bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aortic valve disease augments vesicular microRNA-145-5p to regulate the calcification of valvular interstitial cells via cellular crosstalk
Authors: Hosen D R , Goody M E D , Christmann M E D , Nehl M R S , Wilhelm-Juengling D R , Abplanalp D R , Moore Iv D R , Uchida M R , Zimmer D R , Bakhtiary D R , Pfeifer D R , Latz D R , Jansen M E D , Nickenig D R 
Published: October 2024

Abstract
Rationale: Aortic valve stenosis (AVS) is a major contributor to cardiovascular death in the elderly population worldwide. MicroRNAs (miRNAs) are highly dysregulated in patients with AVS undergoing surgical aortic valve replacement (SAVR). However, miRNA-dependent mechanisms regulating inflammation and calcification or miRNA-mediated cell-cell crossstalk during the pathogenesis of AVS are still poorly understood. Here, we explored the role of extracellular vesicles (EV)-associated miR-145-5p, which we showed to be highly upregulated upon valvular calcification in AVS in mice and humans.

Methods
Human TaqMan miRNA arrays identified dysregulated miRNAs in aortic valve tissue explants from AVS patients compared to non-calcified valvular tissue explants of patients undergoing SAVR. Echocardiographic parameters were measured in association with the quantification of dysregulated miRNAs in a murine AVS model. In vitro calcification experiments were performed to explore the effects of EV-miR-145-5p on calcification and crosstalk in valvular cells. To dissect molecular miRNA signatures and their effect on signaling pathways, integrated OMICS analyses were performed. RNA sequencing (RNA-seq), high-throughput transcription factor (TF) and proteome arrays showed that a number of genes, miRNAs, TFs, and proteins are crucial for calcification and apoptosis, which are involved in the pathogenesis of AVS.

Results
Among several miRNAs dysregulated in valve explants of AVS patients, miR-145-5p was the most highly gender-independently dysregulated miRNA (AUC, 0.780, p-value, 0.01). MiRNA arrays utilizing patient-derived- and murine aortic-stenosis samples demonstrated that the expression of miR-145-5p is significantly upregulated and correlates positively with cardiac function based on echocardiography. In vitro experiments confirmed that miR-145-5p is encapsulated into EVs and shuttled into valvular interstitial cells. Based on the integrated OMICs results, miR-145-5p interrelates with markers of inflammation, calcification, and apoptosis. In vitro calcification experiments demonstrated that miR-145-5p regulates the ALPL gene, a hallmark of calcification in vascular and valvular cells. EV-mediated shuttling of miR-145-5p suppressed the expression of ZEB2, a negative regulator of the ALPL gene, by binding to its 3' untranslated region to inhibit its translation, thereby diminishing the calcification of target valvular interstitial cells.

Conclusion
Elevated levels of pro-calcific and pro-apoptotic EV-associated miR-145-5p contribute to the progression of AVS via the ZEB2-ALPL axis, which could potentially be therapeutically targeted to minimize the burden of AVS.
Left ventricular mass index and prognosis of symptomatic severe aortic stenosis in women and men
Authors: Avakian S D , Tarasoutchi F , Mansur A 
Published: October 2024

Abstract

Background
Symptomatic severe aortic stenosis (AS) requires surgical (SAVR) or transcatheter aortic valve replacement (TAVR), and many patients are on the procedure waiting list. The diagnosis of severe AS is based on clinical and echocardiographic criteria, such as left ventricular ejection fraction (LVEF), aortic valve area (AVA), mean transvalvular gradient, and peak aortic jet velocity. However, there is a gap in knowledge regarding the influence of left ventricular mass on the prognosis of these patients, especially considering differences between women and men.

Purpose
To evaluate the influence of left ventricular mass index (LVMi) on the mortality of women and men with severe AS awaiting SAVR or TAVR.

Methods
A prospective study analysed the death rate in 531 outpatients with symptomatic severe AS with mean transvalvular gradient ≥40 mmHg, AVA ≤1.0 cm2, or peak aortic jet velocity ≥4.0m/s at echocardiography with the indication for TAVR or SAVR in the period from April 2020 to February 2024. Baseline data included analysis of clinical characteristics, echocardiographic variables, and the presence of coronary artery disease (CAD). Statistical analyses were performed using the Kaplan-Meier (K-M) and Cox proportional hazards methods to analyze mortality rates in women and men.

