bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sarcoidosis is associated with a higher long-term risk of ischaemic heart disease, venous thromboembolism, and ischaemic stroke: a nationwide study
Authors: Yafasova A , Fosboel E L , Gustafsson F , Petersen J K , Sun G , Rossing K , Koeber L , Butt J H 
Published: November 2023

Abstract

Background
Sarcoidosis shares a number of pathophysiological mechanisms and risk factors with ischaemic heart disease and thromboembolism. Patients with sarcoidosis are at risk of cardiac involvement with heart failure and arrhythmias, but unlike other inflammatory diseases, such as systemic lupus erythematosus and rheumatoid arthritis, data on the risk of ischaemic heart disease, venous thromboembolism, and ischaemic stroke in patients with sarcoidosis are sparse. This may prevent patients with sarcoidosis from the benefits of screening for these cardiovascular diseases.

Purpose
To examine the long-term risk of ischaemic heart disease, venous thromboembolism, and ischaemic stroke in patients with sarcoidosis compared to a matched background population.

Methods
In this Danish nationwide cohort study, all patients &gt;18 years diagnosed with sarcoidosis between 1996-2020 were matched 1:4 by age, sex, and cardiovascular risk factors with individuals from the background population without sarcoidosis. Patients with a history of ischaemic heart disease, venous thromboembolism, and ischaemic stroke were excluded from the sarcoidosis and background population prior to matching. Absolute 10-year risks of outcomes were estimated using the Aalen-Johansen estimator, and rates of outcomes were compared between sarcoidosis patients and the background population using Cox regression.

Results
We identified 15,454 patients with sarcoidosis and 61,816 matched individuals from the background population (median age 43.8 years, 56% males). The median follow-up was 9.4 years. Absolute 10-year risks of outcomes were as follows: ischaemic heart disease, 5.2% (95% confidence interval [CI], 4.8-5.6%) vs. 3.8% (95% CI, 3.6-4.0%) in the sarcoidosis vs. background population; venous thromboembolism, 3.3% (95% CI, 3.0-3.6%) vs. 1.6% (95% CI, 1.5-1.8%) in the sarcoidosis vs. background population; ischaemic stroke, 2.5% (95% CI, 2.2-2.8%) vs. 2.0 (95% CI, 1.9-2.1%) in the sarcoidosis vs. background population. In multivariable Cox regression analysis, sarcoidosis was associated with an increased risk of ischaemic heart disease (hazard ratio [HR] 1.47 [95% CI, 1.31-1.65]), venous thromboembolism (HR 1.99 [95% CI, 1.70-2.31]), and ischaemic stroke (HR 1.41 [95% CI, 1.21-1.64]) compared with the matched background population (Figure 1).

Conclusions
In this nationwide cohort study, sarcoidosis was associated with a higher long-term risk of ischaemic heart disease, venous thromboembolism, and ischaemic stroke compared with a matched background population. Although further studies on pathophysiological mechanisms are needed, it may be relevant to screen for cardiovascular diseases in patients with sarcoidosis, as we do in patients with other inflammatory diseases.
Reduced left ventricular elastance as a novel marker of cardiac dysfunction in patients with severe liver disease
Authors: Dimitroglou Y , Koukos M , Patsourakos D , Tsartsalis D , Valatsou A , Tolis E , Gialeli F , Kalompatsou A , Sakalidis A , Larisa V , Alexopoulou A , Tousoulis D , Aggeli C , Tsioufis K 
Published: November 2023

Abstract

Introduction
Left ventricular (LV) elastance reflects the contractility of the myocardium and is an index of cardiac performance. Liver cirrhosis is characterized by reduced systemic vascular resistance, leading to reduced afterload on the LV. This, combined with increased blood volume, results in increased preload, increased stroke volume and remodeling of the LV. The latter may result to alterations in end-systolic LV elastance (Ees) a parameter that has not been extensively studied in cirrhotics.

Purpose
To investigate the relationship between Ees and the severity of liver cirrhosis.

Methods
We conducted a cross-sectional study in which transthoracic echocardiography was performed in 75 patients with liver cirrhosis (mean age 58.9±8.5 years, 74.7% males). A verified noninvasive single-beat formula was used to calculate Ees. Specifically, Ees was calculated employing systolic and diastolic blood pressures, echo-derived stroke volume (SV), ejection fraction (LVEF) and the estimated normalized ventricular elastance at arterial end-diastole (ENd). The ENd was estimated from a group-averaged value adjusted for individual contractile/loading effects. The Model for End-Stage Liver Disease-Sodium (MELDNa) score, a widely used tool for assessing liver disease severity was also calculated. We compared Ees between patients with MELDNa scores above and below 15, which is the cutoff commonly used to indicate severe liver disease.

