bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of COVID-19 pandemic on the management of hypertension and the prevalence of lifestyle disease
Authors: Isogaki T , Takase H , Kawakatsu N , Hayashi K , Kin F , Dohi Y
Published: October 2024

Background/Introduction

Behavior restrictions after the advent of COVID-19 dramatically changed our lifestyle, which may have affected self-management of metabolic factors in individuals.

Purpose

We examined possible changes in the prevalence and management of lifestyle-related diseases in the general population.

Methods

We enrolled 2582 consecutive participants aged ≥20 years (male=6984, 49.5±11.9 year-old) who visited our hospital for their annual physical check-up at least five times between 2017 and 2022. Participants were divided into 2 groups (with [n=739] or without antihypertensive medication [n=1843]) and changes in parameters that are closely related with lifestyle were examined before (2017-2019) and after (2020-2022) the pandemic of COVID-19. Hypertension was defined as systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or the use of antihypertensive medications. Diabetes mellitus was defined as fasting plasma glucose ≥126 mg/dL, HbA1c ≥ 6.5% or the use of antidiabetic medications. Dyslipidemia was defined as LDL-cholesterol ≥140 mg/dL, HDL-cholesterol <40 mg/dL, triglyceride ≥150 mg/dL, or the use of antidyslipidemic medications. Hyperuricemia was defined as uric acid >7.0 mg/dL for men, >6.0 mg/dL for women or the use of anti-hyperuricemic medications. Metabolic syndrome was defined based on Japanese diagnostic criteria (2005).

Results

The main results are shown in Table. The levels of all parameters were worse in participants with than without anti-hypertensive medication. The prevalence of hypertension, diabetes, dyslipidemia, hyperuricemia and metabolic syndrome which was higher in subjects with than without anti-hypertensive medication increased after the COVID-19 pandemic. Although the most of parameters were deteriorated after the pandemic, only the management of blood pressure in subjects under antihypertensive medication was improved.

Conclusion

Behavior restrictions during the pandemic might have unfavorable impact on the prevalence of lifestyle-related diseases. Although the control of blood pressure was not worsened, total management was not excellent during the pandemic in hypertensive individuals under medication.Characteristics of study participants
Nationwide trends in major cardiovascular risk factors in England in the last 2 decades: Health Survey of England 2003-2019
Authors: Gupta A , Graham C , Capel M , Steckelmacher J , Prasher J
Published: October 2024

Cardiovascular disease (CVD) accounts for a quarter of deaths annually in the UK, with more than 7.6 million people living with the disease. Hypertension, diabetes, and obesity are among the most prevalent modifiable risk factors for CVD, and the strategies to reduce the incidence and prevalence of these CV risk factors are deemed the most effective to reduce this immense toll. In the UK, over the last few decades, several health policy decisions and pathways have been developed to reduce this toll.

We used data from 11 nationally representative, cross-sectional surveys from the Health Survey of England between 2003 and 2019 to evaluate trends in the prevalence of these CV risk factors and whether there has been any population-wide improvement in them. These surveys have cumulative information on 94,100 adults, and we applied sample weights, accounting for oversampling and nonresponse. We used "period definitions and cut-offs" to define those with diabetes. For example, for undiagnosed diabetes, we used glycated haemoglobin cut-off equivalent of 7% or more for years before 2011 and the current diagnostic threshold of > 6.5% thereafter. This was done to facilitate and compare the trends after accounting for changes in medical practice and understanding across this period. Similarly, hypertension was defined as doctor-diagnosed hypertension or in its absence regular use of antihypertensive medications or blood pressure ≥ 140/90mmHg (period diagnostic threshold remains unchanged during). Python and STATA were used to conduct analyses, and Join Point regression software was used to develop and compare trends.

In England, from 2003-2019, mean population BMI consistently increased over this period, rising by 0.8kg/m2 from 27.6 to 28.8 kg/m2. Obesity prevalence (BMI ≥30kg/m2) increased by 5.4% from 22.6% to 28.0%. Concurrently, mean glycated haemoglobin increased by 0.36% from 6.18% to 6.54%, surpassing the current diabetes diagnostic threshold. Diabetes period prevalence surged from 4.2% to 11.6%, a trend consistent when the current diagnostic threshold was alternatively applied across all periods. Conversely, doctor-diagnosed and total hypertension (including those who are unaware) prevalence exhibited a slight decrease (1.4% and 3%, respectively), mirrored by reductions in population-wide mean systolic and diastolic blood pressure by 4.6mmHg and 1.9mmHg.

These results suggest that, with the total population in England standing at 56.3 million in 2019, an estimated 15.8 million adults were within the obese BMI range, 6.5 million had diabetes and 17.6 million had hypertension. The obesity epidemic is likely fuelling the increase in diabetes prevalence. These findings underscore the importance of prioritising obesity reduction in public health initiatives, aiming to subsequently curb diabetes prevalence. Hypertension still remains a major CV risk factor, affecting almost one third of the adult population.
Effects of mineralocorticoid receptor antagonists on new-onset or recurrent atrial fibrillation: a Bayesian and frequentist network meta-analysis of randomized trials
Authors: Karakasis P , Dimitrios D , Popovic D , Pamporis K , Theofilis P , Nasoufidou A , Stachteas P , Samaras A , Tzikas A , Giannakoulas G , Stavropoulos G , Kassimis G , Karamitsos T , Fragakis N
Published: October 2024

Aims

Clinical and translational research suggests that mineralocorticoid receptor antagonists (MRAs) may prevent atrial fibrosis and electrical remodeling associated with atrial fibrillation (AF). This study aimed to consolidate existing evidence from randomized controlled trials (RCTs) evaluating the effect of MRAs on incident or recurrent AF.

