Valvular Heart Disease Research Articles

Nomogram-based prediction of MACE in older adults with STEMI

Abstract Introduction Despite the significant progress made in diagnosing and treating patients with ST elevation myocardial infarction (STEMI), high-risk subgroups such as older adults (those over 65 years-old) still face considerable residual risk of major adverse cardiovascular events (MACE) following treatment for their index event. Thus, it is crucial to create accurate, validated, and actionable tools to stratify patients according to their risk of MACE after admission for STEMI. Purpose Utilizing clinical data obtained from a registry of patients diagnosed with STEMI, this study aims to develop a nomogram that can reliably predict the likelihood of MACE incidence. Methods Using a large electronic single-center registry, all consecutive patients with STEMI, undergoing primary percutaneous coronary intervention (PCI), and aged 65 and above were identified. Demographic, laboratory, clinical and intra-procedural variables were examined. Univariate and multivariate logistic regression analyses were utilized to identify those factors which were independently associated with MACE incidence in the post PCI follow-up period. A nomogram was developed in a training set, and performance metrics such as receiver operating curves (ROC), calibration plots, and decision curve analysis were used for validation in a testing set. Analyses were performed using tidyverse and rms packages in R programming language. Results 1946 patients were included in the study and split into 70% training and 30% testing sets. Both groups were similar in terms of baseline demographic and clinical characteristics. Mean follow-up period was 17 months. Total MACE incidence in the post PCI follow-up period was 18%. Thirty-eight factors with limited missing information (<5%) were examined for their relationship with MACE incidence and after performing univariate and multivariate analysis 8 were selected for construction of the nomogram: left-ventricular ejection fraction (LVEF), serum creatinine, hemoglobin and fasting blood glucose levels, presence of valvular heart disease, post PCI TIMI flow grade, diameter of the stent placed in the culprit lesion, and presence of shock in the post PCI setting. The area under the curve (AUC) for MACE prediction in post PCI follow-up period showed acceptable discrimination (c-statistic=73%, 95%CI 71.2% to 76.3%). Calibration plots demonstrated that the nomogram model was well-calibrated, and its predictions were closely aligned with observed outcomes. Additionally, decision curve analysis indicated that the model exhibited strong discriminatory ability in predicting MACE. Conclusions A nomogram developed using a combination of laboratory, clinical, and procedural parameters reliably predicts future risk for MACE in older adults following STEMI. Future implementation of this model may identify the highest risk individuals to target more aggressive preventive efforts in a vulnerable cohort of patients.Plot 1Plot 2

Prognostic impact of cardiac events in asymptomatic mitral regurgitation

Abstract Background Mitral regurgitation (MR) is the most common valvular heart disease in adults and is associated with increased morbidity and mortality. Treatment recommendations of degenerative MR have been liberalized, however, the role of asymptomatic patients is still insufficiently defined. Purpose The purpose of this study were to evaluate the prevalence of cardiac events in a large asymptomatic MR cohort, based on health insurance data analysis, in comparison with healthy propensity score-matched general population and to define the prognostic impact of such cardiac events on ten-year survival. Methods We retrospectively analyzed health insurance claims data from Germany’s second largest health insurance fund, which maintains longitudinal data on outpatient and inpatient medical services for 8.7 million German residents. We included all patients with an outpatient diagnosis of MR (I34.0) in a minimum of two quarters during a calendar year and first recorded diagnosis between 2008 and 2011. To identify an asymptomatic MR cohort (study group), all patients with at least one complication attributable to MR / mitral valve intervention during the incidence quarter of MR were excluded. Ten-year outcomes were compared between study group vs. age- and sex-matched healthy control group. Cardiac events of interest were new congestive heart failure, new-onset atrial fibrillation, pulmonary hypertension, or cardiac decompensation. Results A total of 56.577 (62.7%) asymptomatic MR patients were identified from the whole cohort of 90.245 individuals with a newly diagnosed MR in the BARMER database. During a ten-year follow-up, 26.282 (46.5%) patients in the study group experienced at least one cardiac event vs. 11.763 (20.8%) individuals in the control group (OR: 3.31, 95%CI: 0.251-0.262, P<0.0001). The occurrence of at least one cardiac event (i.e., congestive heart failure, new-onset atrial fibrillation, pulmonary hypertension or cardiac decompensation) in the study group was associated with a significantly worse ten-year survival as compared to the control group. The risk of cardiac events was age- and sex-dependent, while female patients with an asymptomatic MR had a lower risk as compared to males in all age groups (OR: 0.38, 95%CI: -1.193- -0.754, P<0.0001). Only 1.530 (2.7%) patients underwent mitral valve (MV) intervention in the study group during ten-year follow-up. Conclusions Our study reveals high incidence of asymptomatic MR in a representative cohort of health insurance claims data in Germany. Every second patient with an asymptomatic MR experiences at least one cardiac event during a ten-year follow-up period that is associated with a significantly worse survival. The definition of asymptomatic MR cohort at risk of developing cardiac events may potentially improve early treatment strategies and lead to better outcome in the future.Abstract picture

