LncRNA MFRL regulates the phenotypic switch of vascular smooth muscle cells to attenuate arterial remodeling by encoding a novel micropeptide MFRLP.

BACKGROUND: Arterial remodeling is a common pathophysiological change in the pathogenesis of cardiovascular diseases in which the phenotypic switch of vascular smooth muscle cells (VSMC) plays an important role. Recently, an increasing number of long non-coding RNAs(lncRNAs) have been shown to encode micropeptides that play biological roles and have great clinical transformation potential. However, the role of micropeptides encoded by lncRNAs in arterial remodeling has not been well studied and requires further exploration. METHODS AND RESULTS: Through bioinformatic analysis and experimental verification, we found that a new lncRNA, the mitochondrial function-related lncRNA (MFRL), encodes a 64-amino acid micropeptide, MFRLP. MFRL and MFRLP play important roles in the phenotypic switch of VSMC. Further experiments showed that MFRLP interacts with mitochondrial cytochrome b to reduce accumulation of reactive oxygen species, suppress mitophagy and inhibit the VSMC switch from contractile to synthetic phenotype. CONCLUSIONS: LncRNA MFRL encodes the micropeptide MFRLP, which interacts with mitochondrial cytochrome b to inhibit the VSMC switch from contractile to synthetic phenotype and improve arterial remodeling.

Baseline characteristics of patients with heart failure with mildly reduced or preserved ejection fraction: The FINEARTS-HF trial.

AIMS: To describe the baseline characteristics of participants in the FINEARTS-HF trial, contextualized with prior trials including patients with heart failure (HF) with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF). The FINEARTS-HF trial is comparing the effects of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo in reducing cardiovascular death and total worsening HF events in patients with HFmrEF/HFpEF. METHODS AND RESULTS: Patients with symptomatic HF, left ventricular ejection fraction (LVEF) ≥40%, estimated glomerular filtration rate ≥ 25 ml/min/1.73 m2, elevated natriuretic peptide levels and evidence of structural heart disease were enrolled and randomized to finerenone titrated to a maximum of 40 mg once daily or matching placebo. We validly randomized 6001 patients to finerenone or placebo (mean age 72 ± 10 years, 46% women). The majority were New York Heart Association functional class II (69%). The baseline mean LVEF was 53 ± 8% (range 34-84%); 36% of participants had a LVEF <50% and 64% had a LVEF ≥50%. The median N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 1041 (interquartile range 449-1946) pg/ml. A total of 1219 (20%) patients were enrolled during or within 7 days of a worsening HF event, and 3247 (54%) patients were enrolled within 3 months of a worsening HF event. Compared with prior large-scale HFmrEF/HFpEF trials, FINEARTS-HF participants were more likely to have recent (within 6 months) HF hospitalization and greater symptoms and functional limitations. Further, concomitant medications included a larger percentage of sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors than previous trials. CONCLUSIONS: FINEARTS-HF has enrolled a broad range of high-risk patients with HFmrEF and HFpEF. The trial will determine the safety and efficacy of finerenone in this population.

Early LAAO device migration after combined atrial fibrillation ablation and left atrial appendage occlusion.

The combined procedure of catheter ablation and percutaneous left atrial appendage occlusion for patients with atrial fibrillation has been shown to be safe and feasible using radiofrequency energy or cryoballoon.

Genetic Association of Lipid-Lowering Drugs with Aortic Aneurysms: A Mendelian Randomization Study.

AIMS: The lack of effective pharmacotherapies for aortic aneurysms (AA) is a persistent clinical challenge. Lipid metabolism plays an essential role in AA. However, the impact of lipid-lowering drugs on AA remains controversial. The study aimed to investigate the genetic association between lipid-lowering drugs and AA. METHODS: Our research used publicly available data on genome-wide association studies (GWASs) and expression quantitative trait loci (eQTL) studies. Genetic instruments, specifically eQTLs related to drug-target genes and SNPs (single nucleotide polymorphisms) located near or within the drug-target loci associated with low-density lipoprotein cholesterol (LDL-C), have been served as proxies for lipid-lowering medications. Drug-Target Mendelian Randomization (MR) study is used to determine the causal association between lipid-lowering drugs and different types of AA. RESULTS: The MR analysis revealed that higher expression of HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase) was associated with increased risk of AA (OR = 1.58, 95% CI = 1.20-2.09, p = 1.20 × 10-03) and larger lumen size (aortic maximum area: OR = 1.28, 95% CI = 1.13-1.46, p = 1.48 × 10-04; aortic minimum area: OR = 1.26, 95% CI = 1.21-1.42, p = 1.78 × 10-04). PCSK9 (Proprotein convertase subtilisin/kexin type 9) and CETP (Cholesteryl ester transfer protein) show a suggestive relationship with AA (PCSK9: OR = 1.34, 95% CI = 1.10-1.63, p = 3.07 × 10-03; CETP: OR = 1.38, 95% CI = 1.06-1.80, p = 1.47 × 10-02). No evidence to support genetically mediated NPC1L1 (Niemann-Pick C1-Like 1) and LDLR (low-density lipoprotein cholesterol receptor) are associated with AA. CONCLUSIONS: This study provides causal evidence for the genetic association between lipid-lowering drugs and aortic aneurysms. Higher gene expression of HMGCR, PCSK9, and CETP increases AA risk. Furthermore, HMGCR inhibitors may link with smaller aortic lumen size.