Methods

Medline, Cochrane Library and Scopus were searched until February 12, 2024. Triple-independent study selection, data extraction and quality assessment were performed. Evidence was pooled using both pairwise and Bayesian and frequentist network meta-analyses.

Results

Twenty-three RCTs (13,358 participants) were identified. Based on the pairwise random effects meta-analysis, MRAs were associated with a significant reduction in AF events compared to placebo or usual care (risk ratio {RR}= 0.75; 95% confidence interval {CI}= [0.66, 0.87]; P< 0.001; I2= 3%). This protective effect was robust both for new-onset and recurrent AF episodes (subgroup p-value= 0.69), while the baseline HF status was not a significant effect modifier (subgroup p-value= 0.58). MRAs demonstrated a significantly higher reduction in AF events for patients with chronic renal disease compared to placebo (RR= 0.78; 95% CI= [0.62, 0.98]; P= 0.03; I2= 0%). The network meta-analyses revealed that only spironolactone was associated with a significant reduction in AF events (Bayesian RR= 0.76; 95% CI= [0.65, 0.89]; P< 0.001; level of evidence moderate; SUCRA 0.731), while eplerenone and finerenone showed a neutral effect.

Conclusion

MRAs confer a significant benefit in terms of reducing incident or recurrent AF episodes, irrespective of HF status. In this context, spironolactone may be preferable compared to eplerenone or finerenone.
Investigating N6-methyladenosin RNA modification as a mediator of microRNA mechanical regulation in the heart
Authors: Martino F , Anwar M , Nicastro L , Ben-Aicha S , Terracciano C , Emanueli C
Published: October 2024

Background

The heart is exposed to mechanical forces and continuously adapts to its environment in a process known as cardiac remodeling. Excessive mechanical load is a primary driver of pathological cardiac remodeling, leading to heart failure (HF), a prominent cause of morbidity and mortality worldwide. A set of microRNAs (miRs), termed mechano-miRs, has been identified to respond to mechanical forces and contribute to heart pathophysiology and HF.

N6-methyladenosine (m6A) RNA modification is emerging as a novel regulatory layer impacting gene expression and occurring both in coding and non-coding RNAs. In this context, the N6-adenosine-methyltransferase METTL-3 regulates the processing of miR primary transcripts (pri-miRs) to functional miRs, promoting angiogenesis and cardiac repair after myocardial infarction. On the other side, dysregulation of m6A due to a defect in FTO, a m6A demethylase, has been implicated in HF. However, the role of m6A RNA modifications in heart mechanical responses and mechano-miR regulation remains unexplored.

Purpose

This project aims to: 1) investigate the impact of mechanical overload on the expression of m6A regulatory machinery components; 2) unveil the role of m6A-mechano-miRs axis in mechanically induced responses driving pathological cardiac remodeling leading to heart failure.

Methods and Results

Using living myocardial slices (LMS) technology, we modulate mechanical load in a multicellular environment while maintaining physiological behavior. Human LMS, obtained from the left ventricle of human donor non-failing hearts (NHS Blood and Transplant INOAR program, IRAS project ID: 189069) and rat LMS are subjected to two degrees of mechanical preload: physiological sarcomere length (SL) (SL = 2.2 μm) and overload (SL = 2.4 μm). This enables us to mimic the effects of mechanical stress on the heart during HF (volume overload model). LMS are maintained for 48 hours under electrical stimulation in circulating oxygenated media at 37°C.

Mechanically overloaded LMS exhibit decreased contractility, accompanied by an increase in global m6A levels compared to physiological controls. Consistent with this finding, the analysis of the expression of m6A machinery reveals a downregulation of m6A demethylases (FTO and ALKBH5) in overloaded LMS.

We identified putative cardiac mechano-miRs by small-RNA sequencing in both human and rat LMS and next predicted potential m6A sites on their primary transcripts via SRAMP (sequence-based RNA adenosine methylation site predictor).

Conclusions

Mechanical overload affects global m6A levels and the expression of m6A demethylases in the heart. Ongoing analysis of the m6A profile on the identified mechano-miR primary transcripts and mRNA targets holds promise for unveiling novel mechanically regulated m6A events, providing insights for transformative therapeutic strategies.
Single cell multi-omics analysis unveils a distinct mechanism of exercise-mediated cardioprotection in ischemic cardiomyopathy
Authors: Jimba T , Ko T , Zhang B , Nomura S , Takeda N , Komuro I
Published: October 2024

Background

Exercise is pivotal in heart disease prevention, with proven cardioprotective effects in clinical trials. However, its precise molecular mechanisms remain elusive. Recent advancements in single-cell omics have revealed cellular heterogeneity within heart tissues, offering a deeper understanding of the pathophysiology of cardiac diseases.

Purpose

To investigate the exercise-induced physiological changes in heart tissue at the single-cell level and elucidate the molecular mechanisms underlying its cardioprotective effect on ischemic cardiomyopathy.

