to simulate the progression of ten- year-old children screened for FH and treated immediately with statins if found to have FH. The underlying prevalence of FH in this target population was assumed to be 56.8%, and the sensitivity and specificity of testing was 100%. The comparator was usual care, which assumed that subjects started statins spontaneously at a later point or when they experienced a cardiovascular event. The effect of reducing low-density lipoprotein cholesterol (LDL-C) on the risk of a first event at each age assumed that risk was proportional to total lifetime exposure and was implemented using Mendelian randomisation analysis data. Cost and other outcome data were sourced from published sources. Outcome of interests were costs in Australian dollars (AUD), life years gained (LYG) and quality-adjusted life years (QALYs) gained, as well as incremental cost-effectiveness ratios (ICERs) of costs per LYG and per QALY gained. All future costs and outcomes were discounted by 5% annually.

Results
Undiscounted results showed that compared with usual care, cascade screening of ten year-old children for FH and initiation of treatment of affected individuals saved 7.77 LYG and 7.53 QALYs per person over a lifetime. With 5% annual discounting, there were 0.97 LYG and 1.07 QALYs gained per person, at an additional cost of $3,244. These equated to ICERs of $3334 per LYG and $3023 per QALY gained. The equivalent ICERs in USD would be $5089 per LYG gained and $4615 per QALY gained. Sensitivity analysis showed the results to be robust.

Conclusions
Compared to usual care, cascade screening of ten year old children for FH and treating affected individuals is likely to be highly cost-effective.
Table 1. Granular cost and benefit data

Funding Acknowledgement
Type of funding source: None
Cholinergic regulation of cardiac pacemaker activity by l-type cav1.3 channels
Authors: Talssi L , Bidaud I , Mesirca P , Mangoni M 
Published: November 2020

Abstract

Introduction
The cholinergic regulation of heart rate (HR) is mediated by acetylcholine (ACh)-dependent activation of M2-receptors (M2R). Activated M2R promote release of the βγ-subunit of G-proteins to directly gate GIRK1/4 channels (underlying the cardiac IKACh current), while αi-subunits inhibit adenylate cyclase (AC) activity. AC inhibition reduces the intracellular concentration of cAMP, decreasing the activity of ion channels involved in pacemaking, including “funny” f-(HCN4) and L-type Cav1.3 calcium channels.

Purpose
To determine the importance of L-type Cav1.3 channels in the cholinergic regulation of heart rate.

Methods
We recorded the frequency and the position of the pacemaker leading site in ex vivo sinus nodes and the HR of isolated Langendorff perfused hearts of mice in control or during ACh perfusion. We used control wild type (WT) mice, and five genetically modified mouse models: Cav1.3 knockout (KO, ablated Cav1.3-mediated L-type current), GIRK4KO (ablated IKACh current), HCN4-CNBD (selective deletion of cAMP-dependent regulation of HCN4), GIRK4KO/HCN4-CNBD and GIRK4KO/Cav1.3KO.

Results
Data from optical mapping experiments showed that, under basal conditions, perfusion of 3 μM ACh significantly reduced the frequency of action potentials in WT (44%), HCN4-CNBD (38%), Cav1.3KO (65%) and GIRK4KO (8%) isolated mouse sinus node tissues. ACh application did not significantly affect the frequency of action potentials recorded in tissue from GIRK4KO/HCN4-CNBD and GIRK4KO/Cav1.3KO animals. Furthermore, in all the sinus node tissues tested, regardless of the genotypes, ACh shifted the pacemaker leading site from its normal position by at least 0.7 mm.
Upon stimulation of the β-adrenergic pathway by Isoproterenol, to reproduce conditions of accentuated antagonism, 3μM ACh reduced HR in isolated hearts from WT (43.8%), HCN4-CNBD (38.7%), Cav1.3KO (25,4%), GIRK4KO (16.9%) and GIRK4KO/HCN4-CNBD (16.4%) mice. No significant HR reduction was recorded in hearts from GIRK4KO/Cav1.3KO animals.

