bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of device detected atrial high rate episodes with embolic events
Authors: Tao M , Despotidis G , Moussa S , Gier C , Kim P , Henriques M , Rahman T
Published: November 2023

Background

Subclinical atrial fibrillation (AFib) is a common etiology of embolic events such as embolic strokes of undetermined source. With the advent of cardiac implantable electronic devices (CIED), there has been increased detection of subclinical AFib, or atrial high rate episodes (AHRE) in asymptomatic patients without a known diagnosis of AFib. The clinical significance of AHRE detected with CIED remains poorly characterized with studies reporting conflicting results. The purpose of this meta-analysis is to evaluate the association of AHRE with cerebrovascular accidents (CVA), transient ischemic attacks (TIA), and systemic embolic events.

Methods

A literature search was conducted for studies reporting on the association of subclinical AFib or AHRE with CVA, TIA, and systemic embolic events. The search included the following databases: Ovid MEDLINE, EMBASE, Google Scholar, and Web of Science. The search was not restricted to time or publication status.

Results

A total of 19 studies and 50,968 patients (12,879 with AHRE vs 38,089 without AHRE) were included. Mean follow-up was 32 months, mean age was 72 years old, 53.3% were male. Patients with device detected AHRE had increased risk of composite endpoint of CVA, TIA, and systemic embolic events (OR 2.98, 95% CI 2.03-4.39; P<0.01). Subgroup analysis by maximum AHRE burden demonstrated that both maximum AHRE burden >24 hours and burden <24 hours are associated with increased risk of CVA, TIA, and systemic embolic events (OR 4.82, 95% CI 2.07-11.24; p<0.01; OR 1.55, 95% CI 1.11-2.15; p<0.01). The overall effect size is larger for maximum AHRE burden >24 hours compared to <24 hours (Z=3.64 vs Z=2.61).

Conclusions

Our results suggest that AHRE detected with CIED is associated with increased risk of CVA, TIA, and systemic embolic events regardless of maximum AHRE burden >24 hours or <24 hours. Additional studies are required to determine the utility anticoagulation therapy for treatment of asymptomatic patients with device detected AHRE.
Systematic review and meta-analysis of increased ischemic heart disease vulnerability in schizophrenia patients
Authors: Wang J , Hoydal M A
Published: November 2023

Background

Ischemic heart disease (IHD) is the leading cause of death in Europe and worldwide and past studies have shown its unusually high prevalence in schizophrenia patients. We conducted the first review to synthesise the prevalence of ischemic heart disease (IHD) in schizophrenia patients of the developed world in a quantitative review using the PRISMA standards (Preferred Reporting Items for Systematic Reviews and Meta-Analysis).

Purpose

The aim of this systematic review and meta-analysis is to assess the current state of research on the prevalence of ischemic heart disease in schizophrenia patients in the developed world.

Methods

Studies included were primary research in the form of population-based cohort studies for both males and females. Articles that were not in English, not peer-reviewed, were unspecific in cardiac conditions and mental illnesses, or of an unsuitable data type were excluded. The searches were conducted in PubMed and Embase (Ovid) on 12th of October 2022, and last updated on January 4th, 2023. Data were extracted and analysed in R for meta-analysis, with possible biases investigated. The protocol and review were carried out in accordance with the PRISMA guidelines and are accessible online at Open Science Framework.

Results

Five population-based longitudinal cohort studies were included from various regions of the developed world, four of which were meta-analysed. In all studies, schizophrenia patients had a higher risk of IHD than controls, which was supported by the meta-analysis indicating that schizophrenics are 1.66 times more likely to develop IHD (HR = 1.66; 95%CI: 1.30-2.12; p<0.01). However, the analyses displayed significant heterogeneity (I2 = 82%). Furthermore, all studies demonstrated a particularly concerning vulnerability for IHD among female and younger schizophrenia patients.

Conclusions

This review demonstrated a significant increase in the risk of IHD among schizophrenia patients, particularly in younger age groups and females. Although the small number of studies with diverse patient characteristics (inpatient or both inpatient and outpatient) in each study limited the precision of the overall hazard ratio, the meta-analysis confirmed the negative trend presented in the review process. The especially broad coverage of the sample population in the publications has suggested that this risk has persisted throughout the socio-economic and medical advancements in the developed world since the Second World War.
Prognostic significance of pulmonary hypertension in patients with connective tissue disorders: review and meta-analysis
Authors: Gegenava M , Gegenava T
Published: November 2023

Background

Pulmonary hypertension (PH) is a frequent complication of connective tissue disorders (CTD) with major impact on prognosis of the disease, especially in patients with systemic sclerosis (SSc). Recently suggested new classification based on the hemodynamic assessment of PH and currently available pharmacologic treatment can be associated with improved survival, therefore underlining the group of the patients with PH and most affected survival function is crucial.