Methods

Murine myocardial infarction (MI) model was established by ligating the left ascending coronary artery, and a six-week voluntary wheel running exercise regimen was implemented to investigate the effect of aerobic exercise on ischemic cardiomyopathy. Integrated multi-omics analyses of single-cell DNA methylation profiling, single-nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq) and single-nucleus RNA sequencing (snRNA-seq) were conducted to clarify the molecular mechanism of exercise-mediated cardioprotection at single-cell resolution. Overexpression and short hairpin RNA-mediated knockdown of gene X were conducted for murine MI model using cardiomyocyte-specific Myo-AAV2a vector. snRNA-seq of heart tissues from heart failure patients was performed to validate the clinical significance of the expression of gene X in cardiomyocytes.

Results

Exercise attenuates pathological cardiac remodeling, inducing physiological hypertrophy in non-infarcted areas while suppressing pathological remodeling of cardiomyocytes in infarct border zones. Single-cell epigenetic analysis unveiled intricate molecular mechanisms underlying exercise-induced transcriptome changes, providing insights into the gene regulatory networks modulated by exercise in the heart. In addition, integrated with snRNA-seq, we identified exercise-specific cardiomyocyte clusters, highlighting the substantial role of gene X in the molecular mechanism of exercise. Functional studies confirmed the essential role of gene X in exercise-induced cardioprotection, as its overexpression suppressed the adverse remodeling after MI and knockdown abolished the beneficial effects of exercise. Furthermore, snRNA-seq of heart failure patients revealed that higher expression of gene X was associated with ventricular reverse remodeling and favorable clinical outcomes, underscoring its significance in the pathophysiology of patients with heart failure.

Conclusion

Our study elucidates exercise-specific gene expression regulation networks in ischemic cardiomyopathy by unraveling the cellular heterogeneity and molecular changes associated with exercise. We identified gene X as a central player in exercise-mediated cardioprotection and further confirmed its significance in clinical settings, providing a potential therapeutic target for heart failure.
Proteogenomic analysis in population biobanks identifies new therapeutic targets across heart failure subtypes
Authors: Henry A , Finan C , Gratton J , Paliwal N , Chopade S , Jassal S , Hedman A K , Fauman E B , Malarstig A , Hingorani A D , Lumbers R T
Published: October 2024

Background

Heart failure (HF) represents a multifactorial clinical syndrome with differential response to existing therapies across its subtypes. Proteogenomic analysis of genetic variants associated with changes in circulating protein level and risk of heart failure subtypes provides an opportunity for a systematic identification of proteins with subtype-specific causal effects as novel therapeutic targets.

Purpose

To identify proteins as potential therapeutic targets for specific heart failure subtypes by leveraging proteomics and genomics data in population biobanks.

Methods

We evaluated the causal effects of 2,773 proteins on 5 HF-related outcomes, including overall HF, non-ischaemic HF (ni-HF), ni-HF with reduced / preserved ejection fraction (ni-HFrEF / ni-HFpEF), and dilated cardiomyopathy (DCM). For each protein-phenotype pair, we performed a two-sample Mendelian randomisation (MR) analysis using protein-specific genetic association estimates derived from protein quantitative trait locus (pQTL) studies in 114,145 individuals from deCODE, UK Biobank, Fenland study, and SCALLOP consortium and genome-wide association studies (GWAS) of HF outcomes in 145,795 individuals by HERMES Consortium. We further prioritised candidate protein targets based on replication of results across datasets, model parameters, assays, and colocalization of causal genetic variants. Finally, we profiled the causal effects of identified proteins on 32 related cardiac traits and risk factors to explore potential mechanisms of actions and on-target side effects.

Results

We identified 493 proteins associated with at least one HF outcome at a false discovery rate (FDR) < 1% in the primary MR analysis. We further prioritised 44 proteins with concordant effect direction across datasets, model parameters, and assays or colocalization in at least one dataset. All 44 identified proteins showed cross association with at least one of 35 tested traits other than HF or cardiomyopathies at FDR <1%, including coronary artery disease (18 proteins), body mass index (11 proteins), type 2 diabetes (6 proteins), systolic / diastolic blood pressure (13 proteins), and chronic kidney disease (9 proteins).

Conclusion

We characterised the causal associations of 2,773 circulating proteins across HF-related outcomes and prioritised 44 proteins by integrating proteomics and genomics data in population biobanks. These findings extend our understanding of the molecular mechanism underlying different forms of HF and may inform the development of new therapeutic strategies.Study design
The implantation of a left ventricular assist device causes changes in the aortic miRNome and proteome - an integrative analysis
Authors: Dlouha D , Pompach P , Chytilova S , Ivak P , Novakova S , Tucanova Z , Hlavacek D , Netuka I
Published: October 2024

Background

Left ventricular assist devices (LVAD) have been widely used and accepted to treat patients with end-stage heart failure. LVAD non-physiological blood flow velocity, wall shear stress distribution, vorticity current intensity, and vorticity flow generation affect the pathophysiology of vascular changes in aortic tissue.

Purpose

In this study, we performed multi-omics-based analysis of the aorta to identify molecular markers that could clarify vascular remodeling during LVAD support.

Methods

Aortic specimens from 48 patients (pair matched samples N=96) were excised during implantation and explantation of LVAD. Small RNA-Seq screening using Next Generation Sequencing and proteomic profile using Data-Independent Acquisition mass spectroscopy were conducted. Experimental and computational approaches, proteomics and transcriptomics data, were integrated and bioinformatics analyses were performed.