Results
Mean Ees in the cohort of the 75 patients was 2.34±0.81mmHg/ml. Ees was correlated with end-systolic LV volume (rho=-0.448, p&lt;0.001), SV (rho=-0.568, p&lt;0.001) and systolic blood pressure (rho=0.283, p=0.014), but not with LVEF. Mean MELDNa score was 15.5±7.3 and 32 (42.7%) of patients had MELDNa score ≥ 15. Mean Ees in patients with MELDNa score above 15 was significantly lower than in patients with MELDNa score below 15 (2.08±0.61mmHg/ml vs 2.54±0.89mmHg/ml, p=0.015). The association remained significant in a multivariate model after adjusting for age, sex, and body surface area (B=-0.426, p=0.015).

Conclusion
Our study demonstrates that patients with severe liver disease have lower Ees, indicating impaired LV function. Ees could be a useful marker for identifying patients with liver cirrhosis who are at increased risk of cardiovascular complications. Further research is needed to better understand the mechanisms underlying this association and to propose therapeutic interventions aimed at improving LV function in this special population.
Characterization and comparison of rhythm disturbances after atrial or arterial switch surgeries for dextro-transposition of the great arteries: a long-term follow-up study
Authors: Marques C , Pinto R A , Proenca T , Carvalho M M , Cabrita A , Costa C M , Amador A F , Calvao J , Oliveira C , Santos L D , Pinho A I , Rocha M , Palma P M , Moreira H S , Cruz C 
Published: November 2023

Abstract

Introduction and objectives
Dextro-transposition of the great arteries (D-TGA) is a congenital heart disease (CHD) palliated with atrial switch (ATR-S) and, more recently, with arterial switch (ART-S). As late complications from ATR-S are expected, novel challenges from ART-S surgery arises. Our aim was to evaluate these patients’ (pts) arrhythmic disturbances after a long-term follow-up.

Methods
We retrospectively analyzed D-TGA pts born between 1974 and 2001 and followed in Adult CHD Outpatient Clinic at a tertiary care hospital. Clinical records were used to collect pts data.

Results
A total of 79 pts were enrolled with a mean follow-up time after surgery of 27±6 years. Pts median age was 27 years-old and 46% were female. 54% were submitted to ATR-S, while 46% underwent ART-S; median age at intervention was 13 months and 10 days, respectively. Focusing arrhythmic events (Table 1), almost all ART-S pts remained in sinus rhythm versus 64% of ATR-S (p=0.002). The latter presented significantly higher frequencies of arrythmias (41% vs 3%, p &lt; 0.001), mainly atrial flutter or fibrillation (26% vs 0%), as well as bradyarrhythmias (12% vs 0%). Chronotropic incompetence was also more frequent after ATR-S (46% vs 9%, p=0.011). Inversely, intraventricular (IV) conduction disturbances were more frequent after ART-S (54% vs 15%, p &lt; 0.001), the majority due to incomplete right bundle branch block. Cardiac Implantable Electronic Devices (CIED) were implanted in 6 pts (5 pacemakers and 1 implantable cardioverter defibrillator) and 1 patient was submitted to catheter ablation of cavotricuspid isthmus, all of them from ATR-S group. The overall median time to first arrhythmia was 23±9 years.

Conclusion
ATR-S presented significantly fewer pts in sinus rhythm and higher rates of chronotropic incompetence, as well as need for CIED. Additionally, ATR-S pts had higher rates of arrhythmia development, namely supraventricular (SV) ones. These findings highlight the advantages of ART-S over ATR-S in reducing SV arrhythmias occurrence. Curiously, IV conduction disturbances, mainly incomplete right bundle brunch block, were more frequent after ART-S. This fact emphasizes the importance of long-term follow-up of all pts, regardless of the initial surgical approach, as ART-S pts were not arrhythmic-free. Our work raises awareness for arrhythmic disturbances in this subgroup of CHD pts, irrespective of surgical strategy adopted.Table 1
Effects of colchicine treatment after myocardial infarction on top of standard therapy: evidence from a preclinical study
Authors: Aimo A , Burchielli S , Aquaro G D , Barison A , Musetti V , Masotti S , Pucci A , Galvez-Monton C , Martinez-Falguera D , Passino C , Emdin M , Bayes-Genis A 
Published: November 2023

Abstract

Background
An intense inflammatory and fibrotic response after myocardial infarction (MI) may lead to scar expansion and left ventricular (LV) remodeling, increasing the risk for ventricular arrhythmias and heart failure. Colchicine is an anti-inflammatory drug that has been reported to improve the outcome of patients with MI; its effects on LV remodeling have not been specifically investigated. We aimed to characterize the effects of the anti-inflammatory drug colchicine in an animal model of reperfused MI.