Sex differences in severe aortic stenosis undergoing surgical replacement

Abstract Background Aortic stenosis (AS) is the most common valvular heart disease in developed countries. Sex differences have been described in AS pathophysiology and left ventricular (LV) remodelling, as well as clinical presentation and response to therapies (1). However, sex differences in LV function parameters, namely global longitudinal strain (GLS), have been scarcely explored so far. Purpose To investigate sex differences, taking into account GLS, in patients with severe AS referred to surgical aortic valve replacement (SAVR). Methods The study population was from a single centre, prospective registry of patients with severe native valve AS who were referred for SAVR between June 2020 to October 2022. Severe AS was defined by standard guideline criteria (2). All patients underwent an echocardiogram immediately before and at least 3 months after surgery. Results Table 1 recapitulates sex differences in our population (n=119, 43% women). No differences in age or cardiovascular (CV) risk factors were noted. Clinical presentation and AS etiology were also similar. At baseline, women had lower EuroSCORE (p=0.039), creatinine (p <0.001), and haemoglobin levels (p=0.001). The echocardiogram showed a higher mean aortic valve gradient in women (Gmean, 62 vs. 50 mmHg, p=0.002). Women also had higher relative wall thickness (RWT, 0.49 vs. 0.42, p=0.037), despite lower LV mass index (124.9 vs. 136.6 g/m², p=0.037). Regarding LV function, women showed higher EF (64% vs. 60%, p=0.002) and GLS (16.5% vs. 14.6%, p=0.006) values. This is partially explained by the higher prevalence of concomitant coronary artery disease (CAD) in men, more frequently subjected to a concomitant coronary artery bypass graft than women (CABG, 38% vs. 8%, p <0.001). Post-operative complications had similar rates in men and women. After a median follow-up of 16 (6-18) months, death from any cause (6.0% vs. 1.5%, p=0.186) and rehospitalization for CV causes (14.0% vs. 4.0%, p=0.055) tended to be more frequent among women. When considering patients with severe AS alone (n=89), women had higher Gmean (64 vs. 53 mmHg, p=0.035) and EF (65% vs. 62%, p=0.045) but similar GLS (16.9% vs. 16.6%, p=0.230) as compared to men (Figure 2). At follow-up, EF and GLS failed to improve in both sexes and no differences were noted between women and men (EF 60% vs. 60%, p=0.476; GLS 15.9% vs. 16.0%, p=0.976). Conclusions In a population of all-comers patients with severe AS undergoing SAVR, women showed higher Gmean, EF, and GLS values. This is partially due to the higher prevalence of a concomitant CAD in men. When considering patients with AS alone, women still had higher EF and Gmean than men, despite a similar GLS. Future larger prospective studies with longer follow-up are needed in order to further characterize such differences and correlate them with specific outcomes.

Aortic valve tract dynamics in normal-flow low-gradient and normal-flow high-gradient severe aortic stenosis

Abstract Introduction Aortic stenosis (AS) is the most common valvular heart disease in developed countries. Severe AS is defined as a mean pressure gradient (MG) ≥ 40 mmHg, a maximum aortic jet velocity≥4 m/s and an aortic valve area (AVA)≤1 cm2. However, classification of AS severity may be challenging due to discordant results on echocardiography. The normal-flow low-gradient severe AS (NFLG-AS) is defined as AVA≤1 cm2, MG<40 mmHg, left ventricular ejection fraction ≥ 50%, and stroke volume index (SVi) ≥ 35 ml/m2, whereas in the presence of MG > 40mmHg the condition is described as normal-flow high-gradient AS (NFHG-AS). Purpose The purpose of this study was to seek differences in the dynamic changes of the aortic valve tract throughout the cardiac cycle between the two clinical entities: NFHG-AS (Group 1) and NFLG-AS (Group 2). Methods In total, 130 patients with normal flow severe AS who underwent TAVI and had 3D transoesophageal echocardiographic data sets were screened. 38 patients with NFHG-severe AS and 40 patients with NFLG-severe AS with matching clinical characteristics and aortic valve area were identified. A custom-made semi-automated application developed by SQ was used. The application allows tracking of the aortic valve tract surface throughout the cardiac cycle in 3D transoesophageal echocardiograms and provides measurements of the geometrical planes at 4 levels: left ventricular outflow tract (LVOT), aortic annulus (AoA), sinuses of Valsalva (SoV) and sinotubular junction (STJ). Results The echocardiographic characteristics and the dynamic changes of the aortic valve tract between the two groups are shown in Tables 1 and 2. Both groups had comparable echocardiographic characteristic apart from the mean aortic valve pressure gradient as expected. With regards to the aortic valve tract geometrical dynamic changes, the relative LVOT and AoA area changes were bigger in Group 1 (36.8±15.9% vs 29.1±11.9%; p=0.017 and 21.0±8.39% vs 17.1±6.6%; p=0.028). The SoV and STJ relative changes were similar between the two groups. The same applies to aortic stiffness parameters, namely compliance and distensibility of the ascending aorta, systemic arterial compliance, and valvulo-arterial impedance. Conclusion The LVOT and aortic annulus area demonstrate more prominent dynamic changes in patients with normal-flow high-gradient severe AS compared to individuals with normal-flow low-gradient severe AS. While the SoV and the STJ geometry does not change significantly through the cardiac cycle, a more elastic outflow tract allows larger expansion in systole and higher pressure gradients across the aortic valve, whereas a stiffer outflow tract and annulus result in lower pressure gradients, despite the presence of severe aortic stenosis (AVA<1.0cm2). These differences in dynamic LVOT and aortic annulus changes may explain the discrepancy between aortic valve area and pressure gradients in patients with normal-flow low-gradient AS.