Results

The principal component analysis of miRNome and permutational multivariate analysis of variance of proteomic profile clearly segregated samples before and after LVAD support. We identified a total of 113 differently expressed (DE) miRNAs (61 up-regulated; Padj<0.05 and log2 fold change>|0.5|) after long-term LVAD support. Proteomic analysis identified in total 93 protein significantly changed (47 increased; Padj<0.05 and log2 fold change>|0.5|). Correlation analysis identified strong association between 270 proteins and 66 DE-miRNAs (Padj<0.05 and correlation coefficient>|0.7|). Gene Set Enrichment Analysis revealed, that predicted target genes of DE-miRNAs were mainly engaged in axon guidance, regulation of actin cytoskeleton, endocytosis, and MAP signaling pathway (Padj<0.05). DE-proteins participated mainly in ECM-receptor interaction, focal adhesion, and platelet activation (Padj<0.05).

Conclusion

Our study presents a network-based method of integrating microRNAs and proteome data and reveals molecular signatures that reflects aortic vascular remodeling due to LVAD treatment.PCA of miRNA DESeq2PCA of protemic profile
The effect of CD38 inhibition in age-associated vascular dysfunction
Authors: Puspitasari Y M , Yang K , Ministrini S , Bengs S , Luscher T F , Camici G G
Published: October 2024

Introduction

Aging is characterized by age-related vascular dysfunction, mainly caused by endothelial dysfunction and arterial stiffness. Levels of nicotinamide adenine dinucleotide (NAD) decrease with aging and accordingly, NAD is thought to be involved in the progression of age-related vascular dysfunction. Recent studies reported the involvement of CD38 in NAD regulation; indeed, its inhibition significantly prolongs the lifespan of progeroid and aged mice. However, whether CD38 is involved in the progression of age-related vascular dysfunction remains to be investigated.

Methods

CD38 expression was investigated in aortic homogenates of young (12-16 weeks) and aged (18-24 months) C57BL/6 wild-type mice, as well as in vitro in young (passage 5-7) and senescent (passage 14-15) primary human aortic endothelial cells (HAECs). Ex vivo tension myograph experiments were performed on thoracic aortas isolated from aged C57BL/6 mice (22-24 months old) pre-incubated for 1 hour with CD38-specific inhibitor, 78c, or DMSO as control. The effect of CD38 inhibition was also observed in vitro in senescent HAECs.

Results

A significant upregulation of CD38 expression was detected in the aortas of aged mice compared to the young ones as well as in senescent HAECs compared to young cells. Ex vivo tension myograph experiments showed a significant increase in endothelium-dependent relaxation responses to acetylcholine upon CD38 inhibition. The improvement of endothelial function was prevented by the addition of endothelial nitric oxide synthase (eNOS) inhibitor (L-NAME), but not by the COXs inhibitor, indomethacin, indicating that the observed effect achieved by CD38 inhibition is eNOS dependent. The involvement of the eNOS pathway was further supported by the in vitro finding in HAECs of increased eNOS activation upon CD38 inhibition.

Conclusion

The herein-reported data suggests an involvement of CD38 in the development of age-related endothelial dysfunction. Further studies are ongoing to investigate the underlying molecular mechanisms as well as the effect of long-term CD38 inhibitor supplementation on the progression of age-related vascular dysfunction.
Lipoprotein(a) induces spontaneous aortic dissection via increasing monocyte mediated vascular smooth muscle cell phenotype transformation in human Lp(a) transgenic mice
Authors: Han C Z , Wang Z M , Fu Y Y , Wang Q Z , Huang Z Y , Ge J B
Published: October 2024

Background

Elevated lipoprotein(a) [Lp(a)] is a prevalent, independent risk factor of atherosclerotic cardiovascular disease and aortic valve stenosis. Recent studies have reported that high levels of Lp(a) are strongly associated with aortic dissection (AD), independent of other cardiovascular risk factors. However, orthologues of Lp(a) are only found in humans, Old World monkeys, apes, and hedgehogs. The lack of a proper animal model has hindered elucidation of the true pathophysiological mechanisms of Lp(a). Here, we conducted the first humanized Lp(a) transgenic mice experiment to verify the pathological mechanism of Lp(a) in aortic dissection.

Methods

We conducted ApoE knock out and human ApoA transgenic mice via CRISPR-Cas9 and then crossed with human ApoB transgenic mice to achieve high levels of human-like Lp(a) particles in plasma. Plasma was assayed by ELISA for the concentrations of each lipoprotein. Echocardiography was performed to detect aortic morphology in vivo. Single cell transcriptome analysis was performed on the dissection lesion. Cell interaction was examined in macrophage from Lp(a) transgenic mice and vascular smooth muscle cell (VSMC) coculture system.

Result

Our results indicate that the concentration of ApoA and ApoB in plasma were increased in transgenic mice fed a chow diet. Low density lipoprotein (LDL) levels were increased and shows that LDL is the major cholesterol carrier in these mice. We were surprised to find that the dissection of the ascending aortic arch could be seen by echocardiography in transgenic mice as early as 2 months, and transgenic mice showed significant increase in aortic enlargement, dissection, and rupture in both the thoracic and abdominal aortic regions, resulting in a survival rate of only 58% after 12 months. Single cell transcriptome analysis revealed that Lp(a) transgene induced the inflammatory response, dedifferentiation and pathological VSMC phenotypical switch, and matrix metalloproteinase expression in macrophages. Monocytes isolated from transgenic mice with elevated Lp(a) remain in a long-lasting primed state, as evidenced by an increased capacity to transmigrate and produce proinflammatory cytokines on stimulation. Monocytes isolated from wild type mice cultured in media with high level Lp(a) for 24h also showed the ability to facilitated cocultured VSMC phenotype transformation, which was reversed by E06, a monoclonal antibody blocking the oxidized phospholipids in Lp(a).

