bluuebunny/crossref_metadata_2025_split huggingface dataset:
Embedding a text message recall system to increase the uptake of cardiovascular screening in Australian general practice. Results of the Text to Detect randomised controlled trial
Authors: Raffoul N , Brims K , Knight J , Nelson A , Asham A , Bonner C 
Published: October 2024

Abstract

Background
Australian guidelines recommend cardiovascular disease (CVD) risk screening for adults aged 45-74 years, but less than one in three have blood pressure and cholesterol recorded within their general practitioner (GP) records. Medicare subsidised ‘Heart Health Checks’ were introduced in primary care in 2019, however uptake has been suboptimal.

Purpose
The aims of this study were to; 1) implement a text mediated Heart Health Check recall program within general practice at scale, 2) determine whether uptake can be increased with nudge reminder text messages and 3) evaluate the impact on risk factor measurement and medication prescription.

Methods
Australian general practices were invited via advertisement and mailing list. Medical record software identified patients eligible for a Heart Health Check. Practices were randomised to one of three arms: 1) standard SMS: 1 SMS inviting patients to see their GP for a Heart Health Check, 2) nudge reminder: standard SMS + nudge reminder two weeks later, 3) control: no SMS. Aggregate, deidentified, practice-level data was extracted at baseline and 3-months. The primary outcome was the proportion of Heart Health Checks delivered at a practice level. Secondary outcomes included updated CVD risk factor assessment and new medication prescriptions. Analyses used ANOVA and Tukey's HSD.

Results
Between 2022 and 2023, 206 general practices participated, each with 560 median eligible patients (IQR:297-909). A total of 70,679 recall text messages and 34,406 nudge reminder messages were sent. Heart Health Check uptake was 11 and 16 times higher in the standard and nudge arms (respectively) compared to control (0.4 vs 4.5 vs 6.3 per 100 patients, p&lt;0.001), with a 40% statistically significant increase (p=0.02) for 2 SMS vs 1 SMS. Updated cholesterol values were 31.6 and 60.2% higher in standard and nudge arms (respectively) compared to control (13.7 vs 16.8 vs 17.4 per 100 patients, p=0.02). Both active arms were statistically significantly different from control (standard p=0.047, nudge p=&lt;0.001). Updated blood pressure was 23.0 and 26.8% higher in the standard and nudge arms (respectively) compared to control (13.7 vs 16.8 vs 17.4 per 100 participants), however only the nudge arm was statistically significantly different (p=0.38). New medication prescription (lipid or blood pressure-lowering) was 36.8% higher in the nudge arm compared to control (32.1 vs 43.9 patients per practice, p=0.03).

Conclusions
This study demonstrates the effectiveness of text mediated recall of eligible patients to increase the uptake of cardiovascular risk screening in Australian general practice. The findings will inform the implementation of new Australian guidelines and policy reform.
Analysis of safety and outcome of use of NOAC in intracardiac thrombi over warfarin
Authors: Al-Assaf O , Baaj B , Abumuaileq M , Roqia S , Elberry M , Musa A 
Published: October 2024

Abstract

Introduction
Intracardiac clots occur in 15- 25% of patients post myocardial infarction and in patient with atrial fibrillation. It holds poor outcome if not treated with anticoagulation. Warfarin remains the drug of choice in such patients, however recently according to the newly published data, the European Society of Cardiology (ESC) has recommended non-vitamin K antagonist anticoagulant (NOAC) for intracardiac clots as a class 2A recommendation. There is no documented data in the region of the gulf regarding the use of NOAC in intracardiac clots.

Aim
We aim in this study to evaluate the use of NOAC in the treatment of intracardiac clots over warfarin, by studying the effectiveness, safety and associated complications.

Methodology
A retrospective cohort study from April 2017 to December 2023 was conducted of patient’s above 18 years old who have a documented intracardiac clot on echocardiography. The patient were grouped into patients discharged on NOAC and those discharged on warfarin. The participants were studied for resolution of clot and development of complication; death, bleeding and thrombosis.