Results
The mean age was 74.7±11.6 years, with 283 (53.3%) men. Over a follow-up period of 2.67±1.22 years, death occurred in 165 (31.1%), 148 (86%) due to cardiovascular disease, and 152 (92%) had heart failure (HF) NYHA II to IV, 51 (9,6%) had angina, and syncope in 11 (2.1%) of the patients. Patients who died had lower LVEF (61.4%±8.9% vs. 58.8%±10.8%; p=0.008) and higher LVMi (125.3±32.5 g/m2 vs. 115.5±29.3 g/m2; p=0.001). Angina, syncope, hypertension, dyslipidemia, diabetes, smoking, atrial fibrillation, and CAD prevalence were similar in living patients and in those who died. Both groups had similar echocardiographic data, such as left atrial volume, mean transvalvular gradient, and peak jet velocity. TAVR and SAVR were done in 111 (20.9%) and 162 (30.5%) patients. Of these, 21 (18.9%) and 20 (12.4%) died during follow-up, respectively. Cumulative mortality of all patients was higher with LVMi &gt;115 g/m2 compared to ≤115 g/m2 (p=0.008)(Figure). In women but not in men, cumulative mortality was higher with LVMi &gt;115 g/m2 compared to ≤115 g/m2 (p=0.046). Cox multivariate analysis, adjusted for LVEF, LVMi, CAD, and age, showed LVMi as an independent variable for death [HR=1.50 (95%CI: 1.10-2.05); p=0.011]. LVEF [HR=0.97 (95%CI: 0.95-0.99); p=0.009] and LVMi [HR=1.75 (95%CI: 1.10-2.79); p=0.016] were independent variables for death in women, but not in men.

Conclusion
Women with higher LVMi and lower LVEF should have valve intervention prioritized.Figure
Lead-related tricuspid regurgitation: an important phenotype seen through the lens of computed tomography
Authors: Margonato D , Enriquez-Sarano M , Hamid N , Wang C , Fukui M , Phichaphop A , Okada A , Sorajja P , Bapat V , Cavalcante J 
Published: October 2024

Abstract

Background
The imaging diagnostic approach of patients with cardiac implantable electronic devices (CIED)-related tricuspid regurgitation (TR) is undefined. Functional cardiac computed tomography angiography (4D-CTA) provides a complementary role to echocardiography in the evaluation of tricuspid valve (TV) apparatus and right ventricle (RV) remodeling, but the capability to assess lead-leaflet interaction is unknown.

Purpose
To evaluate the role of 4D-CTA anatomical and morphological diagnostic assessment in a cohort of patients with severe TR and CIED vs those without.

Methods
Clinical, echocardiographic and CTA data were collected from two quaternary centers for patients with severe TR and a CIED evaluated between January 2017 to October 2023. Functional and morphological CTA information assessed lead-leaflet relationship to divide patients in those with lead-related TR, those with no lead-TR causal relationship, and those with severe isolated TR but without CIED. Primary end-point was the occurrence of all-cause death.

Results
A total of 143 patients were identified, roughly dividng the cohort into thirds. Baseline characteristics and imaging characteristics of these 3 groups revealed important differences suggesting a more advanced patophysiology phenotype for those with lead-related TR, particularly presenting both the largest 4D-CTA-derived TV maximum coaptation gap and anatomical regurgitant orifice area (see Figure 1).
At regression analysis, time from CIED implantation (OR 1.01, CI 1.00-1.09, p=0.031) and &gt;3 leaflets valve morphology (OR 2.90, CI 1.01-8.32, p=0.040) were independently associated with lead-related TR.
After a median follow-up of 18 months, the primary end-point occurred in 36 patients (25%) and was more common among patients with lead-related TR (p-value overall= 0.007, see Figure 2). While no differences in the rate of TV intervention were found, excessive mortality persisted for lead-related TR group even after adjustement for age and gender (HR 6.49, CI 1.72-14.47, p=0.006).

Conclusion
Systematic 4D-CTA in patients with severe TR and presence of a CIED, identified a large number of patients with lead-related TR with important functional and anatomical implications including greater TR severity and &gt; 3 leaflets. These findings appear to have prognostic relevance that might have decision-making implications for patient management.Figure 1Figure 2
Causal association of serum calcium, phosphate, vitamin D, parathyroid hormone, and FGF23 with the risk of aortic stenosis
Authors: Nie W , Zhao Q , Liu J 
Published: October 2024

Abstract

Aim
Disorders of mineral metabolism, including elevated levels of serum calcium, phosphate, 25-hydroxyvitamin D (25OH-VitD), parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23), have been reported in patients with calcific aortic valve stenosis (CAVS). However, evidence of the causal role of mineral metabolism in CAVS is still lacking. We aimed to investigate the causality between mineral metabolism and CAVS.