Conclusion

These findings demonstrate that Lp(a) induces spontaneous aortic dissection via increasing monocyte trafficking to the arterial wall, mediating proinflammatory responses and VSMC phenotype transformation through its OxPL content. The study presents a rodent model of spontaneous aortic dissection and provide a novel mechanism by which Lp(a) mediates aortic dissection.Graphical abstract
STING-mediated DNA damage response in diabetes-induced vascular complications
Authors: Bavuu O , Pham P, T , Sata M , Fukuda D
Published: October 2024

Background

Hyperglycemia drives endothelial dysfunction, a key factor in the development of diabetes vascular complications. The stimulator of interferon genes (STING) signal, plays a crucial role in the immune system and is implicated in the pathogenesis of inflammatory diseases. Therefore we investigated the role of STING in endothelial dysfunction in streptozotocin (STZ)-induced diabetic mice.

Methods and Results

Diabetes was induced by single-dose administration of STZ in 8-week-old C57BL/6 and Sting-/- mice. STZ injection promoted the expression of STING and DNA damage markers in the aorta of C57BL/6 mice. Genetic deletion of STING ameliorated endothelial dysfunction as determined by vascular reactivity assay (P < 0.001) and increased aortic eNOS phosphorylation (P < 0.05) in STZ-injected mice. Stimulation of STING agonist (cGAMP), or mtDNA increased inflammatory molecules expression (e.g., VCAM1 and IFNB) and decreased eNOS phosphorylation in HUVECs. In ex-vivo experiments, cGAMP significantly impaired endothelial function which was ameliorated in the presence of an STING inhibitor or a neutralizing IFN-β antibody. Furthermore, the administration of STING inhibitor ameliorated endothelial dysfunction in STZ-induced diabetic mice (P < 0.01).

Conclusion

The DNA damage response regulated by STING aggravated diabetes-induced endothelial dysfunction. STING signaling may be a potential therapeutic target for diabetic vascular complications.
Elevation of circulating FGF23 in chronic kidney disease promotes atrial fibrosis through the AKT pathway
Authors: Gao P , Xie B , Zhou Z , Tse G , Liu T
Published: October 2024

Background

The relationship between chronic kidney disease (CKD) and atrial fibrillation (AF) remains unclear. Elevated level of fibroblast growth factor 23 (FGF23) is highly associated with increased cardiovascular disease and mortality in patients suffering from CKD. In recent years, studies have shown that FGF23 promotes cardiac hypertrophy through FGFR4, suggesting that FGF23 may be an important bridge between the heart and kidney.

Purpose

In this study, we sought to use a well-established rat model of CKD to further characterize the effects of CKD on AF and to identify potential drivers of CKD-induced AF.

Methods

14 SD rats were randomly selected to undergo 5/6 nephrectomy and fed for 15 weeks to establish a CKD model, while the SHAM group (8 rats) underwent the same surgery without removing kidney tissue. Body weight, blood pressure, renal function, cardiac ultrasound, epicardial electrocardiography, and pathological indices were monitored in both groups. Gene sequencing was performed on the left atria to search for differentially expressed genes. Rat atrial fibroblasts were selected for further mechanism exploration. We chose TGF-β to stimulate fibroblasts to mimic the process of fibrosis in vivo, and then administered FGFR inhibitors to explore the downstream molecular mechanisms.

Results

Systolic blood pressure and creatinine were elevated in the CKD group. Compared with the SHAM group, the incidence of AF was significantly higher, left atrial diameter was significantly larger, and epicardial electrical markers showed that left atrial electrical conduction velocity was significantly slower and conduction heterogeneity was significantly increased in the CKD group. Pathologic staining of the left atrium showed significant fibrosis in the CKD group. Consistent with previous findings, FGF23 was significantly elevated in CKD rats. Transcriptomic sequencing revealed that FGFR4 expression was significantly upregulated in the left atrium of CKD rats, The results in rat atrial fibroblasts showed that blocking FGFR4 expression inhibited TGF-β-induced fibrosis and was mediated by the AKT pathway.

Conclusions

The mechanism of CKD-induced AF is that CKD promotes both structural and electrical remodeling of the atria. Further investigation of its possible downstream molecules revealed that elevated FGF23 in the CKD circulation promotes the development of atrial fibrosis by binding to FGFR4 through the AKT pathway.
Treated obstructive sleep apnoea and incident arrhythmias
Authors: He H , Lachlan T , Osman F
Published: October 2024

Background

Obstructive sleep apnoea (OSA) is prevalent in approximately 15% of western populations. Cardiovascular disease and arrhythmia are extremely common in this group with significant morbidity overlap. Whilst treatment of OSA with continuous positive airways pressure (CPAP) appears to reduce hypertension, bradycardia and recurrence of atrial fibrillation (AF), large randomised control trials and meta-analyses do not demonstrate a significant reduction of incident tachyarrhythmias such as atrial fibrillation or sudden cardiac death. Some smaller studies suggest that AF may have up to 20% incidence. Analysis of these studies suggest that there may be significant heterogeneity in both CPAP usage and OSA phenotype, confounding the results. Furthermore, standard arrhythmia detection often underestimates paroxysmal arrhythmias. This on-going trial investigates a treated OSA population using CPAP monitoring and implantable loop recorders (ILR).