Effects of empagliflozin on myocardial transcriptome in rats with aortic stenosis-induced heart failure

Abstract Introduction Aortic stenosis (AS) represents one of the most prevalent valvular heart diseases and an important cause of heart failure. Currently, no medical therapies influence the natural history of aortic stenosis. Although sodium glucose co-transporter 2 inhibitors (SGLT2i) have improved cardiovascular outcomes in heart failure patients with both reduced and preserved ejection fraction, their action mechanisms are not clear. Transcriptome analysis present great potential to identify biomarkers of disease and to gain insight into disease pathophysiology. In this study, we analyzed myocardial mRNA profile in aortic stenosis rats treated with empagliflozin. Methods Eighteen weeks after supra-aortic banding surgery, male Wistar rats were divided into 3 groups: Sham (n=15); aortic stenosis (AS, n=27); AS+empagliflozin (AS-EMP, n=27). Empagliflozin (10 mg/kg/day) was added to rat chow for 8 weeks. Transcriptome of left ventricle (LV) myocardium was studied by RNA-sequencing (sample size: 5 per group). Differential gene expression was analyzed in R environment using the DESeq2 package. Genes were considered differentially expressed (DEG) when they exhibited a log2 fold change (log2FC) higher than 1 (upregulated) or lower than -1 (downregulated), coupled with an adjusted p-value below 0.05. Functional enrichment analysis using gene ontology was performed by the online tool Enrich. Statistical analysis: ANOVA and Tukey. Results AS-EMP had lower LV diastolic diameter (Sham 8.39±0.57; AS 9.80±0.53*; AS-EMP 9.08±0.87# mm; p<0.05: * vs Sham; # vs AS), left atrium diameter (Sham 5.68±0.40; AS 9.67±1.00*; AS-EMP 8.97±1.36*# mm; p<0.05: * vs Sham; # vs AS), and LV mass (Sham 0.85±0.11; AS 2.19±0.27*; AS-EMP 1.76±0.34*# g; p<0.05: * vs Sham; # vs AS) than AS. A total of 1246 differentially expressed genes were identified, comprising 663 upregulated genes (70 genes in AS vs SHAM; 593 in AS-EMP vs AS) and 583 downregulated genes (35 genes in AS vs SHAM; 548 in AS-EMP vs AS). Most of the differentially expressed genes were enriched in processes such as extracellular matrix and structure organization, signal transduction regulation, and substrate-dependent cell migration (AS vs SHAM), as well as myocardial contraction, negative regulation of programmed cell death, and mitochondrial membrane organization (AS-EMP vs AS). The main upregulated genes were Loxl1, Mfap4, Postn, Col8a1, Pi16, and Nppa in AS vs SHAM; and Mxra8, Zfta, Pnisr, Thoc1, and Ralbp1 in AS-EMP vs AS comparison. The main downregulated genes were Mxra8, Ralbp1, and Tubgcp6 in AS vs SHAM; and Itgb5, Ltbp2, Tmem109, Plec, and Rorc in AS-EMP vs AS comparison. Conclusion We identified myocardial genes and biological processes that are potentially involved in aortic stenosis-induced heart failure. Empagliflozin attenuates cardiac remodeling and modulates myocardial genes involved with myocyte contraction, apoptosis, and mitochondrial organization in aortic stenosis rats.

Racial and ethnic disparities in the incidence of stroke and mortality in atrial fibrillation: a US nationwide study