Methods
A systematic pipeline combining Mendelian randomization (MR), Steiger directionality test, colocalization analysis, protein-protein network, and enrichment analysis was applied to investigate the causal effect. Genome-wide association study (GWAS) and protein quantitative trait loci data for mineral metabolism markers were extracted from large-scale meta-analyses. Summary statistics for CAVS were obtained from two independent GWAS datasets as discovery and replication cohorts (n=374,277 and 653,867).

Results
In MR analysis, genetic mimicry of serum FGF23 elevation was associated with increased CAVS risk [ORdiscovery=3.081 (1.649-5.760), Pdiscovery=4.21×10-4; ORreplication=2.280 (1.461-3.558), Preplication=2.82×10-4] without evidence of reverse causation (Psteiger=7.21×10-98). Strong colocalisation association with CAVS was observed for FGF23 expression in the blood (PP.H4 = 0.96). Additionally, we identified some protein-protein interactions between FGF23 and known CAVS causative genes. Serum calcium, phosphate, 25OH-VitD, and PTH failed to show causal effects on CAVS at Bonferroni-corrected significance (all P&gt;0.05/5=0.01).

Conclusions
Elevated serum FGF23 level is a causal risk factor for CAVS, and its mechanism of action in CAVS development may be independent of its function in regulating mineral metabolism. Hence, FGF23 may serve as a circulating marker and a promising preventive target for CAVS, warranting further investigation.
Electrocardiographic criteria for the diagnosis of left ventricular hypertrophy in patients with severe aortic stenosis
Authors: Emer Egypto Rosa V , Pires L J N T , Nazzetta D C , Tessari F C , Campos C M , Lopes M P , Andrade C E , Trentin B R P , Fernandes J R C , Sampaio R O , Tarasoutchi F 
Published: October 2024

Abstract

Introduction
There is a lack of data regarding the performance of current electrocardiographic (EKG) criteria for left ventricular hypertrophy (LVH) in patients with severe aortic stenosis (AS).

Purpose
To test the performance of the current EKG scores to diagnosis LVH in AS patients, and also to compare the performance of a new proposed score.

Methods
The present study evaluated 80 patients with severe AS that underwent cardiac magnetic resonance to diagnose LVH, defined as left ventricular indexed mass of 95 g/m² for female and 115 g/m² for male patients. The EKG criteria used for left ventricular hypertrophy were Sokolow-Lyon criteria, Romhilt-Estes point score system, Cornell voltage criteria and Peguero-Lo Presti criteria.

Results
Among the 80 patients included in analysis, 58.7% were male and the mean age was 64±8 years. There was a high prevalence of comorbidities, highlighting diabetes (32.5%), hypertension (67.5%), atrial fibrillation (5.0%) and coronary artery disease (11.3%). Regarding echocardiogram, the median left ventricle ejection fraction was 64 (56-68)% and the median indexed aortic valve area was 0.43 (0.35-0.49) cm²/m². Cardiac magnetic resonance analysis demonstrated a mean left ventricle mass of 168±55g, and the LVH incidence was 26.3%. Regarding EKG, Strain pattern was found in 49.1% of the patients, Cornell voltage criteria was positive in 51.3%, Sokolow-Lyon criteria in 51.3%, Romhilt-Estes point score system in 42.5% and Peguero-Lo Presti criteria in 61.3%. Discriminative capacity of electrocardiographic criteria for LVH is shown in Figure 1. Peguero-Lo Presti score had the best diagnostic accuracy in the overall population and in male sex (AUC 0.776), while Cornell voltage criteria had the best diagnostic accuracy in female patients (AUC 0.776). Based on linear regression model, the proposed score was created to predict LVH at cardiac magnetic resonance: 48 + (1.3 x Deepest S wave) + (0.5 x S wave in V1 or V2 plus R wave in V5). The proposed score cutoff value of 90.5 mm had a sensitivity of 0.765 and specificity of 0.707 (for male sex: 0.769 and 0.655, respectively; for female sex: 0.750 and 0.759, respectively). Compared to the scores described in the literature, the proposed score had the best area AUC for the overall population (Figure 1), for female and male patients (AUC 0.796, 0.819 and 0.780, respectively).

Conclusion
In patients with severe AS, the proposed score had the best diagnostic accuracy compared to the scores described in the literature for LVH identification, followed by Peguero-Lo Presti score, even when analyzed based on gender. Besides, the proposed score had also acceptable sensitivity and specificity for LVH detection.AUC of electrocardiographic scores.
Prognostic impact of left ventricular myocardial work in patients undergoing surgery for primary mitral regurgitation
Authors: Nabeta T , Peters F , Wu H , Palmen M , Tomsic A , Marsan N A , Bax J J , Van Der Bijl P 
Published: October 2024

Abstract

Background
Although left ventricular ejection fraction (LVEF) is widely used as a parameter for the assessment of LV systolic function, LVEF can overestimate LV systolic function in patients with severe mitral regurgitation (MR) due to its high load-dependency. Echocardiography-based, left ventricular myocardial work (LVMW) can assess LV function by incorporating LV afterload.