Purpose

This study aims to identify the incidence of arrhythmia in a treated OSA population with comprehensive arrhythmia monitoring and CPAP usage. It also explores the mechanisms linking OSA and arrhythmia such as heart rate variability and turbulence and cardiac biomarkers in order to identify at risk sub populations.

Methods

Continuous moderate-to-severe OSA patients were recruited from a major UK sleep centre after ECG and medical history confirmed the absence of arrhythmia. Each patient was then randomised to receive either standard-care or standard-care with an ILR with 24-hour heart rate variability/turbulence measurements, echocardiography (where possible) and cardiac biomarkers at baseline and 12 months. All patients had remote CPAP usage monitoring (where possible). The trial ended at 36 months after enrolment.

Results

200 patients were recruited to the trial. Current mean average follow-up is 28 months in this on-going trial. Mean age and apnoea hypopnea index at enrolment was 53 years and 43.8 respectively. To date we have diagnosed atrial fibrillation in 15% of the ILR group compared to 2% in the standard care group. Other arrhythmias detected in the ILR group include two with supraventricular tachycardia and 2 with significant pauses but not requiring further treatment. Final analysis of arrhythmia incidence with CPAP usage and heart rate variability/turbulence, and cardiac biomarkers is ongoing with final results due by the time of final submission.

Conclusion

Arrhythmias, particularly AF, are highly incident in OSA despite CPAP treatment. This study may determine if heterogenous CPAP usage confounds the above observation and whether there may be predictors of arrhythmia that may indicate a need for arrhythmia screening in the OSA population.
Secretoneurin plasma levels are decreased after catheter ablation for atrial fibrillation, patients with AF produce lower SN levels than healthy individuals
Authors: Plasek J , Jiri Vrtal J V , David Sipula D S , Jozef Dodulik J D , Diana Drienikova D D , Martin Rachela M R , Jiri Pudich J P , Zdenek Svagera Z S , Nela Chobolova N C H , David Stejskal D S , Jan Vaclavik J V
Published: October 2024

Background

Secretoneurin (SN) is a novel biomarker with potential use in cardiovascular medicine. The main effect of SN is mediated through its inhibition of calmodulin-dependent kinase II (CaMKII), which influences calcium handling[1], plasma SN levels differ in ischemic vs. dilated cardiomyopathy [2]. We aim to associate the levels of SN pre- and postprocedurally and according to the type of atrial fibrillation (AF).

Methods

We prospectively enrolled patients indicated for catheter ablation (CA) for AF, sequentially sampled patients for SN before, during and after CA for AF. We also sampled healthy individuals as controls. SN was analysed from venous, left atrial and coronary sinus (CS) blood by the use of the ELISA method. Values are expressed as means±SD, variables are compared by standard statistical methods.

Results

A total of 104 patients (59.4% male) with AF aged 64±10.4, with BMI 30.1±5 and 34 healthy individuals (38% male) were included in the analysis. SN plasma levels were significantly lower 32.3±15.1 after the procedure (SN2) as compared to levels before (SN1) 38.4±17.5 pmol/L (P=0.02, Fig.1). SN was not associated with any marker of cardiac injury or overload, echocardiographic parameters, or ablation characteristics (P=NS), even though Troponin I was significantly increased after the procedure (P<0.0001, Fig.2). Left atrial SN was numerically higher 40.9±19.1 than SN sampled from CS 32.9±13 (P=NS).The SN levels in our patients with AF were generally lower than in healthy individuals (50.7±15.3 pmol/L) before (P=0.0004) as well as after the procedure (P=0.0001).

Conclusion

Catheter ablation of AF leads to a decrease in SN plasma levels even though markers of cardiac injury are increased. Patients with AF irrespective of actual rhythm produce lower levels of SN than healthy individuals.
The impact of escape mapping for roof line completion during BOX isolation for atrial fibrillation
Authors: Kaitani K , Kyo S , Oi M , Suenaga A , Onishi N
Published: October 2024

Background and Aim

The creation of complete roof line (RL) is often challenging due to the presence of epicardial myocardial bundle or fat interposition. The disconnecting the septopulmonary bundle from the Buchmann bundle arrays requires for RL completion. Therefore, the conduction time to the left atrial appendage (LAA) and the high right atrium (HRA) potentials under left superior pulmonary vein pacing (LSPVp), so-called •escape mapping•, should be significantly prolonged after the creation of the transmural RL. This study investigates whether the changes conduction times from LSPVp to LAA and HRA (∆LSPVp-LAA and ∆LSPVp-HRA) between before and after the creation of the line as the assessment of bi-directional RL block.

Methods

76 de-novo non-paroxysmal atrial fibrillation (nPAF) patients underwent BOXI strategy ablation. We initially intended single ring protocol BOXI for all patients. The activation times were measured at LAA and HRA under LSPV pacing at baseline and after application for the RL. Then we compared the change of activation time at LAA (∆LSPVp-LAA) and at HRA (∆LSPVp-HRA) between 2 groups; the group that completed BOXI with the first-pass roof line (fp-RL group) and the other group (Nfp-RL group).