Conclusion
Our data indicate that L-type Cav1.3 channels are involved in cholinergic regulation of heart rate in mice. In addition, when the intracellular concentration of cAMP is elevated (i.e. under conditions of accentuated antagonism), the cholinergic regulation of sinus node pacemaking is predominantly ensured by Cav1.3 and KACh channels.

Funding Acknowledgement
Type of funding source: Foundation. Main funding source(s): “Fondation pour la recherche medicale” FRM
Usefulness of collaboration between mathematical models and cell engineering for elucidating complex disease mechanisms and discover effective drugs
Authors: Kohjitani H , Kashiwa A , Makiyama T , Toyoda F , Yamamoto Y , Wuriyanghai Y , Ohno S , Aizawa T , Imamura T , Shizuta S , Kimura T 
Published: November 2020

Abstract

Background
A missense mutation, CACNA1C-E1115K, located in the cardiac L-type calcium channel (LTCC), was recently reported to be associated with diverse arrhythmias. Several studies reported in-vivo and in-vitro modeling of this mutation, but actual mechanism and target drug of this disease has not been clarified due to its complex ion-mechanisms.

Objective
To reveal the mechanism of this diverse arrhythmogenic phenotype using combination of in-vitro and in-silico model.

Methods and results
Cell-Engineering Phase: We generated human induced pluripotent stem cell (hiPSC) from a patient carrying heterozygous CACNA1C-E1115K and differentiated into cardiomyocytes. Spontaneous APs were recorded from spontaneously beating single cardiomyocytes by using the perforated patch-clamp technique.
Mathematical-Modeling Phase: We newly developed ICaL-mutation mathematical model, fitted into experimental data, including its impaired ion selectivity. Furthermore, we installed this mathematical model into hiPSC-CM simulation model.
Collaboration Phase: Mutant in-silico model showed APD prolongation and frequent early afterdepolarization (EAD), which are same as in-vitro model. In-silico model revealed this EAD was mostly related to robust late-mode of sodium current occurred by Na+ overload and suggested that mexiletine is capable of reducing arrhythmia. Afterward, we applicated mexiletine onto hiPSC-CMs mutant model and found mexiletine suppress EADs.

Conclusions
Precise in-silico disease model can elucidate complicated ion currents and contribute predicting result of drug-testing.

Funding Acknowledgement
Type of funding source: Public Institution(s). Main funding source(s): Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists
MicroRNA-330-5p inhibits NLRP3 inflammasome-mediated myocardial ischemia-reperfusion injury by targeting TIM3
Authors: Zuo W , Tian R , Chen Q , Wang L , Gu Q , Huang C.M , Yang X.L , Xu L.H , Zhang B , Liu Z.Y 
Published: November 2020

Abstract

Background
Myocardial ischemia-reperfusion injury (MIRI) is one of the leading causes of human death. Nod-like receptor protein-3 (NLRP3) inflammasome signaling pathway involved in the pathogenesis of MIRI. However, the upstream regulating mechanisms of NLRP3 at molecular level remains unknown.

Purpose
This study investigated the role of microRNA330-5p (miR-330-5p) in NLRP3 inflammasome-mediated MIRI and the associated mechanism.

Methods
Mice underwent 45 min occlusion of the left anterior descending coronary artery followed by different times of reperfusion. Myocardial miR-330-5p expression was examined by quantitative polymerase chain reaction (PCR), and miR-330-5p antagomir and agomir were used to regulate miR-330-5p expression. To evaluate the role of miR-330-5p in MIRI, Evans Blue (EB)/2, 3, 5-triphenyltetrazolium chloride (TTC) staining, echocardiography, and immunoblotting were used to assess infarct volume, cardiac function, and NLRP3 inflammasome activation, respectively. Further, in vitro myocardial ischemia-reperfusion model was established in cardiomyocytes (H9C2 cell line). A luciferase binding assay was used to examine whether miR-330-5p directly bound to T-cell immunoglobulin domain and mucin domain-containing molecule-3 (TIM3). Finally, the role of miR-330-5p/TIM3 axis in regulating apoptosis and NLRP3 inflammasome formation were evaluated using flow cytometry assay and immunofluorescence staining.