Results
A total of 253 patients fulfilled the inclusion criteria. Out of which 45 ( 18%) patients were discharged on NOAC and 208 (82%) on warfarin. The two groups had similar demographics with equally mean age of 71 years old , 89% being males, 38% hypertensive and most common clot in the left ventricle in both groups. From those patients with documented follow up ( NOAC 45% average of 8 months, Warfarin 62% average of 7 months); 48% in the NOAC group had a documented resolution of the clot while 44% in the warfarin group had a documented resolution of the intracardiac clot.(p value of 0.7) The median resolution time in the NOAC group was 4 months while in the warfarin group 3.5 months. Bleeding occurred in 19% and mortality rate was 5% in NOAC group, while in the warfarin group 10% developed bleeding and mortality rate was 6%.

Conclusion
Our data pointed out the safety of NOAC as a reasonable alternative to warfarin inpatient with intracardiac clots emphasizing the ESC recommendation in this regards. We recommend a randomized studies to prove the superiority of NOAC as anticoagulation of choice in intracardiac thrombi.
Cost differences between oral anticoagulation therapies in atrial fibrillation patients
Authors: Lehtonen O , Halminen O , Airaksinen K E J , Haukka J , Putaala J , Mustonen P , Teppo K , Lehto M , Linna M 
Published: October 2024

Abstract

Background
Direct oral anticoagulants (DOACs) have largely replaced warfarin as the primary choice of oral anticoagulation (OAC) in atrial fibrillation (AF) patients. This study uses a nationwide registry data set to compare the health and social care costs of AF patients using different OAC therapies. We studied how these costs were distributed among different care services in the year following AF onset and how the costs develop in time before and after AF diagnosis.

Methods
This study is a part of the Finnish AntiCoagulation in Atrial Fibrillation (FinACAF) research project, which includes data on patients with AF, combining registry data on primary and secondary care services as well as social services, drug purchases and laboratory data. We included all new-onset AF patients from 2011 to 2017 in Finland with an indication for OAC treatment. Patients were divided based on their first OAC purchase. Time in therapeutic range (TTR) values were assessed for warfarin patients, and they were divided into quartiles based on their TTR value.
Standardized costs were determined for different health and social care contacts, accounting for hospital care, primary and ambulatory care, and long-term care. Drug costs were acquired from the Reimbursement for Prescription Medicines registry.

Results
A total of 130,745 patients (66,610 on warfarin, 32,996 on DOACs) were included. First-year total costs after onset of AF were €10,412 for rivaroxaban (n=13,320), €12,631 for apixaban (n=11,886), €10,706 for dabigatran (n=7,514) and €10,689 for edoxaban (n=366). Costs of care clustered near the diagnosis of AF (Figure 1). Costs for warfarin patients increased inversely with TTR, ranging from €10,945 in the highest TTR quartile (TTR over 82%) to €21,387 in the lowest (TTR under 57%). Average first-year costs for warfarin patients were €15,689, higher than DOAC patients by €3,058-€5,277 (Figure 2). Patients without any OAC had the highest first-year costs, €17,898. Patients with high risk of stroke had higher total costs both in patients using DOACS (€7,271 for patients with a CHA2DS2VA score of 1 vs €11,947 for patients with CHA2DS2VA 2+) and warfarin (€9,933 for CHA2DS2VA 1 vs €16,354 for CHA2DS2VA 2+). Drug costs averaged €1,541 for rivaroxaban, €1,659 for apixaban, €1,495 for dabigatran and €1,540 for edoxaban, and €986 warfarin users.
Hospital care was the largest cost driver with 64% of total costs across the whole cohort, followed by primary care (19%), drug purchases (7%), social service costs (6%) and reimbursements for travel and private care (4%).

Conclusions
DOACs were superior to warfarin in a broad range of social and healthcare cost measures despite higher drug expenses. Patients on warfarin with low TTR and patients without any OAC had the highest cost of care.
Sub-Saharan Africa's contribution to clinical trials in international acute coronary syndromes and heart failure guidelines
Authors: Hudson J , Sanga L , Jobe M , Etyang A , Perel P , Ogola E , Shah A S V 
Published: October 2024

Abstract

Introduction
There is a growing burden of acute coronary syndrome (ACS) and heart failure (HF) in sub-Saharan Africa (SSA), yet outcomes remain poor compared to high-income countries (HICs). Global clinical guidelines are pivotal to the delivery of evidence based cardiovascular care, however their applicability to populations in SSA remains unclear.