Methods
In 4-month-old pigs, MI was induced by occluding the LAD artery through an angioplasty balloon for 90 minutes. Pigs surviving MI induction were randomized in a 1:1 fashion to 2 arms:
- control group (n=13): MI induction and reperfusion, standard treatment (the same therapies as in the rat study),
- colchicine group (n=13): MI induction and reperfusion, standard treatment plus colchicine.
The pigs underwent a first CMR scan 72 hours after MI induction, and another CMR at day 30. The pigs were then sacrificed the day after the second CMR. The primary efficacy endpoint was LGE mass (as a percentage of LV mass).

Results
The infarcted area at 72 hours (expressed as absolute mass or as a percentage of the LV mass) and the changes over 1 month did not differ significantly between pigs on colchicine plus standard therapy vs. those on standard therapy alone. When assessing the extent of fibrosis on the explanted hearts (as a percentage of the tissue sample areas) there was a trend toward a lower extent of myocardial fibrosis in pigs on colchicine plus standard therapy (p=0.091). The percent differences in LV volumes, ejection fraction and mass across the two CMR scans did not reach statistical difference.

Conclusions
The results from a pig model of reperfused MI suggest that colchicine has no additional effects to standard MI therapy on MI size and LV remodeling.
Moderate-intensity statin plus ezetimibe combination therapy versus high-intensity statin monotherapy according to baseline LDL-C levels: a prespecified subgroup analysis of RACING Trial
Authors: Lee B , Hong S , Kim J , Rha S , Heo J , Hur S , Choi H , Kim K , Kim J , Kim H , Kim W , Choi Y , Kim B , Hong M , Jang Y 
Published: November 2023

Abstract

Aims
To compare the effects of moderate-intensity statin plus ezetimibe combination therapy to high-intensity statin monotherapy based on baseline low-density lipoprotein cholesterol (LDL-C) levels.

Methods and results
In the RACING trial, 3780 atherosclerotic cardiovascular disease (ASCVD) patients were randomly assigned to moderate-intensity statin plus ezetimibe combination therapy or high-intensity statin monotherapy based on baseline LDL-C levels of &lt;100 mg/dL (n=2817) or ≥100 mg/dL (n=963). In the prespecified analysis, the primary outcome (a composite of cardiovascular death, major cardiovascular event, or stroke at 3 years) and key secondary outcome (achievement of LDL-C &lt;70 mg/dL) were reported according to baseline LDL-C levels. The occurrence of the primary outcome did not differ between the combination therapy and the monotherapy groups among those with lower and higher baseline LDL-C levels (8.6% versus 10.1%, hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.37 to 1.09; and 10.5% versus 9.3%, HR 1.13, 95% CI 0.76 to 1.70, respectively) without an interaction (P=0.232). The 1-, 2-, and 3-year achievement of LDL-C &lt;70 mg/dL was greater in the combination therapy group, regardless of baseline LDL-C levels. For secondary safety outcomes, no significant interactions between the treatment strategies and baseline LDL-C levels were found.

Conclusion
Among ASCVD patients, the effect of moderate-intensity statin plus ezetimibe combination therapy was consistent across the baseline LDL-C levels for the 3-year composite of cardiovascular death, major cardiovascular event, or stroke, and even associated with greater achievement of LDL-C &lt;70 mg/dL compared to high-intensity statin monotherapy.
RBD5044 - a novel anti-ApoC3 GalNAc-siRNA drug resulted in sustained and profound reduction of triglycerides in mice and Rhesus monkeys
Authors: Gao S , Luo H , Guo Z , Zheng S , Wikstrom J , Cao H , Yu H , Tong C , Zhang H , Liang Z , Gan L 
Published: November 2023

Abstract

Introduction
Hypertriglyceridemia leads to endothelial dysfunction and contributes to the onset and progression of atherosclerosis as well as an increased risk of acute pancreatitis. Inhibition of Apolipoprotein-CIII (APOC3) via the RNA interference mechanism is supposed to reduce plasma Triglycerides (TG) levels with durable and high efficacy. RBD5044, which targets APOC3 mRNA in the liver, is a chemically-modified double-stranded small interfering RNA (siRNA) conjugated with N-acetylgalactosamine (Ribo-GalSTAR).

Purpose
To investigate the preclinical efficacy and safety profile of RBD5044.