Results
Compared to the model group, inhibiting miR-330-5p significantly aggravated MIRI resulting in increased infarct volume (58.09±6.39% vs. 37.82±8.86%, P&lt;0.01) and more severe cardiac dysfunction (left ventricular ejection fraction [LVEF] 12.77%±6.07% vs. 27.44%±4.47%, P&lt;0.01; left ventricular end-diastolic volume [LVEDV] 147.18±25.82 vs. 101.31±33.20, P&lt;0.05; left ventricular end-systolic volume [LVESV] 129.11±30.17 vs. 74.29±28.54, P&lt;0.05). Moreover, inhibiting miR-330-5p significantly increased the levels of NLRP3 inflammasome related proteins including caspase-1 (0.80±0.083 vs. 0.60±0.062, P&lt;0.05), interleukin (IL)-1β (0.87±0.053 vs. 0.79±0.083, P&lt;0.05), IL-18 (0.52±0.063 vs. 0.49±0.098, P&lt;0.05) and tissue necrosis factor (TNF)-α (1.47±0.17 vs. 1.03±0.11, P&lt;0.05). Furthermore, TIM3 was confirmed as a potential target of miR-330-5p. As predicted, suppression of TIM3 by small interfering RNA (siRNA) ameliorated the anti-miR-330-5p-mediated apoptosis of cardiomyocytes and activation of NLRP3 inflammasome signaling pathway (Figure 1).

Conclusion
Overall, our study indicated that miR-330-5p/TIM3 axis involved in the regulating mechanism of NLRP3 inflammasome-mediated myocardial ischemia-reperfusion injury.
Figure 1

Funding Acknowledgement
Type of funding source: Foundation. Main funding source(s): National Natural Science Foundation of China Grants
Systemic mesenchymal stem cell-derived exosomes reduce myocardial infarct size: characterization with MRI in a porcine model
Authors: Charles C.J , Li R.R , Yeung T , Mazlan S.M.I , Lai R.C , De Kleijn D.P.V , Lim S.K , Richards A.M 
Published: November 2020

Abstract

Background
Mesenchymal stem cells (MSCs) have been shown to exert cardiac protection and repair via their secretome with the active component(s) identified as exosomes.

Purpose
To determine whether MSC-derived exosomes administered systemically by the convenient method of intravenous (IV) bolus injection reduce infarct size and improve cardiac function in an established porcine model of myocardial infarction (MI).

Methods
A total of 20 pigs underwent experimental MI by permanent ligation of the left circumflex coronary artery (LCX). Ten pigs (exosome treated) received twice daily IV injection of exosomes (1000ug protein equivalent) for 7 days. The remaining 10 pigs received vehicle control injections. Cardiac structure and function were measured by MRI which was performed at baseline (pre-MI) and repeated on days 7 and 28 post-MI. Infarct size was also confirmed post-mortem. Blood samples were drawn over first 7 days for measurement of hs Troponin T. The study followed the principles of laboratory animal care and was approved by our institution's IACUC.

Results
All LCX ligations resulted in permanent ischaemia with MI as evidenced by pallor of the myocardium, ECG changes including ST segment elevation and increases in plasma hs Troponin T. Exosomes administered IV for 7 days resulted in clear reduction (30–40%) of infarct size measured at both 7 (p&lt;0.05) and 28 days (p&lt;0.01) post-MI, despite near identical release of hs Troponin T. Together with reduced infarct size, exosome treatment reduced transmurality and lessened wall thinning (p&lt;0.01) in the infarct zone. Exosome treated pigs showed relative preservation of LV function with significant amelioration of falls in fractional wall thickening (p&lt;0.01) compared with control. However, global measures of LV function were less protected by exosome treatment. It is possible that greater preservation of global LV function may have been attenuated by increased cardiac fibrosis, as T1 values showed significant increase in the exosome pigs compared to control particularly in the infarct related segments.

Conclusion
Taken together, our results show clear effects of IV exosomes administered over 7 days to reduce infarct size with relatively preserved cardiac function compared to control treated infarct pigs.
Figure 1

Funding Acknowledgement
Type of funding source: Public grant(s) – National budget only. Main funding source(s): STaR Award (AM Richards), National Medical Research Council, Singapore. IAF-ICP, National Research Foundation, Singapore (RC Lai and SK Lim).