Results

In 47 patients, the first-pass roof line was successfully obtained and in patients was done with additional application for gap(s) on the roof line to complete BOXI. There was a stepwise increase in mean ∆LSPVp-HRA not ∆LSPVp-LAA. Increased LA diameter, lower LVEF, and thinner LA wall were associated with the first-pass roof line. ∆LSPVp-HRA ≥33ms predict roof line block with high specificity and sensitivity.

Conclusions

Our findings suggest that the changes conduction times between LSPV and HRA during LSPV pacing help in the assessment of RL block.
Severity of anemia is correlated with the prevalence of left atrial low-voltage areas in patients with atrial fibrillation ablation
Authors: Matsuda Y , Masuda M , Uematsu H , Sugino A , Ooka H , Kudo S , Fujii S , Asai M , Okamoto S , Ishihara T , Nanto K , Tsujimura T , Hata Y , Higashino N , Mano T
Published: October 2024

Background

Although left atrial low-voltage areas (LVAs) are well-known indicator of atrial fibrosis and atrial fibrillation (AF) recurrence after catheter ablation, the association between anemia and prevalence of LVAs has not been clarified. We hypothesized that LVAs were more frequently found in patients with anemia than in those with normal hemoglobin levels.

Purpose

The purpose of this study was to investigate the association between hemoglobin levels and the prevalence of LVAs in patients with AF ablation.

Methods

In total, 1,473 (age, 68±10 years; female, 492 [33%]; persistent AF, 895 [61%]; CHA2DS2-VASc score, 2.5±1.5 points) consecutive patients who underwent initial AF ablation were enrolled in this study. Hemoglobin levels were measured before the ablation procedure, and anemia was defined as hemoglobin levels < 13.5 g/dL in male and < 12.0 g/dL in female. LVAs was defined as areas with bipolar voltage of <0.5 mV covered ≥5 cm² of left atrial surface area.

Results

Of 1,473 patients, LVAs existed in 348 (24%) patients. Hemoglobin levels was significantly lower in patients with LVAs than those without (13.4 ± 1.7 vs. 14.2 ± 1.5 g/dL, p <0.001). On classification by gender, only in male, hemoglobin levels were significantly lower in patients with LVAs than those without (Figure 1). The prevalence of LVAs increased with decreasing hemoglobin levels (Figure 2). On multivariate analysis including gender as a variable, anemia was an independent predictor of LVAs (odds ratio, 1.6; 95% confidence interval: 1.1–2.3; p=0.03).

Conclusions

The prevalence of LVAs increased with decreasing hemoglobin levels in patients with AF ablation. In particular, hemoglobin levels < 13.5 g/dL in male and < 12.0 g/dL in female was an independent predictor of LVA presence.Hemoglobin levels and LVAs presenceHemoglobin and the prevalence of LVAs
Fewer redo procedures in catheter ablation of atrial fibrillation: data from the swedish national catheter ablation registry
Authors: Mannewald C , Platonov P G , Fengsrud E , Hoglund N , Karlsson L , Lonnerholm S , Ringborn M , Sigurjonsdottir R , Tabrizi F , Tapanainen J , Braunschweig F , Holmqvist F
Published: October 2024

Background

The number of patients undergoing catheter ablation of atrial fibrillation (AF) is continuously growing, and techniques are improving. However, AF recurrences are still common and demand frequent redo procedures that expose patients to repeat complication risks and cause extensive health care costs. Real-life data regarding redo rates is scarce. Using a national registry, we examined current trends in long-term outcomes as illustrated by the need for redo procedures.

Purpose

The purpose of this study was to investigate the long-term outcome of catheter ablation of AF as a function of when the initial procedure was performed.

Methods

The Swedish Catheter Ablation Registry covers virtually all (>97%) catheter ablations performed in Sweden since 2005. Patients >18 years of age undergoing pulmonary vein isolation (PVI) during January 1st 2006 until December 31st 2020 were included in the analysis. Follow up data was registered until December 31st 2021. The number of procedures performed, characteristics of patients, acute success (defined as all pulmonary veins isolated), and repeat ablation at 1 and 3 years were analyzed. Characteristics and periprocedural data were compared between 2006, 2015 and 2020 to find possible trends.

Results

A total of 23909 PVI were performed during the studied period. In 2006, 2015 and 2020, respectively, 352, 1861 and 2609 procedures were performed, constituting 18%, 40% and 48% of all ablation procedures. There was an increase in patient age (58, 62, 64 years) and more women were ablated (22%, 27%, 28%) over time. Acute success rate remained high at 98% during the study period. Repeat ablation at 1 and 3 years was 23% and 45% respectively for patients ablated in 2006, compared to 14% and 30% in 2015, and 10% and 23% in 2018 (p <0.001 for both trends), see figure 1.