Methods
Rhesus monkeys with spontaneously developed hypertriglyceridemia were given a single subcutaneous (sc) injection of RBD5044. Humanized APOC3 transgenic mice were treated with a single dose or repeated doses (once every two weeks for three doses, Q2W×3) of RBD5044. Plasma was collected to quantify APOC3 and lipid biomarkers to evaluate preclinical efficacy of RBD5044. SD rats and cynomolgus monkeys were used to evaluate the preclinical toxicology for subcutaneously injected RBD5044, including single-dose toxicity studies and 4-week repeat-dose pivotal toxicology studies.

Results
In the rhesus monkeys with spontaneous hypertriglyceridemia, the maximum level of inhibition reached 61.2 % in APOC3 and resulted in a TG reduction by 53.3%. The levels of both APOC3 and TG were recovered to baseline till Day 85 after a single dose of 3 mg/kg RBD5044. In humanized APOC3 transgenic mice, RBD5044 achieved an average maximum inhibition level of over 90% for APOC3 and around 90% for TG after both single and repeated doses. The APOC3 and TG levels were recovered on Day 63 after a single dose of 3 mg/kg. On Day 63 after the last repeated dose at 3 mg/kg, the inhibition level remained at 41.6% for APOC3 and 49.4% for TG, hence did not recover to baseline within the study period. RBD5044 also showed reductions in total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels and elevations in high-density lipoprotein cholesterol (HDL-C) levels. Toxicology studies showed there is a sufficient therapeutic margin that supports the clinical development of RBD5044 with NOAEL of 40 mg/kg in rats and 300 mg/kg in monkeys.

Conclusions
RBD5044 shows high efficacy, long duration and a good safety profile in preclinical studies. The Phase I trial of RBD5044 injection in healthy volunteers has been initiated in Australia.Figure 1Figure 2
Comparing the drug target effects of Cholesteryl ester transfer protein (CETP) on cardiovascular diseases in East Asian and European populations
Authors: Dunca D , Hingorani A D H , Finan C F , Schmidt A F S 
Published: November 2023

Abstract

Introduction
Cholesteryl ester transfer protein (CETP) is a drug target originally evaluated for raising HDL-C, for efficacy against coronary heart disease (CHD). Previous attempts to develop a licensed drug compound inhibiting CETP have heterogeneous CHD effects, which are likely attributable to the developed compound rather than CETP itself. Currently, novel CETP inhibitors are being pursued for the treatment of CHD. Drug target Mendelian randomization studies, leveraging genetic evidence, have shown that on-target CETP inhibition reduces CHD risk in individuals of European ancestries. However, similar MR studies conducted in East Asian ancestries have failed to show a CHD effect, questioning the value of pharmacological inhibition of CETP in this population.

Purpose
In this study, we compared drug target MR effects of CETP inhibition in Europeans and East Asians, focusing on cardiovascular efficacy outcomes, and relevant safety outcomes.

Methods
We used ancestry-specific GWAS summary statistics for Europeans (n=1,320,016) and East Asians (n=146,492) from the Global Lipids Genetics Consortium, taking variants from within and around ±50 kbp of the CETP locus. Colocalization was employed to determine potential trans-ancestry signals between CETP variants for HDL-C and LDL-C. Subsequently, drug target MR was used to estimate ancestry-specific effects of on-target CETP inhibition on 11 plasma biomarkers and 15 clinical outcomes between East Asian and European populations. Differences between ancestries were evaluated using interaction tests.

Results
There was strong support (posterior probability: 99.8%) of a shared causal CETP variant affecting HDL-C in both populations. Given the absence of a LDL-C signal in East Asians, similar colocalization was not observed for LDL-C. Employing drug target MR scaled to a standard deviation increase in HDL-C, we found that lower CETP had more pronounced decreasing effects in Europeans on LDL-C, LP[a], systolic blood pressure and pulse pressure (interaction p-values &gt;1.9×10-3). Nevertheless, lower CETP protected against CHD, angina, intracerebral haemorrhage, and heart failure in both ancestries, for example for CHD (OR, 0.89; 95%CI, 0.84-0.94) in East Asians, compared to Europeans (OR, 0.95; 95%CI, 0.92-0.99, interaction p-value: 0.05). Exploring potential safety outcomes, lower CETP was protective against pneumonia in Europeans and East Asians (interaction p-value=0.53) and had a potential harmful effect on asthma and chronic kidney disease in East Asians (interaction p-value &gt; 1.9×10-3).