Abstract Background Atrial fibrillation (AF) is the most common arrhythmia globally and is associated with increased risks of cardiovascular mortality and ischemic stroke. Prior research has demonstrated racial/ethnic disparities in AF outcomes yet this work has been limited to small cohorts and did not adjust for anticoagulant therapy. Purpose We compared incidence of ischemic stroke and death by race/ethnicity for patients with AF in the Veterans Health Administration (VA), the largest integrated, low-cost, national healthcare system in the US. Methods In this retrospective cohort study we identified those with an outpatient diagnosis of AF and a confirmatory diagnosis ≦ 180 days of their index AF diagnosis enrolled in VA from January 1, 2014 to December 31, 2021, with follow-up for outcomes from the index AF diagnosis date until May 31, 2022. To create a cohort of incident AF cases, we excluded patients with an AF diagnosis or anticoagulant therapy in the 2 years prior to their index AF diagnosis. We also excluded patients with pre-existing valvular heart disease, prior stroke, receiving hospice care or who died within 180 days of index AF diagnosis. We categorized our independent variable as race (i.e., non-Hispanic American Indian / Alaska Native [AI/AN], Asian, Black, or White [reference group]), and ethnicity (i.e., Hispanic). Our primary outcomes were incidence of stroke or death at any point within the study follow-up period. To compare these outcomes by race/ethnicity we conducted a survival analysis, adjusting for anticoagulant use as a time-varying covariate along with sociodemographic factors (age, sex, region, area deprivation index), clinical factors (CHADS2VA2Sc stroke risk and HAS-BLED bleeding risk), and facility type. Results There were 187,080 patients in the final cohort including 0.5% AI/AN, 1% Asian, 9% Black, 4% Hispanic, 85% White; mean age was 73 years. Over a mean study follow-up period of 4.43 years, 65,375 (34.9%) patients died and 24,910 (13.3%) developed stroke. The adjusted hazard ratio [95% CI] for death was lower for Hispanic (0.84 [0.78, 0.91]) and Black (0.94 [0.91, 0.97]) patients than White patients. In contrast, the adjusted hazard ratio for stroke incidence was higher for Black (1.21 [1.16, 1.27]) and Hispanic (1.10 [1.03, 1.17]) patients than White patients. There was no difference observed between AI/AN or Asian and White patients in either outcome. Conclusions In a national cohort of patients with incident AF, we identified significantly higher rates of stroke in Black and Hispanic than White patients even controlling for myriad factors including anticoagulant use. Conversely, racial/ethnic disparities in mortality appear to be eliminated in VA, counter to prior data. Understanding the factors, beyond anticoagulation, driving disparities in stroke outcomes and identifying factors reducing mortality among minority groups is critical to improving overall AF care in the largest integrated US health system.Adjusted Hazard Ratios of Study Outcomes

Calcific aortic valve disease-associated long noncoding RNA H19 promotes the osteogenic transition of valvular interstitial cells via the JAG1/NOTCH1 axis

Abstract Background Calcific aortic valve disease (CAVD) is the most prevalent valvular heart disease causing tremendous suffering globally. The osteogenic differentiation of the valvular interstitial cells (VICs) is a key process in the pathogenesis of CAVD leading to calcification and stiffening. Here, we focus on the contribution of long noncoding RNA H19 in the osteogenic differentiation of VICs promoting CAVD. Methods and results A human lncRNA array performed in AVS patients with coronary artery disease (CAD) revealed the differential expression of lncRNA H19. For the experiments in this study, loss of function (LOF) was performed in primary VICs isolated from the aortic valves of patients with CAVD, and commercially-available VICs. Therefore, H19 expression was effectively downregulated via RNAi. Subsequent gene expression analysis via RT-qPCR revealed that the expression of calcification markers RUNX2 and BMP2, as well as the expression of the H19 downstream targets JAG1 and NOTCH1 were unchanged after the H19 knockdown alone. Then, the VICs were additionally treated with osteogenic medium (OM) and procalcifying medium (PCM) for 7 d to induce the calcification of the cells. In the OM, inorganic phosphate is generated in an alkaline phosphatase (ALPL)-dependent manner and integrated into newly formed hydroxyapatite crystals, thus promoting cellular calcification. PCM contains inorganic phosphate to form hydroxyapatite crystals and is therefore not ALPL-dependent. Gene expression analysis via RT-qPCR and protein analysis via immunofluorescence revealed that the calcification markers BMP2 and RUNX2 were upregulated after H19 knockdown and calcification induction. This indicates that H19 regulates the expression of calcification makers promoting cellular calcification. Furthermore, RT-qPCR and immunoblotting revealed the differential expression of several potential H19 downstream targets, namely JAG1, NOTCH1, and STAT3. The analysis showed that the potential downstream targets were upregulated after H19 knockdown and calcification treatment hinting at the involvement of the NOTCH1 or STAT3 pathway in the pathogenesis of CAVD. Moreover, an Alizarin Red S staining of calcified nodules revealed reduced calcification after H19 knockdown and calcification treatment for 21 d. This demonstrates that H19 also regulates a late-stage event in the cellular calcification of VICs. Conclusion Our study showed that H19 regulates calcification marker expression and the expression of potential downstream targets JAG1, NOTCH1, and STAT3 both in healthy and AVS patient VICs. This hints at the involvement of the H19/JAG1/NOTCH1 pathway in the calcification of VICs, which might play a critical role in the pathogenesis of CAVD.

Impact of systolic coronary flow reversal in patients with aortic stenosis: assessment with transthoracic echocardiography