Purpose
To evaluate the extent to which populations from SSA contribute to pharmacotherapeutic randomised clinical trials informing international ACS and HF clinical guidelines.

Methods
We extracted details on pharmacotherapeutic randomised control trials (RCTs) contributing to Class I or II guideline recommendations from the 2023 European Society of Cardiology (ESC) guidelines for ACS and the 2021 ESC guidelines for HF. Data on RCTs contributing to these guidelines were extracted from the ClinicalTrials.gov or published articles. We analysed the proportion of RCTs which had a contribution from countries in each World Bank income group. Then we specifically assessed the contribution of SSA countries to clinical trials and analysed temporal trends.

Results
Of 119 RCTs from the ESC HF guidelines and the 343 pharmacotherapy RCTs from the ESC ASC guidelines 75.9% were exclusively conducted in high-income countries, 22.2% of the trials included at least one site from a middle-income country and none included sites from a low-income country (figure 1). The global distribution of HF (figure 2a) and ACS (figure 2b) pharmacotherapy guidelines is demonstrated in figure 2. The only country represented from SSA was South Africa which is an upper middle-income country. A site from South Africa was included in 17 (14.2%) HF RCTs and 28 (8.2%) ACS RCTs. There has been a significant increase in the proportion HF RCTs conducted in SSA, increasing from 2.6% between 1990 and 1999 to 50% since 2020 (OR 28.8, 95% CI 2.6 – 983.4, p-value for trend&lt; 0.0001). For ACS RCTs, the proportion of trials conducted in SSA increased from 1.8% pre 1990 to 23.4% during 2000-2009 (OR 15.9, 95% CI 4.2 - 112.9, p value for trend = 0.003) then declined to 11.3% from 2010-2019.

Conclusions
There is a marked under-representation of SSA countries in ACS and HF pharmacotherapy RCTs, despite the region's escalating cardiovascular disease burden. South Africa is the sole contributor from the region, with all other SSA countries absent. This finding could potentially affect the applicability and generalisability of global guidelines to populations in SSA with distinct clinical presentations and healthcare challenges.Figure 1 Figure 2
Impact of glucose fluctuation on the paracrine secretome profile of human epicardial adipocyte
Authors: Kondo H , Takano M , Takahashi N 
Published: October 2024

Abstract

Background
Glucose fluctuations (GF) is known to be the significant factor related to poor cardiovascular outcome in the diabetic patients. We investigated the potential impact of GF on paracrine effect of human epicardial adipocyte on cardiomyocyte.

Methods
Human EAT biopsies obtained during surgery and isolated preadipocyte/adipocytes were used to evaluate the direct impact of GF on the adipocytes. Matured adipocytes were exposed to the media containing normal glucose (100 mg/dl, NG), high glucose (300 mg/dl, HG), or high-low glucose (75-300 mg/dl, GF) for 1 week. Transcriptomic profiling of the cultured matured adipocyte was performed using microarray analysis. The impact of GF on the paracrine effect of adipocyte was evaluated using a co-culture with human iPS-derived atrial cardiomyocytes and the adipocytes. Clinical association study verified the validity of the findings.

Results
GF for 1 week altered the expression of 595 differentially expressed genes (up-regulated or down-regulated) with an effect size of &gt;50% or `−50% and a significant statistical difference (P &lt; 0.05) in human epicardial adipocytes, while the continuous HG for 1 week altered the expression of only 182 differentially expressed genes. Of the genes affected by GF, top 3 most affected genes included IL1β, IL33, IL8. Regarding the other major pro-inflammatory cytokines, IL1α, CCL2 and IL6 were also significantly increased in the adipocyte treated with GF, however these were not increased in the adipocyte treated with HG. Co-culture of human iPS cell-derived atrial cardiomyocytes and adipocytes treated with NG, HG and GF revealed that GF-treated adipocyte strikingly increased oxidative stress in the cardiomyocyte through the paracrine effect. In the real-world clinical association study, IL1β mRNA expression in human epicardial adipose tissue showed significant positive correlation with the severity of GF during hospitalization and oxidative stress in the left atrial myocardium.