Purpose
This study aims to evaluate the prognostic value of LVMW indices in patients with primary MR undergoing mitral valve surgery.

Methods
Individuals who underwent mitral valve surgery for severe primary MR were included. All patients underwent transthoracic echocardiography before surgery. LVMW was derived from a vendor-specific package which integrates LV global longitudinal strain with sphygmomanometric blood pressure to construct pressure-strain loops during the cardiac cycle. (Figure 1) For the LVMW indices, previously-established normal values were used as thresholds. The primary endpoint was all-cause mortality after mitral valve surgery.

Results
A total of 309 patients (mean age 63 ± 12 years, 68% male) with severe, primary MR who underwent surgery, were included. The mean LV global work index (LVGWI) was 1977 ± 537 mmHg% and 132 (43%) patients had impaired LVGWI (≤ 1900 mmHg%). During a median follow-up of 5.0 years (interquartile range, 2.5-8.9), 27 (8.7%) patients died after mitral valve surgery. Patients with impaired LVGWI or LV GLS (≤ 20%) had lower survival rates compared to the group with preserved LVGWI (p &lt;0.01) or LVGLS (p = 0.02), whereas there was no significant difference in the survival rate between patients with LVEF ≤ 60% and &gt; 60%. (Figure 2) Furthermore, LVGWI ≤ 1900 mmHg% demonstrated incremental prognostic value over LVGLS (p = 0.049) for all-cause mortality.

Conclusions
In patients with severe, primary MR who underwent surgery, impaired pre-operative LVGWI was associated with a higher mortality risk. In addition, impaired LVGWI had incremental prognostic value over LVGLS. Based on these findings, LVMW is a promising parameter for predicting postoperative outcome and determining the optimal timing of valve surgery in patients with severe, primary MR.Fig1.Echo-derived Myocardial workFig2.Kaplan-Meier curves
Epidemiological profile and mortality of infective endocarditis over the past decade: a systematic review and meta-analysis of 133 studies comprising 132,355 cases
Authors: Sagris M , Tzoumas A T , Xenos D X , Ntoumaziou A N , Kakargias F K , Liaquat W L , Patel R P , Nagraj S N , Kokkinidis D K , Tsioufis K T , Tousoulis D T , Palaiodimos L P 
Published: October 2024

Abstract

Background
Understanding the epidemiology of infective endocarditis (IE) is crucial in the context of an aging population, increased comorbidities, and the heightened occurrence of healthcare-associated cases. Comprehensive data on causative agents, affected valves, and associated mortality are essential for current clinical practice.

Methods
This systematic review was conducted according to the PRISMA guidelines. A random effects model meta-analysis was conducted. Eligible studies reporting outcomes on IE were identified through a search of the PubMed/Medline database from 2010 to 2021.

Results
One hundred-thirty-three studies with 132,584 patients from six continents were included in the analysis. The most common causative agents of IE were Staphylococci species in 36% of cases, followed by Streptococci species in 26% of cases and Enterococci species in 10% of cases. Of the studies providing further speciation, the predominant species was Staphylococcus aureus with an incidence of 29%, followed by Viridans Streptococcus with an incidence of 12%. We found an in-hospital/30-day mortality of 17% (CI: 16%-19%) from 109 studies worldwide. In the subgroup analysis, the highest mortality rates were observed in Latin America 33% (CI: 28%-38%) and Africa 25% (CI: 21%-30%), while the lowest mortality rates were reported in Oceania 13% (CI: 8%-19%), followed by North America 14% (CI: 11%-18%), Asia 15% (CI: 12%-18%), and Europe 17% (CI: 16%-19%). The aortic valve was affected in 46% of cases, followed by the mitral valve in 43%. Tricuspid valve IE and multivalvular IE were identified in 7% and 14% of the cases, respectively.