Abstract Background In patients with aortic stenosis (AS), increased systolic wall stress due to increased afterload reduces systolic coronary flow, often leading to systolic coronary flow reversal (SFR) in epicardial coronary arteries. Purpose We used transthoracic echocardiography (TTE) to evaluate severity of AS, left ventricular function, and coronary flow, and investigated echocardiographic indicators associated with SFR. Methods We prospectively evaluated consecutively presenting patients who visited our valvular heart disease outpatient clinic or were admitted to our hospital for investigation of AS (July 2023 to February 2024). Based on ESC guidelines, severity of AS and the left ventricular function were assessed with TTE. At the same time, TTE was used to measure distal left anterior descending coronary artery flow. SFR was defined as the presence of a reversal coronary flow component in systole. Based on the presence or absence of SFR in coronary flow measurements, patients were classified into SFR+ or SFR− groups. The inclusion criteria were AS of moderate or greater severity, and the exclusion criteria were known coronary stenosis and the inability to assess coronary flow. Results Enrolled 28 patients were classified into SFR+ (7 patients) and SFR − (21 patients) groups. Comparing baseline characteristics between the SFR+ and SFR− groups, although there were no significant differences in left ventricular indicators such as left ventricular mass index, left ventricular ejection fraction, stroke volume index, and E/e’ between the two groups, left ventricular global longitudinal strain was significantly lower in the SFR+ group (12.0±3.1%, 14.9±3.0%, p=0.026) (Table 1). Regarding indexes of AS assessment, aortic valve peak velocity and aortic valve mean pressure gradient values were significantly higher in the SFR+ group than in the SFR − group ([475±68 cm/s, 379±55 cm/s, p<0.001] and [56.2±16.5 mm Hg, 34.8±10.5 mm Hg, p<0.001], respectively) (Table 1). Representative cases show Figure 1. Conclusion The presence of SFR in patients with AS assessed using TTE may be a simple echocardiographic index that may be associated with potential decline in left ventricular function and progression of AS.

DELINEATE-Regurgitation: deep learning for automated assessment of aortic, mitral, and tricuspid regurgitation from echocardiography

Abstract Background Valvular heart diseases, including aortic regurgitation (AR), mitral regurgitation (MR), and tricuspid regurgitation (TR) are significant contributors to cardiovascular morbidity and mortality worldwide. Artificial intelligence (AI) may improve echocardiographic assessment, but no models to date have successfully evaluated valvular regurgitation. Purpose The goal of this study was to develop an AI system to improve the accuracy of echocardiographic AR, MR, and TR interpretation. Methods Complete transthoracic echocardiogram (TTE) studies performed at a single center were split into train (n=65,301), validation (14,018), and test sets (13,746). The Deep Learning for Echo Analysis, Tracking, and Evaluation of Valvular Regurgitation (DELINEATE-Regurgitation) system intakes entire TTE studies, identifies color Doppler clips showing each valve, and yields a study level classification of AR, MR, and TR on a 6-grade scale (none/trace, mild, mild-moderate, moderate, moderate-severe, severe) using the cardiologist interpretation as a reference standard. This system used a hybrid neural network, leveraging the spatiotemporal feature learning capabilities of convolutional neural networks with the sequential processing strengths of transformer networks. The end-to-end hybrid approach allows the model to learn nuanced representations of the data including features within and across color Doppler videos. Model accuracy was assessed using quadratically weighted Cohen’s kappa (k), area under the receiver operator characteristic curve (AUROC) for the detection of both "moderate or greater" and "severe" regurgitation, and AI-cardiologist agreement the 6-grade scale. Additionally, an analysis was conducted using a 4-grade regurgitation scale (none/trace, mild, moderate, and severe) by rolling up intermediate classes (mild-moderate and moderate-severe) into the next higher class for both cardiologist determinations and model predictions. Results The DELINEATE-Regurgitation system demonstrated a high accuracy in the classification of AR (k=0.857), MR (k=0.867), and TR (k=0.847) (Figure 1). DELINEATE predicted the same severity as cardiologists (AR 91.8%, MR 79.9%, TR 77.7%) or within ±1 grade accuracy (AR 99.5%, MR 98.6%, TR 98.6%). The models had excellent binary discrimination in the detection of moderate or greater (AR AUROC 99.4, MR 98.6, TR 98.1) and severe (AR 99.7, MR 99.3, TR 99.6) regurgitation (Figure 2). In the 4-grade scale, the model had exact agreement with cardiologists in 92.3% of AR, 82.4% of MR, and 80.6% of TR cases. Panel adjudication of AI-cardiologist disagreement and correlation with quantitative metrics at higher levels of regurgitation will be presented. Conclusions The DELINEATE-Regurgitation AI system demonstrates a high level of accuracy in the assessment of AR, MR, and TR using color Doppler TTE videos. Future work will focus on automating quantification and developing strategies for optimal clinical deployment.Figure 1 - Confusion MatricesFigure 2 - ROC Curves

Targeting an altered sphingolipid profile with consecutive lipotoxicity as therapeutic approach to calcific aortic valve disease