Conclusions
GF adversely affect the paracrine secretome profile of human epicardial adipocyte. IL1β may be a critical epicardial adipocyte-derived adipokine that is enhanced by GF.
Cardiomyocyte proliferation is promoted by intracellular Gas6-mediated Yap activity during neonatal heart regeneration
Authors: Liu Y , Zhou W , Xu Y , Xiao Y , Xie W , Ma G , Fan Y 
Published: October 2024

Abstract

Purpose
The adult mammalian heart has limited regenerative capacity after injury, mostly attributable to postnatal cardiomyocyte (CM) cell cycle arrest. The key to unlocking the regenerative potential of the adult hearts may lie within the developmental transitions occurring during neonatal life. Gas6, a secretory protein, stimulates the proliferation of various type cells through binding to TAM receptor family, such as endothelial progenitor cells, tumor cells, and hair follicle stem-cell. However, no study to date has studied the role of Gas6 during the proliferation of CMs. Herein, our study uncovers that Gas6 is transiently expressed during early postnatal heart and regenerative heart, and functions through intracellular pathway by regulating Yap activity to promote CM proliferation.

Methods
CM isolation was conducted to assess the change of Gas6 expression in both postnatal development and regenerated stages using the CM-specific Tdtomato mice. Cardiac deletion of Gas6 gene mice was used to evaluate the impaired heart regeneration. CM-specific Gas6 overexpression mice were generated using adeno-associated virus system to evaluate Gas6 pro-proliferate and protect effect after ischemic injury. Secreted signal peptide truncation (ΔSP-Gas6) and predicted functional region truncation (ΔCC-Gas6) were generated to identify the intracellular mechanism of Gas6 via Sav1/p-mst1/p-lats1/ p-yap axis.

Results
We found that Gas6 expression is enriched in CM4 and the expression profile correlates with the expression of the CM4 marker Acta2, as well as cell-cycle genes Mki67 and Aurora B, in individual CM. Gas6 was highly expressed in the neonatal heart and continued to increase during the neonatal heart regenerative process, but was nearly absent in the adult heart under physiological and ischemia conditions. CM-specific Gas6 deletion resulted in significantly reduced CM proliferation rate and increased CM size in P0 hearts, and congestive heart failure in P28 hearts. Conversely, sustained CM-specific overexpression of Gas6 in postnatal hearts increased CM division, elevated CM numbers, and reduced CM size; and reduced infarct scar area and enhanced cardiac function after ischemia injury. Pre-overexpression of Gas6 in adult CMs protected adult cardiac function against ischemia injury, indicated by the activation of mitosis, angiogenesis and reduced oxidative phosphorylation. In primary neonatal CMs, both Gas6 and ΔSP-Gas6promoted CM proliferation with sarcomere disassembly. Mechanistically, Gas6 interacted with Sav1to inhibit Mst1recruitment and Mst1/Lats1/Yap phosphorylation cascade, therefore, promoted Yap translocation into nucleus.

Conclusions
We demonstrate that Gas6 is an important intrinsic regulator of neonatal heart regeneration, which acts as a promoter of Yap transcriptional activity to enhance CM proliferation. Supplementing Gas6 in the adult heart represents a potential therapeutic approach for cardiac repair.
A Genome-Wide Association Study (GWAS) of Takotsubo syndrome
Authors: Hakansson H F K , Tornvall P 
Published: October 2024

Abstract

Background
Takotsubo syndrome (TS) is an acute cardiac condition of unknown etiology characterized by transient regional systolic dysfunction of the left and/or right ventricle. Several studies have suggested the importance of genetics; however, studies are limited and have presented conflicting results.

Purpose
To identify potential genetic risk variants associated with TS.

Methods
A case-control GWAS in three steps; I) A discovery study with Swedish takotsubo cases (n=260) and age- and sex-matched controls without heart disease from the UK Biobank (n=3034), II) A replication study of Swedish takotsubo cases (n=250) and sex- and age-matched Swedish controls without myocardial infarction from the Swedish coronary angiography and angioplasty register (n=229), III) A Meta-analysis of study I-II with extended controls from the UK-biobank (n=5161). Genotyping was performed using the Axiom® UK Biobank Genotyping Array including 820 000 single nucleotide polymorphisms (SNPs). After applying filters and QC control around 480 000 SNPs remained with a Bonferroni corrected p-value 1*10^-7, minor allele frequency (MAF 1.5-2%), Hardy-Weinberg (HWE) 10^-6. QC, filtering and analysis were performed in PLINK 1.9 and R v 4.0.