Conclusion

In a setting of a universal healthcare system, with a continuous increase in amount of catheter ablation of AF, in spite of an unchanged, high acute success throughout the study period, a continuous decrease of repeat ablation was observed indicating a substantial gain in patient value by AF ablation over time.Repeat ablation atrial fibrillation
Novel predictor of thrombosis after left atrial appendage closure -Neutrophil to Lymphocyte Ratio (NLR), platelet to LymPhocyte Ratio (PLR), and Lymphocyte to Monocyte Ratio (LMR)-
Authors: Ryuzaki S , Kondo Y , Nakano M , Nakano M , Kajiyama T , Ito R , Yoshino Y , Komai Y , Takanashi Y , Kobayashi Y
Published: October 2024

Background

Cardiogenic embolism by left atrial thrombi is one of the most important atrial fibrillation (AF)-related clinical problems. In a previous survey, 91% of nonrheumatic AF-related left atrial thrombi was originated in the left atrial appendage (LAA). The WATCHMAN device was developed as a permanent implantable device to seal off the LAA to prevent cardiogenic embolism. It has been used in Japan since September 2019. The WATCHMAN family is the only left atrial appendage closure (LAAC) device in Japan. After percutaneous left atrial appendage closure (LAAC), DRT is an important issue in some cases. Neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and lymphocyte to monocyte ratio (LMR) are known as cancer prognostic factors and indicators of immune status. There are few reports on the predictor for device related thrombosis (DRT), transient ischemic attack (TIA), and ischemic stroke. Finding novel biomarkers could help clinical decision in antithrombotic therapy post LAAC and follow-up intervals.

Purpose

To investigate the association of NLR, PLR, and LMR with device related thrombosis, transient ischemic attack, and ischemic stroke in patients with LAAC.

Methods

Our database of LAAC was respectively analyzed. All LAAC cases were performed between January 2020 and September 2023. Blood cell counts were sampled in three days before LAAC. Postoperative antithrombotic therapy was individualized based on the patient’s background. We examined their background and clinical events.

Results

A total of 116 consecutive patients underwent LAAC in our institution excepting for one case that could not be performed due to a huge LAA (follow-up period, 610±37 days; age, 75±1 years; male sex, 73%; left ventricular ejection fraction, 58±1%; CHAD2S2-VASc, 4.6±0.1; HAS-BLED, 3.4±0.1). The results are shown in the Figure. Receiver-operating characteristic curve analysis confirmed the best cut-off value of NLR, PLR, and LMR for composite of DRT, TIA, and ischemic stroke (AUC = 0.69; 0.70; 0.67). In the univariate analysis, NLR<1.88, PLR<144, and LMR>3.40 are the independent predictor for the combination of DRT, TIA, and ischemic stroke (p-value = 0.02; 0.04; 0.05, respectively).

Conclusion

Low NLR, low PLR, and high LMR are the independent predictor for the combination of DRT, TIA, and ischemic stroke. These parameters can be useful in routine use because they can be easily calculated without additional costs.
Long-term changes in frailty and incident atrial fibrillation: multicenter prospective cohort study
Authors: Wang N , Cai L , Sun Y , Zhu J , Wang B , Tan X , Shi W , Xu D , Lu Y
Published: October 2024

Background

Atrial fibrillation is the most common sustained cardiac arrhythmia and is prevalent among the elderly. Previous findings indicated a higher prevalence of AF in frail adults and frailty prevalent in AF patients. However, the association between dynamic changes of frailty and risk of new-onset AF is unclear.

Purpose

We aimed to investigate the associations of long-term changes in frailty with incident AF. Its associations with heart failure (HF), coronary heart disease (CHD), and stroke were also evaluated as a secondary aim.

Methods

Over 50,000 participants from UK Biobank cohort were included, with available frailty index (FI) data and free of AF, HF, CHD or stroke in both baseline and final follow-up assessments. Participants were categorized into nonfrailty, prefrailty and frailty based on their FI scores. Changes of frailty status from baseline to final follow-up assessment included alleviation, maintenance, and aggravation. Thus, transitions of frailty status included 7 categories: nonfrailty maintenance, nonfrailty aggravation (nonfrailty to prefrailty or frailty), prefrailty alleviation (prefrailty to nonfrailty), prefrailty maintenance, prefrailty aggravation (prefrailty to frailty), frailty alleviation (frailty to prefrailty or nonfrailty), and frailty maintenance. FI in baseline and follow-ups are used to calculate the trajectories of frailty (ΔFI). Cox proportional hazard models were used.

Results

Compared with nonfrailty at baseline, the HRs (95% CI) of AF for prefrailty and frailty were 1.32 (1.29, 1.36) and 1.89 (1.83, 1.96) in the multivariable-adjusted model. During a median of 5.1 years of follow-up from the final assessment, 1729 cases of AF were recorded. Frailty trajectory analysis showed that even a 0.01 point/year increase in ΔFI was associated with 14% (95% CI 1.08-1.20) higher risk of AF, independent of baseline FI and the risk rose to 1.89 (1.45, 2.46) with per 0.05 point/year increase in ΔFI. This association was strengthened in low genetic risk of AF, but sex, age, smoking status, alcohol intake, obesity, hypertension, diabetes and cancer did not materially modify the associations. Moreover, compared with nonfrailty maintenance, sustained frailty had the highest risk of AF (HR 1.95, 1.61-2.36). Alleviation from frailty reduced the risk of AF by 30% (95%CI 0.53-0.94), compared to sustained frailty. These associations were similar in HF and CHD, however, not significant in stroke.

Conclusions

Middle aged and elderly people, including those with diabetes, obesity and hypertension, may gain substantial benefits in risk of AF, HF and CHD by becoming less frail or maintaining nonfrailty, irrespective of past frailty status and established risk factors, delivering public health implications for the necessity of early identification and timely interventions of frailty in heart health management.