Objectives of our study were to perform systemic review and meta-analysis of published literature evaluating survival function in patients with SSc and Systemic lupus erythematosus (SLE) with and without PH, also to compare PH-associated survival function in between patients with SSc, systemic lupus erythematosus (SLE), other connective tissue disorders (CTD) and conditions characterized with PH.

Methods

Literature search strategies, inclusion and exclusion criteria, outcome measurements, and statistical methods were analyzed according to an established protocol of the cochrane collaboration steps and meta-analysis of observational studies in epidemiology recommendations (MOOSE). Case control studies evaluating PH-associated survival function in SSc (including interstitial lung disease -ILD) and SLE patients and also studies comparing survival function among SSc, various CTD entities and conditions associated with PH were included in the analysis.

Results

A total of 2114 papers were collected according to our searching criteria, of those 7 studies including 1470 SSc patients with PH and 1368 SSc patients without PH, also 4 studies including 108 SLE patients with PH and 1288 SLE patients without PH and evaluated survival function were selected. We also performed meta-analysis of 6 studies (including 777 SSc, 249 SLE, 41 idiopathic PH (IPH), 49 primary PH (PPH) and 29 primary Sjogren’s syndrome (pSS) patients) comparing PH-associated survival function in different subgroups. The mean pooled follow-up was 5.4 years (5.4±4.4 year). We observed that SSc patients with PH showed worst survival as compared to SSc patients without PH [RR (95 %CI) 2.20 (1.52 to 3.20); p<0.00001] (Figure1). Same pattern was observed in patients with SLE [RR (95 %CI) 5.20 (2.34 to 11.56); p<0.00001] (Figure 1). Overall, SSc patients with PH were characterized with lower survival function as compared to other reasons of PH including SLE [RR (95 %CI) 1.77 (1.43 to 2.19); p<0.00001] (Figure 2).

Conclusions

Patients with SSc associated PH are characterized with significantly lower survival function as compared to SSc patients without PH. Among various CTD and other entities of PH, SSc shows worst survival, underlining prognostic significance of detection and evaluation of PH according to currently established approach.Figure 1Figure 2
Investigating the cardiac manifestations of IgG4-related disease using cardiac magnetic resonance imaging
Authors: Henry J A , Xavier R , Selvaraj E , Burrage M K , Thomas K E , Lukaschuk E , Ferreira V M , Piechnik S , Neubauer S , Rider O J , Culver E , Lewis A J M
Published: November 2023

Introduction

IgG4-related disease (IgG4-RD) is a relapsing-remitting immune-mediated condition that affects multiple organ systems. Case reports of suspected cardiovascular involvement in IgG4-RD have emerged though no study has systematically assessed the cardiovascular phenotype of IgG4-RD using cardiac magnetic resonance (CMR) imaging.

Purpose

We systematically assessed patients with IgG4-RD using CMR to identify the cardiovascular manifestations, and compared them to controls.

Methods

We recruited 11 patients with histologically-confirmed IgG4-RD (6 female, 61±11 years, 9 with active disease (8 with pancreatic involvement, 3 parotid, 5 bile ducts, 5 kidneys and 3 cardiovascular)). Patients underwent CMR at 1.5T including cine, myocardial tagging, native T1-mapping, late gadolinium enhancement (LGE), extracellular volume (ECV) and quantitative stress perfusion mapping. Results were compared to 10 healthy controls with no cardiac disease (50% female, 35±8 years). Results are presented as mean ± standard deviation (SD) unless otherwise stated.

Results

Patients with IgG4-RD had similar cardiac geometry to the reference group (Table 1), with similar biventricular and bi-atrial volumes. However, despite similar biventricular ejection fractions compared to controls (patient LVEF: 55-67%, RVEF: 51-65%), IgG4-RD patients showed significantly reduced global longitudinal strain (GLS) (-16.8 ± 2.3% vs -18.7 ± 1.6%, p=0.045). Furthermore, 64% (7/11) of IgG4-RD patients showed LGE, 6 of whom showed non-ischaemic patterns (Figure 1). Male IgG4-RD patients (n=5) as a group showed a significantly higher average myocardial T1 value relative to the reference group, with 3/5 male patients having an abnormally high myocardial T1 (above the 2SD limit of normal). Female IgG4-RD patients (n=6) had similar and normal myocardial T1 values to the reference group. ECV did not significantly differ between the two groups. IgG4-RD patients showed a significantly reduced global myocardial perfusion reserve (MPR), including two patients with a qualitative inducible perfusion defect. Only 3 out of the 11 IgG4-RD patients had a completely normal CMR.