Results
In the discovery (I) 1490 SNP:s fulfilled a significance level of &lt;10^-4, of which 36 SNP:s replicated (II) with a significance level of &lt;10^-2, 11 reached a significance level of 10^-7 in the meta-analysis (III). One of the 36 SNP:s, rs1614887, replicated (II) with a significance level of 10^-3. This SNP is an intron variant in the butyrophilin subfamily 2 member A2 gene, a glycoprotein receptor involved in lipid, fatty-acid and sterol metabolism highly expressed in the heart. Of the 11 SNP:s with a significance level of 10^-7 in the meta-analysis (III) several risk variants were associated with psoriasis.

Conclusions
This is the largest GWAS of takotsubo syndrome performed so far, identifying one candidate gene and several potential risk variants. Further research of genetic risk variants in TS is warranted.
Empagliflozin treatment rescues abnormally reduced Na+ currents in ventricular cardiomyocytes from dystrophin-deficient mdx mice
Authors: Sauer J , Marksteiner J , Lilliu E , Hackl B , Todt H , Kubista H , Dostal C , Podesser B , Kiss A , Koenig X , Hilber K 
Published: October 2024

Abstract

Background
Cardiac arrhythmias represent a major cause of death in Duchenne muscular dystrophy (DMD), a devastating muscle disease caused by dystrophin deficiency. An important source for arrhythmia vulnerability in DMD patients is impaired ventricular impulse conduction, which predisposes for ventricular asynchrony, and the development of reentrant circuits. Using the dystrophin-deficient mdx mouse model for DMD, we and others previously reported that the absence of dystrophin results in a significant peak Na+ current (INa) loss both in ventricular cardiomyocytes of the working myocardium, and in Purkinje fibers, ventricular myocytes specialized for rapid electrical impulse conduction. This finding provided a mechanistic explanation for ventricular conduction defects and concomitant arrhythmias in the dystrophic heart.

Purpose
In the present study, we tested the hypothesis that empagliflozin (EMPA), an inhibitor of sodium/glucose cotransporter 2 in clinical use to treat type II diabetes and nondiabetic heart failure, rescues the loss of peak INa in dystrophin-deficient ventricular cardiomyocytes.

Methods
In a first set of experiments, we treated a cohort of mdx mice with 15 mg/kg body weight/day EMPA via the drinking water. After 4 weeks of treatment, ventricular cardiomyocytes were isolated from these mice, as well as from untreated wild-type and mdx control mice, via Langendorff heart perfusion and enzymatic digestion. Peak INa was measured using the whole cell patch clamp technique. In a second experimental approach, peak INa was compared after a 24 hour exposure of isolated mdx ventricular cardiomyocytes with 1 µM EMPA, 10 µM of the Na+-H+ exchanger 1 inhibitor cariporide, or 10 µM cariporide in combination with 1 µM EMPA. In a third set of experiments, we superfused freshly isolated mdx ventricular cardiomyocytes with 1 or 10 µM EMPA in order to examine the acute action of the drug on peak INa.

Results
Consistent with the literature, we found peak INa of mdx ventricular cardiomyocytes to be substantially decreased compared to wild-type. Peak INa of ventricular cardiomyocytes derived from mdx mice, which had received EMPA for 4 weeks, was restored to wild-type level. Moreover, incubation of isolated mdx ventricular cardiomyocytes with EMPA for 24 hours significantly increased their peak INa. This effect did not depend on Na+-H+ exchanger 1 inhibition by the drug. The voltage dependencies of INa activation and fast inactivation were neither modified by long-term treatment nor incubation with EMPA. Finally, acute application of EMPA did not influence peak INa.

Conclusion
Our findings indicate that EMPA treatment can correct abnormally reduced peak INa of dystrophin-deficient ventricular cardiomyocytes. Long-term EMPA administration may diminish arrhythmia vulnerability in DMD patients.