Abstract Background Aortic stenosis due to calcific aortic valve disease (CAVD) is the most common valvular heart disease. In symptomatic patients, without repair the prognosis is poor. Treatment to date is based on surgery or catheter-based interventions. Pharmacological therapy options to prevent the progression of valve calcification are not available. In vascular smooth muscle cells, cellular accumulation of sphingolipids is associated with a proinflammatory response in the sense of lipotoxicity. Chronic inflammatory processes are indeed also essential for aortic valve calcification. Purpose With the subsequent goal of developing innovative treatment approaches for CAVD, we therefore aim to elucidate the unclear role of sphingolipids in the development of CAVD. Methods Human aortic valve and plasma samples of CAVD patients and controls (n=26) were analysed by liquid chromatography–mass spectrometry for lipidomics and proteomics. Human aortic valve interstitial cells (hVICs) were stimulated with ceramides. Calcification was detected by alizarin red staining. mRNA expression of bone-related proteins was determined by qPCR. NF-kB pathway was assessed by proteome profiler. Myriocin and GW4869 were applied to inhibit ceramide biosynthesis. PDTC and MCC950 were used to inhibit NF-kB Pathway and NLRP3 activation. ApoE-/- mice received a gain-of-function PCSK9 adeno-associated virus vector and fed high cholesterol diet for 14 weeks. Myriocin was applied orally over the treatment period to inhibit ceramide de novo synthesis in vivo. Murine echocardiography was used to measure transvalvular velocity and left ventricular function. Calcification degree of murine aortic valve was determined by histological staining. Results A significantly altered sphingolipid profile was observed in aortic valve tissue of CAVD patients (Fig. 1). Ceramide species e.g. Cer (17:1;2O/16:0) were increased. Verifying the biological relevance of these findings in vitro, C2-Cer (d18:1/2:0) enhanced hVIC calcification (Fig. 2). Accordingly, ALP activity and mRNA expression of osteogenic genes RUNX2, ALPL and MSX2 were increased. Furthermore, C2-Cer (d18:1/2:0) enhanced NF-kB p65 phosphorylation and NLRP3 activation, while treatment with both PDTC and MCC950 protected against C2-Cer (d18:1/2:0) induced calcification. Supporting the role of sphingolipid biosynthesis in hVIC calcification, Myriocin and GW4869 both reduced ox-LDL-induced VIC calcification which was reversed by C2-Cer(d18:1/2:0). Finally, Myriocin reduced the degree of calcification and transvalvular jet velocity of aortic valve in the PCSK9-AAV ApoE-/- mice model. Conclusion CAVD is accompanied by an accumulation of ceramides causing lipotoxicity in human aortic valve tissue. Pharmacological modulation of sphingolipid metabolism is an effective approach to prevent the development and progression of aortic valve calcification in vivo and should be considered as a future therapeutic strategy in CAVD patients.Volcano Plot of CAVD tissue lipidomicsC2 Ceramide enhances hVIC calcification

Rare genetic variants in LDLR, APOB, and PCSK9 are associated with aortic stenosis

Abstract Background Aortic stenosis (AS) is the most common cardiac valvular disease in the developed world. Although AS is associated with substantial morbidity and mortality, current treatment options are limited to invasive procedures and reserved for severe symptomatic disease. Genetic studies have linked common variants near lipid genes to AS and cohort studies have linked diagnoses of familial hypercholesterolemia to AS. In contrast, randomized controlled trials have shown no benefit of lipid-lowering therapy in AS. Purpose We aimed to assess the impact on AS conferred by lifelong decreased or increased LDL levels, by studying rare genetic variation in three important lipid handling genes (LDLR, APOB, PCSK9) from a genome-first perspective. Methods We utilized sequencing data and electronic health records from the UK Biobank (UKB) and the All of Us Research Program (AllofUs). We used LOFTEE to identify carriers of truncating variants in LDLR (LDLRtv), APOB (APOBtv) and PCSK9 (PCSK9tv); we used AlphaMissense to identify predicted-damaging missense variants (LDLR-AM, APOB-AM, PCSK9-AM). Linear regression analyses were used to assess the impact of the variant groupings on LDL levels in the UK Biobank, adjusting for sex, age, age^2, and principal components of ancestry. We then conducted Firth’s logistic regression analyses in UK Biobank and AllofUs modelling AS as outcome and variant status as predictor, adjusting for the same covariates; we used an inverse-variance-weighted meta-analysis to combine results. Results We identified 421,058 unrelated participants (N=5,322 AS cases) in the UK Biobank, and 232,170 unrelated participants (N=1,087 AS cases) in AllofUs. Across both cohorts, we identified 198 LDLRtv carriers, 1095 LDLR-AM carriers, 662 APOBtv carriers, 1422 APOB-AM carriers, 712 PCSK9tv carriers and 794 PCSK9-AM carriers. In the UK Biobank LDL values were substantially elevated in LDLRtv (P=1.9x10-48) and LDLR-AM carriers (P=7.5e-200), while LDL levels were substantially decreased in APOBtv (P<1x10-200), APOB-AM (P=6.3x10-19), PCSK9tv (P=1.2x10-114) and PCSK9-AM carriers (P=9.9x10-73; Figure 1). Across UK Biobank and AllofUs, the risk of being diagnosed with AS was strongly increased in LDLRtv (odds ratio [OR]=9.2 [4.32–19.50], P=8e-9) and LDLR-AM carriers (OR=2.76 [1.75–4.35], P=1e-5; Figure 2). Directionally consistent with these effects, we observed a trend towards decreased AS risk among carriers of either APOBtv or PCSK9tv (OR=0.57, [0.30–1.08], P=0.08) and a significantly reduced risk among carriers of APOB-AM or PCSK9-AM (OR=0.46, [0.26-0.82], P=0.009). Conclusion Rare genetic variants that confer lifelong increased LDL levels are associated with substantially increased risk of AS, and vice versa. Our results support a causal role of LDL in AS pathogenesis. In the context of trials demonstrating no benefit in AS, our findings suggest that lipid-lowering may need to be initiated earlier to affect AS development.LDL levels in UK BiobankAS risk in UK Biobank and AllofUs