Conclusion

Patients with IgG4-RD show frequent cardiac abnormalities as revealed by advanced CMR phenotyping. These include subclinical systolic dysfunction, ischaemic and non-ischaemic myocardial fibrosis, reduced myocardial perfusion reserve, and elevated myocardial T1 times. These abnormalities have been described in inflammatory cardiovascular diseases, supporting a plausible pathophysiological link with IgG4-RD. Future work in larger and multicentre cohorts is warranted, to systematically define the novel cardiovascular phenotype of IgG4-RD.Table 1Figure 1
Longitudinal myocardial deformation and its improvement after treatment has an additive prognostic value to SCORE2 in psoriasis: a 4-year follow-up study
Authors: Ikonomidis I , Makavos G , Lambadiari V , Koliou G A , Pavlidis G , Thymis J , Rafouli-Stergiou P , Kostelli G , Katogiannis K , Kountouri A , Lazarou V , Theodoropoulos K , Frogoudaki A , Katsimbri P , Papadavid E
Published: November 2023

Background/Introduction

Psoriasis has been associated with increased cardiovascular risk.

Purpose

We investigated whether markers of cardiovascular function and their change after treatment have a prognostic value for adverse outcomes.

Methods

In a prospective study, at baseline and after 6 months of treatment with biological agents, we assessed in 298 psoriasis patients a) left ventricular (LV) global longitudinal strain (GLS) and b) carotid-femoral pulse wave velocity (PWV), to evaluate their prognostic value for the composite endpoint of major adverse cardiovascular events (MACE), including coronary artery disease, stroke, hospitalization for heart failure and all-cause death over a 4 year follow-up period.

Results

During follow-up, 26 (8.7%) MACE were recorded. By univariate analysis, decreasing absolute GLS values (hazard ratio [HR]: 0.73, p<0.001), decreasing GLS change after treatment (HR: 0.53, p=0.008) and increasing PWV values (HR: 1.16 p=0.049) were associated with adverse outcomes. Baseline GLS and its change post-treatment remained independent predictors of adverse events after adjusting for several confounders (p<0.05). The addition of baseline GLS and its absolute change post-treatment to SCORE2, increased Harrell’s C from 0.882 to 0.941. By multivariable analysis, for each 1% increase in absolute baseline GLS values, the risk of MACE decreased by 33% and for each 1% absolute increase of GLS post treatment compared to the baseline value, the risk of MACE decreased by 58%.

Conclusion

Global longitudinal strain has an independent and additive prognostic value to SCORE2 for adverse cardiovascular events in psoriasis, providing timely decision-making for intensive anti-inflammatory treatment and aggressive modification of risk factors to reduce cardiovascular risk.
Cardiac involvement in Behcet's syndrome: a case series of 32 patients
Authors: Chadli S , Khibri H , El Fari F , Bourkia M , Moatassim N , Ammouri W , Maamar M , Harmouche H , Adnaoui M , Tazi Mezalek Z
Published: November 2023

Background and Aims

Behçet syndrome (BS) is a complex multisystemic vasculitis of unknown exact etiology. Cardiac involvement (CI) is rarely described, yet associated with high morbidity and mortality rates. Our work aims to depict the profile and outcomes of BS patients presenting with cardiac lesions.

Methods

This descriptive and monocentric study was retrospectively carried out between 2000 and 2022, among 531 patients admitted to our department for BS.