This Mendelian Randomization study used publicly available data involving over 1 million individuals to demonstrate the causal relationship between five target genes of LDL-C-lowering medicines and the risk of aortic aneurysms, and implied one lipid-lowering drug may link with the lumen size of aortic aneurysms. Key findings High expression of HMGCR, PCSK9, and CETP was positively correlated with the risk of aortic aneurysms, highlighting that the corresponding lipid-lowering drugs may be preferred for preventing arterial aneurysms in high-risk individuals with dyslipidemia. We found that genetically predicted HMGCR inhibitors were positively associated with smaller aortic lumen size, which is the first time to support the causal association of gene HMGCR on the lumen size of aortic aneurysms.

Echocardiographic Imaging in Transcatheter Structural Intervention: An AAE Review Paper.

Transcatheter structural heart intervention (TSHI) has gained popularity over the past decade as a means of cardiac intervention in patients with prohibitive surgical risks. Following the exponential rise in cases and devices developed over the period, there has been increased focus on developing the role of "structural imagers" amongst cardiologists. This review, as part of a growing initiative to develop the field of interventional echocardiography, aims to highlight the role of echocardiography in myriad TSHIs available within Asia. We first discuss the various echocardiography-based imaging modalities, including 3-dimensional echocardiography, fusion imaging, and intracardiac echocardiography. We then highlight a selected list of structural interventions available in the region-a combination of established interventions alongside novel approaches-describing key anatomic and pathologic characteristics related to the relevant structural heart diseases, before delving into various aspects of echocardiography imaging for each TSHI.

First-in-human study of the K-Clip™ transcatheter annular repair system for severe functional tricuspid regurgitation.

BACKGROUND: Severe TR is associated with impaired prognosis while limited interventional options available. The purpose of this observational first-in-human experience with the K-Clip™ transcatheter tricuspid annular reconstruction system is to investigate its feasibility, safety as well as short-term clinical impact on patients with severe functional tricuspid regurgitation (TR). METHODS: In this compassionate-use, prospective, multi-center, single-arm study, 15 patients with severe symptomatic functional TR were treated with the K-Clip™ system and followed up at 30 days after discharge. Feasibility endpoints consisted of safety (major clinical cardiovascular events (MACEs), echocardiographic, clinical and functional endpoints. RESULTS: All the 15 patients (9 males, 72.67 ± 9.42 years of age) successfully received implants and no MACEs were reported throughout the study at 30 days. Between baseline and 30 days, echocardiography showed remarkable reduction of tricuspid annular circumference and area by 14.30% and 25.96%. Improvement of ≥ + 2 grade and ≥ +3 grade TR was presented in 9/15(60.00%) and 4/15(26.67%) respectively while 10/15(66.67%) of patients had ≤ moderate TR. Clinical evaluation indicated that 86.67% of patients were finally in NYHA functional class I or II (p<0.001) and overall Kansas City Cardiomyopathy Questionnaire score improved from 62.28 ± 18.97 to 77.90 ± 11.70 (p = 0.016). CONCLUSION: Our first-in-human results of the transcatheter tricuspid annular reconstruction using the K-Clip™ system demonstrated initial favorable procedural success, acceptable safety and remarkable TR reduction in consistent with significant clinical improvement. Larger-scaled prospective trials with longer follow-up duration are warranted to further determine whether these promising findings could be promoted to a broader population in the long term.

Insights into the toxicological effects of nanomaterials on atherosclerosis: mechanisms involved and influence factors.