Predictive factors for recurrent tricuspid regurgitation after tricuspid annuloplasty: 3D echocardiography study

Abstract Introduction There is growing concern about the recurrence of tricuspid regurgitation (TR) after tricuspid annuloplasty (TA) in individuals with functional tricuspid regurgitation (FTR). While TA is effective in treating FTR, a comprehensive understanding of the echocardiographic factors influencing TR recurrence is crucial. Aim This study aims to employ multivariate regression analysis to investigate the prognostic significance of tricuspid valve (TV) geometry and echocardiographic parameters associated with both RV geometry and function. The focus is on comprehending these relationships in the context of recurrent TR subsequent to TA. Methods This prospective observational cohort study aimed to explore factors contributing to recurrent tricuspid regurgitation (TR) after tricuspid annuloplasty (TA). The focus was on patients with moderate or severe functional TR due to left heart valvular disease, particularly severe mitral regurgitation, excluding those with ischemic heart disease. The cohort included 66 individuals undergoing preoperative assessments with 2D and 3D echocardiography, quantifying RV and right atrial (RA) geometry, functional, and tricuspid valve (TV) parameters. TR severity followed ESC guidelines. Patients were categorized into effective TA (50 patients) and recurrent TR (16 patients) groups, defined by mild-moderate TR and significant moderate-severe TR one year post-surgery, respectively. SPSS software facilitated statistical analysis, with adjusted logistic regression considering parameters such as age and gender. Results Among the patients (54% male, mean age 68±9 years), no significant differences were found in gender, left ventricular and atrial parameters, or preoperative TV orifice area between groups (recurrent TR vs. effective TA: 38 [33] mm2 vs. 29 [15] mm2, p=0.117). Univariate logistic regression analysis identified Septal-Lateral Systolic TA Diameter (OR 1.62), Septal-Lateral Diastolic TA Diameter (OR 1.99), and Major Axis Diastolic TA Diameter (OR 1.59) as key predictors. For diagnostic efficacy, ROC analysis revealed Major Axis Diastolic TA Diameter (AUC 0.848; cut-off 52.5 mm), TV Leaflet Tenting Volume (AUC 0.778; cut-off 5.1 ml), and RV Basal Diameter (AUC 0.763; cut-off 47.5 mm) as the most predictive parameters. The combined use of predefined RV basal diameter and Major Axis Diastolic TA Diameter showed the highest odds ratio for recurrent TR. Conclusion Key predictors, including Septal-Lateral Systolic and Diastolic TA Diameters, and Major Axis Diastolic TA Diameter, were identified, emphasizing their significance in understanding TR recurrence after tricuspid annuloplasty. The combination of predefined RV basal diameter and Major Axis Diastolic TA Diameter showed the highest odds ratio for recurrent TR, offering valuable insights for clinical assessment and preventive strategies.

Prognostic preoperative factors for recurrence of tricuspid regurgitation following annuloplasty: examining the influence of 3d echocardiography

Abstract Introduction The increasing worry revolves around the reappearance of tricuspid regurgitation (TR) following tricuspid annuloplasty (TA) among individuals dealing with functional tricuspid regurgitation (FTR). Despite TA's efficacy as a treatment, a complete understanding of the echocardiographic elements influencing the recurrence of TR is pivotal. This knowledge holds the potential to guide the development of more robust preventive strategies, aiming to ease the incidence of recurrent TR after TA. Aim The aim of this study was to examine the prognostic value of tricuspid valve (TV) and echocardiographic parameters related to both right ventricular (RV) geometry and function. Specifically, our focus is on understanding these relationships in the context of recurrent TR following TA. Methods This prospective observational cohort study aimed to investigate determinants of recurrent TR post-surgical TV repair. The focus was on patients with moderate or severe functional TR related to left heart valvular disease, primarily severe mitral regurgitation, excluding those with ischemic heart disease. The study involved 66 participants, assessed preoperatively with 2D and 3D echocardiography, examining RV and right atrial (RA) geometry, functional, and TV parameters. TR severity followed ESC guidelines. Two groups were formed: effective TA group (50 patients) and recurrent TR group (16 patients), defined by mild to moderate TR and significant moderate-severe TR one year post-surgery, respectively. Statistical analysis employed SPSS software, with adjusted univariate logistic regression considering age and gender. Results Of the patients, 54% were male, with a mean age of 68±9 years. Echocardiography parameters in Table 1 showed no significant differences in gender, left ventricular, atrial geometrical, functional parameters, or preoperative effective regurgitant TV orifice area between groups (recurrent TR vs. effective TA: 38 [33] mm2 vs. 29 [15] mm2, p=0.117). Univariate logistic regression analysis highlighted RV and RA geometry, along with TV diameter, as predictors for recurrent TR. Notably, 3D TV geometrical parameters had prognostic significance, as confirmed by univariate adjusted logistic regression analysis. Functional RV parameters did not exhibit statistical significance in this analysis. Conclusion In conclusion, the recurrence of moderate-severe functional tricuspid regurgitation following tricuspid annuloplasty is linked to the tricuspid annulus size, as well as the geometry of the right atrium and right ventricle before surgery. Notably, no correlation was identified between the recurrence of TR and alterations in RV function.