Results

32 cases of CI were enrolled (6%). The sex ratio (M/F) was 3:1 and the mean age was 30 ± 7 years (21-48). Cardiovascular risk factors comprised smoking (21%), high blood pressure (15%), and diabetes mellitus (11%). CI was mostly asymptomatic (71%), discovered during systematic screening. Otherwise, patients presented with chest pain (21%), dyspnea (19%), dry cough (18%), and hemoptysis (17%). Inflammatory parameters were elevated in 71% of the cases, with a median ESR of 46 mm/h and CRP of 55 mg/l. Hemostasis parameters were within the normal ranges for all patients. The lesions visualized were right intracardiac thrombosis (79%), pericarditis (34%), coronary thrombosis (12.5%), myocarditis (6%), and endomyocardial fibrosis (3%). Concomitant vascular involvement was frequent (72%), especially thrombotic lesions in the inferior vena cava (23%), pulmonary arteries (21%), lower extremities (15%), cerebral veins (18%), and superior vena cava (9.5%). Arterial aneurysms were also common, mostly located in the pulmonary arteries (25%). Noncardiovascular involvements were mucocutaneous (78%), articular (28%), ocular (43%), neurological (18%), and digestive (3.6%). Patients were treated with colchicine (96%), glucocorticoids (96%), curative anticoagulation (54%), cyclophosphamide (57%), azathioprine (46%), and TNF-a inhibitor (3%). No patient underwent an endovascular procedure. Surgery was performed in 6.3% of the cases. One relapse of intracardiac thrombosis was recorded. Death was documented in five cases.

Conclusions

CI is a serious manifestation of BS. Although rare, it is also fairly underdiagnosed due to its nonspecific features and discrete evolution. Hence, better knowledge of the disease is crucial for early diagnosis and prompt initiation of immunosuppressive therapy.
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

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 >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

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<0.001), SV (rho=-0.568, p<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

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 < 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 < 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

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

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 <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 <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 <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 <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

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

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 >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 > 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

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 >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

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.
Comparison of sodium-glucose cotransporter-2 (SGLT2) inhibitors to reduce cardiovascular and renal outcomes: a network meta-analysis of randomized controlled trials
Authors: Kani R , Watanabe A , Miyamoto Y , Kuno T
Published: November 2023

Background

Although the cardio- and reno-protective benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors have been established, the differences across agents in various populations have yet to be elucidated.

Purpose

To investigate the profiles of each SGLT2 inhibitor in patients from various backgrounds.

Methods

MEDLINE and EMBASE databases were searched in November 2022 to identify randomized controlled trials (RCTs) comparing SGLT2 inhibitor to placebo. To compare each SGLT2 inhibitor, a network meta-analysis was performed. The primary efficacy endpoint was the composite of cardiovascular (CV) mortality and hospitalisations for heart failure (HHF). The secondary efficacy endpoints were all-cause mortality, CV mortality, HHF, kidney disease progression, and acute kidney injury (AKI). We conducted subgroup analyses based on the underlying comorbidities, including diabetes and chronic kidney disease (CKD). Safety endpoints were also assessed between SGLT2 inhibitors in all cohorts.

Results

This study included 19 RCTs with a total of 94,495 participants, investigating empagliflozin, ertugliflozin, dapagliflozin, canagliflozin, and sotagliflozin. Although there were consistent tendencies favouring SGLT2 inhibitors over placebo, no significant difference between SGLT2 inhibitors was manifested for the primary outcome (Figures 1-2). Compared to placebo, empagliflozin and dapagliflozin improved all studied efficacy outcomes in overall population and demonstrated consistent benefits on reduction in primary outcome, HHF, kidney disease progression, and AKI independent of diabetic status. Among patients without CKD, empagliflozin were associated with lower risks of the primary outcome compared to ertugliflozin (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.60-0.98), CV mortality compared to canagliflozin (HR, 0.62; 95% CI, 0.40-0.96) and dapagliflozin (HR, 0.59; 95%CI, 0.39-0.89), and all-cause mortality compared to dapagliflozin (HR, 0.72; 95% CI, 0.52-0.99). All SGLT2 inhibitors increased the occurrence of genital infections. As compared to a placebo, canagliflozin increased the risks of limb amputation (HR, 1.58; 95% CI 1.07-2.35) and fracture (HR, 1.19; 95%CI 1.01-1.40).

Conclusions

SGLT2 inhibitors have comparable efficacy profiles in reducing cardiovascular and renal events. Whilst empagliflozin and dapagliflozin are beneficial even in patients without diabetes, empagliflozin may be an especially reasonable opiton in patients without CKD.Figure 1Figure 2
Empagliflozin in patients with myocardial infarction: an updated meta-analysis
Authors: Abouzid M , Al-Dardery N M , Ghaith H S , Khitiy H , Khaity A
Published: November 2023

Background/Introduction

Empagliflozin is one of the sodium-glucose cotransporter 2 (SGLT2) inhibitors that is used to treat type 2 diabetes and has recently been studied for its potential benefits in patients with myocardial infarction.