Atherosclerosis is one of the most common types of cardiovascular disease and is driven by lipid accumulation and chronic inflammation in the arteries, which leads to stenosis and thrombosis. Researchers have been working to design multifunctional nanomedicines with the ability to target, diagnose, and treat atherosclerosis, but recent studies have also identified that nanomaterials can cause atherosclerosis. Therefore, this review aims to outline the molecular mechanisms and physicochemical properties of nanomaterials that promote atherosclerosis. By analyzing the toxicological effects of nanomaterials on cells involved in the pathogenesis of atherosclerosis such as vascular endothelial cells, vascular smooth muscle cells and immune cells, we aim to provide new perspectives for the prevention and treatment of atherosclerosis, and raise awareness of nanotoxicology to advance the clinical translation and sustainable development of nanomaterials.

Fragmented Vortex in Heart Failure With Reduced Ejection Fraction: A Prospective Vector Flow Mapping Study.

OBJECTIVE: Heart failure with reduced ejection fraction (HFrEF) is associated with structural and functional left ventricular changes. We compared intracardiac vortices between patients with HFrEF and normal participants using echocardiographic vector flow mapping, a novel intracardiac vortex analysis technology. METHODS: Transthoracic echocardiography was performed on 20 patients with HFrEF (age: 61 ± 15 y, 15 men) and 20 normal participants (age: 59 ± 12 y, 12 men) age- and sex-balanced at the cohort level. Systolic and diastolic energy loss, area (indexed by left ventricular end-diastolic diameter), circulation (reflects vortex strength) and relative positions of the largest vortex during systole (S-vortex), early (E-vortex) and late (A-vortex) diastole and maximal number of vortices in a single frame (MNV) were assessed. DISCUSSION: Patients with HFrEF had disproportionately sized vortices with smaller indexed vortex areas (p < 0.0001), and more fragmented vortices with higher MNV during both systole (p = 0.030) and diastole (p < 0.0001). These accompanied higher diastolic energy loss (p = 0.001). Additionally, the E-vortex (p = 0.002) and A-vortex (p < 0.0001) were more apically positioned, and the S-vortex was weaker (p = 0.033) in patients with HFrEF. More severe fragmentation (higher MNV) correlated with worse energy efficiency (higher energy loss). CONCLUSION: Patients with HFrEF had more fragmented intracardiac vortices and lower energy efficiency predominantly during diastole.

Complete region of interest reconstruction by fusing multiview deformable three-dimensional transesophageal echocardiography images.

BACKGROUND: While three-dimensional transesophageal echocardiography (3D TEE) has been increasingly used for assessing cardiac anatomy and function, it still suffers from a limited field of view (FoV) of the ultrasound transducer. Therefore, it is difficult to examine a complete region of interest without moving the transducer. Existing methods extend the FoV of 3D TEE images by mosaicing multiview static images, which requires synchronization between 3D TEE images and electrocardiogram (ECG) signal to avoid deformations in the images and can only get the widened image at a specific phase. PURPOSE: This work aims to develop a novel multiview nonrigid registration and fusion method to extend the FoV of 3D TEE images at different cardiac phases, avoiding the bias toward the specifically chosen phase. METHODS: A multiview nonrigid registration and fusion method is proposed to enlarge the FoV of 3D TEE images by fusing dynamic images captured from different viewpoints sequentially. The deformation field for registering images is defined by a collection of affine transformations organized in a graph structure and is estimated by a direct (intensity-based) method. The accuracy of the proposed method is evaluated by comparing it with two B-spline-based methods, two Demons-based methods, and one learning-based method VoxelMorph. Twenty-nine sequences of in vivo 3D TEE images captured from four patients are used for the comparative experiments. Four performance metrics including checkerboard volumes, signed distance, mean absolute distance (MAD), and Dice similarity coefficient (DSC) are used jointly to evaluate the accuracy of the results. Additionally, paired t-tests are performed to examine the significance of the results. RESULTS: The qualitative results show that the proposed method can align images more accurately and obtain the fused images with higher quality than the other five methods. Additionally, in the evaluation of the segmented left atrium (LA) walls for the pairwise registration and sequential fusion experiments, the proposed method achieves the MAD of (0.07 ± 0.03) mm for pairwise registration and (0.19 ± 0.02) mm for sequential fusion. Paired t-tests indicate that the results obtained from the proposed method are more accurate than those obtained by the state-of-the-art VoxelMorph and the diffeomorphic Demons methods at the significance level of 0.05. In the evaluation of left ventricle (LV) segmentations for the sequential fusion experiments, the proposed method achieves a DSC of (0.88 ± 0.08), which is also significantly better than diffeomorphic Demons at the 0.05 level. The FoVs of the final fused 3D TEE images obtained by our method are enlarged around two times compared with the original images. CONCLUSIONS: Without selecting the static (ECG-gated) images from the same cardiac phase, this work addressed the problem of limited FoV of 3D TEE images in the deformable scenario, obtaining the fused images with high accuracy and good quality. The proposed method could provide an alternative to the conventional fusion methods that are biased toward the specifically chosen phase.