Conclusion
Our study highlights the shift in epidemiological profile of IE over the last decade with S. aureus identified as the most common causative microorganism of IE in almost one third of cases. IE remains a highly morbid and fatal condition with high mortality rates even in tertiary and high-expertise centers worldwide. While left-sided IE is by far more common, right-sided IE and multivalvular IE are not rare entities and should be considered early in the differential of patients presenting with suspected IE to decrease the risk of future complications.Global burden of infective endocarditis.
Clinical features of infective endocarditis affecting cardiac implantable electronic devices
Authors: Roldan Guerra A , Barreiro Mesa L , Aguayo Cano N , Urbano Sanchez C , Gonzalez Manzanares R , Crespin Crespin M , Lopez Aguilera J , Delgado Ortega M , Ruiz Ortiz M , Rodriguez Almodovar A , Esteban Martinez F , Mesa Rubio D , Pan Alvarez-Ossorio M 
Published: October 2024

Abstract

Introduction
Infective endocarditis (IE) is a serious condition with high rates of serious complications and mortality. Furthermore, implantation of cardiac electronic devices (peacemakers, ICD, CRT) has been increasing in recent years, with technique-associated infections being one of the main adverse events. Our goal was to analise clinical features of IE as associated with cardiac implantable electronic devices (IE-CIED) and its prognostic impact.

Methods
Prospective study of a cohort of patients diagnosed with IE in our centre from 1987 to 2022. A comparative analysis was performed between patients with IE not associated with cardiac implantable electronic devices (group 1) and those who did (group 2). Clinical, microbiological, echocardiographic and therapeutic variables were analysed and the prognostic impact was evaluated in terms of mortality.

Results
569 patients were analysed, of which 540 (94,9%) belonged to group 1, while 29 (5,1%) belonged to group 2. The mean age was higher in group 2 (65,1 years ±12,9 vs 55,7 years ± 18,7; p=0,011) with male predominance in both populations (67.5% overall). Patients with IE-CIED had a higher proportion of staphylococcus aureus (48.3% vs 19.7%; p&lt;0.001) and staphylococcus epidermidis (34.5% vs 15.6%; p&lt;0.001) infections; nosohusial endocarditis (56.5% vs 20.9%; p&lt;0.001); and underlying heart disease (89.7% vs 67.3%; p=0.012). Furthermore, these patients had a higher proportion of tricuspid valve involvement (18.2% vs 81.8%; p&lt;0.001). Regarding the approach, a higher percentage of surgery was performed in patients with IE-CIED (75.9% vs52.7%; p=0.015). On the other hand, patients with IE not associated to cardiac implantable electronic devices had a higher prevalence of cardiac complications (51.5%vs25.7%;p=0.003), defined as valvular rupture or perforation, pseudoaneurysm, abscess or intracardiac fistula; and central nervous system complications (17.2%vs2.9%;p=0.29).
No significative differences were found in terms of echocardiographic findings compatibles with IE, nor were there any differences in severe complications or early, late or total mort ality.

Conclusions
Infective endocarditis affecting cardiac implantable electronic devices is associated to higher prevalence of staphylococci, underlying heart disease and less involvement of the left heart chambers. Surgery was used to a greater extent in this patients. This entity does not imply a worse prognosis in terms of severe complications or mortality.Table 1.Proportion of IE-CIEDTable 2.Microbiology, mortality
Whole-exome sequencing to identify causative variants in cases of sudden cardiac death below 50 years
Authors: Aimo A , Modena M , Botto N , Vittorini S , Aretini P , Bonuccelli D , Emdin M , Di Paolo M , Giannoni A 
Published: October 2024

Abstract

Background
Sudden cardiac death (SCD) in individuals under 50 frequently remains unexplained, especially when no structural cardiac abnormalities are present, a condition known as sudden arrhythmic death (SAD). This study assesses the utility of whole exome sequencing (WES) with a comprehensive gene panel in elucidating the genetic foundations of SCD.

Methods
SCD autopsy cases from a university hospital (1995-2023) were analysed both retrospectively and prospectively. WES was conducted on 32 cases, employing a virtual panel of 1,304 genes. Variant prioritization was based on pathogenicity according to American College of Medical Genetics and Genomics guidelines.

Results
WES unveiled causative variants in 22 out of 32 cases (68% diagnostic yield). Of these, 12 cases (38%) possessed pathogenic or likely pathogenic variants, and 17 highly suspicious variants of uncertain significance (VUS/LP) were identified in 10 patients (31%). The diagnostic yield of our comprehensive panel (69%) surpassed that of major susceptibility gene panels, with 22% for primary susceptibility genes and 56% for the TruSight Cardio Panel. Half of the cases had multiple variants, underscoring the genetic complexity of SCD. Of the genes analysed, 18 were associated with cardiac disease on OMIM or ClinGen, while 9, unique to our panel, were linked to cardiac function but had disputed or limited disease associations.

Conclusions
WES with a specific gene panel, a scheme for variant prioritization, and a comprehensive, multidisciplinary approach to variant interpretation is an effective approach to genetic testing in SCD cases ≤50 years.Added value of WES