Conclusion
In conclusion, on-target and sufficiently potent CETP inhibition is anticipated to prevent cardiovascular diseases in both European and East Asian populations.
Characteristics of patients initiating PCSK9i mAb following myocardial infarction and comparability of treatment groups in the Netherlands
Authors: Chan Q , Wouter Jukema J , Heintjes E M , Smits L , Lemmens L , Herings R , Dhalwani N , O'kelly J , Sibartie M , Vollebregt R , Cars T , James S , Brookhart A , Hagstrom E 
Published: November 2023

Abstract

Background
The clinical benefits of lipid lowering treatment (LLT) for reducing risk of atherosclerotic cardiovascular disease (ASCVD) are well established. Recent findings support early initiation of proprotein convertase subtilisin/kexin type 9 inhibitors monoclonal antibodies (PCSK9i mAb) to maximize clinical benefit. However, when comparing treatment effects in a real-world setting, it is important to establish comparability of treatment groups and assess and adjust for confounding.

Purpose
To compare clinical characteristics and LLT use in patients initiating and not initiating PCSK9i mAb within 365 days following a myocardial infarction (MI).

Methods
MI events occurring in patients ≥18 years between 1 April 2016 and 31 December 2020 were identified in PHARMO Database Network, a population-based network of electronic healthcare databases linking data from general practitioners, out-patient and in-patient pharmacies and hospitals in the Netherlands. The database has about 3.3 million patients, representative of the Dutch population with respect to age and sex albeit with slight over-representation of those &gt;80 years old. Characteristics of patients were presented by treatment groups: initiating PCSK9i mAb and not initiating PCSK9i mAb within 365 days post-MI. Characteristics and LLT use in the two treatment groups was evaluated.

Results
Of the 28,975 MI events, 157 (0.5%) initiated a PCSK9i mAb within 365 days. Patients who initiated a PCSK9i mAb within 365 days post-MI were younger than those who did not (median age of 63 versus 69 years), more likely to have a history of ASCVD prior to the MI event (56% versus 39%) and dyslipidaemia (55% versus. 28%), while non-initiators were more likely to have diabetes mellitus, chronic kidney disease and atrial fibrillation (Table). Patients who initiated PCSK9i mAb within 365 days post-MI had higher low-density lipoprotein cholesterol levels (3.7 versus 2.9 mmol/L), higher use of ezetimibe (25% versus 4%) and high-intensity statins (15% vs 11%, Figure).

Conclusions
In the Netherlands, despite being at very high risk of recurrent ASCVD, based on this dataset excluding Patient Support Programs, fewer than 1% of patients initiated a PCSK9i mAb within 365 days post-MI. Further analyses are needed to reveal if these treatment groups are comparable to assess differences and uncontrolled confounders in cardiovascular outcomes in the real world.
Canagliflozin improves hemodynamic parameters by impedance cardiography and left ventricular diastolic function in patients with type 2 diabetes mellitus
Authors: Liu L , Kuo H H , Lai Y H , Lin P L , Hung C L 
Published: November 2023

Abstract

Background
Sodium-glucose cotransporter type 2 (SGLT2) inhibitors have been shown to reduce cardiovascular risk in patients with type 2 diabetes mellitus (T2DM) in large trials, independent of glycemic control. The mechanisms behind this cardioprotective effect remain uncertain, although evidence suggests that positive hemodynamic changes and favorable cardiac remodeling may contribute to the clinical outcomes. However, results have been conflicting. The aim of this study was to investigate the potential impact of canagliflozin on hemodynamic parameters, cardiac structure, and function.

Methods
This prospective observational study included T2DM patients receiving canagliflozin 100mg per day in addition to their antidiabetic treatment. We analyzed hemodynamic parameters assessed by impedance cardiography (ICG) and echocardiographic measurements to evaluate systolic and diastolic functions from baseline to 24 weeks after treatment.

Results
A total of 47 patients (25 males and 22 females) with an average age of 64.4±10.8 years experienced a significant reduction in HbA1c, hematocrit, body weight, and systolic blood pressure. NT-proBNP levels remained the same. ICG suggested significant improvement in hemodynamic parameters, with increased stroke volume index and cardiac output index and decreased systemic vascular resistance index at 12 and 24 weeks. E/e’, left atrial (LA) volume, and LA stiffness were reduced, while left ventricular (LV) global longitudinal strain (GLS) and LA strain rates increased at 24 weeks, as measured by conventional and speckle tracking echocardiography. LV mass and ejection fraction showed no differences.

Conclusions
Canagliflozin improved hemodynamic parameters and had a favorable impact on LA and LV reverse remodeling. These changes may explain the beneficial effect on cardiovascular outcomes seen in large clinical trials.