Advances in Procedural Echocardiographic Imaging in Transcatheter Edge-to-Edge Repair for Mitral Regurgitation.

Transcatheter edge-to-edge repair (TEER) therapy is recommended by the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for selected patients with symptomatic severe or moderate-severe mitral regurgitation (MR). Echocardiography, in particular transesophageal echocardiography (TEE), plays a critical role in procedural planning and guidance for TEER. Recent innovations and advances in TEE techniques including three-dimensional (3D) imaging, unlimited x-plane imaging, live 3D multiplanar reconstruction, as well as transillumination imaging with color Doppler and transparency rendering have further enhanced procedural imaging for TEER, especially for complex diseases including commissural defects, clefts, and multi-segment pathologies. This review discusses the technology of these advanced procedural imaging techniques and provides a "step-by-step" guide on how to apply them during the TEER procedure with a focus on their added values in treatment of complex valve lesions.

Feasibility and Accuracy of Automated Three-Dimensional Echocardiographic Analysis of Left Atrial Appendage for Transcatheter Closure.

BACKGROUND: Procedural success of transcatheter left atrial appendage closure (LAAC) is dependent on correct device selection. Three-dimensional (3D) transesophageal echocardiography (TEE) is more accurate than the two-dimensional modality for evaluation of the complex anatomy of the left atrial appendage (LAA). However, 3D transesophageal echocardiographic analysis of the LAA is challenging and highly expertise dependent. The aim of this study was to evaluate the feasibility and accuracy of a novel software tool for automated 3D analysis of the LAA using 3D transesophageal echocardiographic data. METHODS: Intraprocedural 3D transesophageal echocardiographic data from 158 patients who underwent LAAC were retrospectively analyzed using a novel automated LAA analysis software tool. On the basis of the 3D transesophageal echocardiographic data, the software semiautomatically segmented the 3D LAA structure, determined the device landing zone, and generated measurements of the landing zone dimensions and LAA length, allowing manual editing if necessary. The accuracy of LAA preimplantation anatomic measurement reproducibility and time for analysis of the automated software were compared against expert manual 3D analysis. The software feasibility to predict the optimal device size was directly compared with implanted models. RESULTS: Automated 3D analysis of the LAA on 3D TEE was feasible in all patients. There was excellent agreement between automated and manual measurements of landing zone maximal diameter (bias, -0.32; limits of agreement, -3.56 to 2.92), area-derived mean diameter (bias, -0.24; limits of agreement, -3.12 to 2.64), and LAA depth (bias, 0.02; limits of agreement, -3.14 to 3.18). Automated 3D analysis, with manual editing if necessary, accurately identified the implanted device size in 90.5% of patients, outperforming two-dimensional TEE (68.9%; P < .01). The automated software showed results competitive against the manual analysis of 3D TEE, with higher intra- and interobserver reproducibility, and allowed quicker analysis (101.9 ± 9.3 vs 183.5 ± 42.7 sec, P < .001) compared with manual analysis. CONCLUSIONS: Automated LAA analysis on the basis of 3D TEE is feasible and allows accurate, reproducible, and rapid device sizing decision for LAAC.

Peri-procedural Trans-esophageal Echocardiographic Sizing of the Native Left Ventricular Outflow Tract During Edwards INTUITY Valve Implantation.