Purpose

We performed this meta-analysis to update the present evidence about the safety and efficacy of empagliflozin in patients with myocardial infarction.

Methods

We searched PubMed, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials for relevant randomized controlled trials (RCTs) from inception until February 2023. Records were screened for eligible studies, and all relevant outcomes were pooled as mean difference (MD) or risk ratios (RR) with the corresponding 95% confidence intervals (CI) in the meta-analysis models using Review Manager (RevMan version 5.4).

Results

Pooling data from 9 RCTs (7300 patients) showed that empagliflozin was superior to placebo in terms of cardiovascular death (RR = 0.57, 95% CI [0.46, 0.71], P < 0.00001), hospitalization due to heart failure (RR = 0.62, 95% CI [0.48, 0.79], P =0.0001), and systolic blood pressure (SBP) (MD = - 8.59, 95% CI [-13.26, -3.93], P = 0.0003). The overall effect did not favor either of the two groups in terms of body weight (MD = - 1.03, 95% CI [-4.05, 1.98], P =0.5), diastolic blood pressure (DBP) (MD = - 1.48, 95% CI [-4.36, 1.41], P =0.3), eGFR (MD = 2.19, 95% CI [-0.10, 4.48], P =0.06), HbA1c (MD = - 0.10, 95% CI [-0.41, 0.22], P =0.5), NT-proBNP (MD = - 115.9, 95% CI [-271.5, 39.6], P =0.1), and adverse events (RR = 0.99, 95% CI [0.97, 1.01], P =0.19).

Conclusions

Ultimately, the current evidence suggests that empagliflozin appears to be an effective treatment option for patients with myocardial infarction who are at high risk for death from cardiovascular causes.Figure 1Figure 2
Effects of SGLT2i on reducing risks of cardiovascular events and dementia in atrial fibrillation patients with diabetes mellitus: a nationwide cohort study
Authors: Chen Y , Chang H C , Chien K L , Hsieh Y C , Chung F P , Lin C H , Lip G Y H , Lin Y L , Chen S A
Published: November 2023

Background/Introduction

Patients with atrial fibrillation (AF) are associated with higher risk for cognitive decline and progression to dementia. There are limited data whether sodium-glucose cotransporter-2 inhibitor (SGLT2i) reduces new-onset cognitive dysfunction, especially in Asian patients with AF who also have diabetes mellitus.

Purpose

This study aimed to investigate whether SGLT2i reduces the risks of cardiovascular events and dementia among AF patients with diabetes.

Methods

We identified AF patients with diabetes based on the Taiwan's National Health Insurance Research Database (2016). AF patients without prior dementia history and aged 55-85 years were studied: 810 patients were prescribed SGLT2i for at least 180 days and were matched with 1620 patients without SGLT2i using propensity scores (Figure 1). Cardiovascular and dementia events were followed through the end of 2021. Subtypes of dementia were investigated using competing risk models.

Results

During a follow-up period of 5 years of AF patients with diabetes receiving SGLT2i, as shown in Figure 2, this study provides a detailed insight into the results of survival analyses for clinical outcomes of AF, stroke, total dementia, vascular dementia, all-cause death, and cardiovascular (CV) death. After multivariable adjustment, the risks of AF-related hospitalization (HR: 0.741, 95% CI: 0.563-0.976), stroke (HR: 0.748, 95% CI: 0.599-0.934) and all-cause death (HR: 0.338, 95% CI: 0.245-0.466), were significantly decreased. Both CV death (HR: 0.449, 95% CI: 0.268-0.755) and non-CV death (HR: 0.298, 95% CI: 0.198-0.448) were significantly reduced. SGLT2i use was associated with a significantly decreased risk of total dementia (HR: 0.615, 95% CI: 0.436-0.869) and vascular dementia (HR: 0.419, 95% CI: 0.221-0.793). The reduced risks of Alzheimer’s dementia and other/mixed dementia were not statistically significant. After multivariable adjustment, total dementia and vascular dementia were associated with higher age and stroke events. The beneficial effect on dementia was irrespective of novel oral anticoagulants (NOAC) use, although the SGLT2i benefits were greater in non-warfarin and non-dipeptidyl peptidase 4 (DPP4) users compared to users.

Conclusions

There were decreased risks of AF-related hospitalization, stroke event, all-cause death, and vascular dementia in the users of SGLT2i in AF patients with diabetes. This was irrespective of NOAC use, although the SGLT2i benefits were greater in non-warfarin users compared to warfarin users.Figure 1:Study flow chart