Background: The Edwards INTUITY rapid deployment valve was anchored on the left ventricular outflow tract (LVOT) by radial force akin to transcatheter balloon-expandable valves. This design feature facilitates minimally invasive and complex procedures but comes at the price of compressing the atrioventricular conduction bundle and potential requirement for pacemaker implantation. Methods: A retrospective observational study was conducted on 30 consecutive patients who received the INTUITY valve at our institution from August 2018 to January 2021. Demographical, clinical, and echocardiographic parameters were collected for 90 days post-operatively. The diameter of the native LVOT at the landing site of the sub-annular stent was retrospectively measured using archived trans-esophageal echocardiographic images. A line was drawn from the inner edge of the septal endocardium to the inner edge of the anterior mitral leaflet in mid-systole, parallel to the aortic annulus, 6-8 mm apical to the aortic annulus depending on the valve size and the corresponding stent length. Risk factors associated with new onset conduction disturbances, defined as the occurrence of bundle branch block or complete heart block, were analyzed. Results: Operative mortality was 3.3%. Pre-operatively, permanent pacemakers were required for two patients who were excluded from the subsequent analysis. New onset conduction disturbances occurred in four of the remaining 28 patients (14.3%). This included two incidences of persistent left bundle branch block and two incidences of permanent pacemaker implantation due to complete heart block. Univariate analysis identified over-sizing of the native LVOT by 5 mm or more as a significant risk factor associated with conduction disturbance. Conclusion: During INTUITY vale implantation, in addition to the aortic annulus, the landing site of the sub-annular stent within the native LVOT should also be sized pre-bypass. Over-sizing the native LVOT by 5 mm or more was associated with an increased risk of new onset conduction disturbances and should be avoided.

Age-Related Changes in Left Ventricular Vortex Formation and Flow Energetics.

Analysis of the cardiac vortex has been used for a deeper understanding of the pathophysiology in heart diseases. However, physiological changes of the cardiac vortex with normal aging are incompletely defined. Vector flow mapping (VFM) is a novel echocardiographic technique based on Doppler and speckle tracking for analysis of the cardiac vortex. Transthoracic echocardiography and VFM analysis were performed in 100 healthy adults (33 men; age = 18-67 years). The intracardiac flow was assessed throughout the cardiac cycle. The size (cross-sectional area) and circulation (equivalent to the integral of normal component of vorticity) of the largest vortices in systole (S-vortex), early diastole (E-vortex), and late diastole (A-vortex) were measured. Peak energy loss (EL) was calculated from information of the velocity vector of intracardiac flow in systole and diastole. With normal aging, the circulation (p = 0.049) of the E-vortex decreased, while that of the A-vortex increased (both p < 0.001). E-vortex circulation correlated directly to e' (p = 0.003), A-vortex circulation correlated directly to A and a' (both p < 0.001), and S-vortex circulation correlated directly to s' (p = 0.032). Despite changes in vortex patterns, energy loss was not significantly different in older individuals. Normal aging is associated with altered intracardiac vortex patterns throughout the cardiac cycle, with the late-diastolic A-vortex becoming physiologically more dominant. Maintained energy efficiency accompanies changes in vortex patterns in aging hearts.

Association of C-reactive protein and non-steroidal anti-inflammatory drugs with cardiovascular events in patients with psoriatic arthritis: a time-dependent Cox regression analysis.

AIMS: Psoriatic arthritis (PsA) is associated with accelerated atherosclerosis due to underlying inflammation. Whether inflammatory burden and drugs used to suppress inflammation over time are associated with cardiovascular (CV) events remained unclear. This study aims to examine the time-varying effect of C-reactive protein (CRP) levels and the use of drugs, including non-steroidal anti-inflammatory drugs (NSAIDs) and disease modifying anti-rheumatic drugs, on the risk of CV events independent of traditional CV risk factors in PsA patients. METHODS: A retrospective cohort analysis was performed in patients with PsA who were recruited from 2008 to 2015 and followed until the end of 2019. The outcome was occurrence of a first CV event. Framingham risk score (FRS) was used to quantify the traditional CV risk. Cox proportional hazard models with time-varying CRP levels and drugs used were analysed to identify the risk factors for CV events in PsA patients. RESULTS: Two hundred patients with PsA [median age: 47.5 (40.0-56.0); male: 119 (59.5%)] were recruited. After a mean follow-up of 8.8 ± 3.8 years, 30 (15%) patients developed a first CV event. The multivariable Cox regression model showed that time-varying CRP level [hazard ratio (HR) 1.02, 95% confidence interval (CI) 1.00-1.04] and NSAIDs exposure (HR 0.38, 95% CI 0.15-0.96) were significantly associated with CV events after adjusting for baseline FRS (HR 5.06, 95% CI 1.84-13.92). CONCLUSION: Increased inflammatory burden as reflected by elevated CRP level was associated with increased risk of CV events, while the risk was significantly reduced with NSAIDs use in PsA patients.