Safety and quality of life assessment at 6 months follow-up of the valvosoft pivotal study

Abstract Background Calcific Aortic stenosis (CAS) is currently the most common heart valve disease. Patients suffering from severe CAS are treated with invasive surgeries based on valve replacement. Symptoms heavily impact quality of life, including chest pain, shortness of breath, dizziness, fatigue, and major risks as heart failure or sudden death, and daily activities might also be strongly impacted. Purpose A prospective, multi-centre, single-arm, pivotal study (NCT05235568) was initiated in 2021 to treat severe CAS patients with Valvosoft, a medical device based on Non-Invasive Ultrasound Therapy (NIUT) intended to treat CAS in patients not eligible for immediate aortic valve replacement (SAVR/TAVR) or refusing such a treatment, to confirm safety and performance at 1-, 3-, 6- and 12 months. We present here the safety and quality of life results at 6M follow-up. Methods Valvosoft NIUT procedure is based on a trans-thoracic delivery of focused, high intensity short therapeutic ultrasound pulses, to precisely generate a cavitation bubble cloud on the aortic valve. Echocardiographic imaging enables to monitor the valve in real-time while cavitation causes both non-thermal tissue softening and calcification fractionation of the diseased valve. 60 planned subjects, suffering from severe calcific aortic stenosis, not recommended for aortic valve replacement or refusing such a procedure, were enrolled in 11 centres in Europe. Patients were awake or lightly sedated, NIUT was delivered during up to 70 minutes per patient per procedure. DSMB and CEC were installed to monitor safety, performance and effectiveness of Valvosoft device, and safety related to participation in the clinical investigation. Results Sixty high-risk patients advanced in age (85.2 ± 9.1) with multiple severe comorbidities were included. Primary safety endpoint (less than 25% MACE) was met at 30D (p=0.002). Furthermore patients experienced an overall quality of life improved. 6 minutes’ walk test increases from baseline towards 6 months with 10 %. At 6M follow-up, no stroke was reported, an average KCCQ score improvement of 17% was noticed, and NYHA class improved or stabilized for 78% of patients. The calcium score or volume on the aortic did not change pre- and post-procedure. Conclusion Valvosoft NIUT safety and quality of life improvement are proven at 6MFU, and the technology is presented as potentially disruptive, in the treatment of severe calcific aortic stenosis.

Assessment of a new index of myocardial strain for the diagnosis of cardiac sarcoidosis

Abstract Background The diagnosis of cardiac involvement in sarcoidosis is challenging and often expensive. Purpose The aim of this study is to assess whether a new strain index proposed by the authors has incremental value in the evaluation of cardiac involvement, compared to the use of left ventricular (LV) global longitudinal strain (GLS). Methods This is a single-center, non-blinded, pilot cross-sectional study. Patients of both genders, >18 years old, with confirmed diagnosis of cardiac sarcoidosis according to the Heart Rhythm Society criteria, and controls consisting of individuals diagnosed with systemic sarcoidosis without cardiac involvement, were included. Patients with obesity grade 2 or higher , moderate or severe primary heart valve disease, myocardial diseases of other etiologies, established coronary artery disease, and inadequate acoustic window were excluded. All patients underwent transthoracic echocardiography, with subsequent measurements performed on a workstation. The following LV indexes were evaluated: GLS and the new proposed index, calculated by the ratio between LVEF and the sum of the two segments with the lowest absolute strain values. ROC curves were calculated for both parameters using an online dedicated software, with determination of the optimal cutoff point for both variables, corresponding to the point of highest sensitivity and specificity. Confidence intervals were established by the DeLong method, and curves were compared using the Bonferroni method. A two-tailed p value of 0.05 was considered significant. Results Twenty patients with cardiac involvement and twenty patients without cardiac involvement were evaluated. The results of the variables are presented in table 1. Conclusions The new index showed a larger area under the curve compared to isolated GLS, as well as higher sensitivity and specificity for the identified cutoff point, although without statistical significance, possibly due to the small sample size. Further studies are needed for subsequent validation of this innovative index.

Real-world analysis of transcatheter aortic valve replacement in patients with prostate cancer and severe aortic stenosis

Abstract Background Patients with prostate cancer have a high prevalence of cardiovascular disease, including degenerative heart valve diseases such as aortic stenosis. It is not uncommon in clinical practice to perform transcatheter aortic valve replacement (TAVR) in patients with severe aortic stenosis and active prostate cancer. Still, the prognosis after this procedure in this population is not well known. Purpose To evaluate 1-year and 3-year survival rates after TAVR in patients with prostate cancer who have undergone TAVR when compared with patients without active cancer. Methods Data were extracted from electronic medical records of a large multinational collaborative network (TriNetX) that currently englobes 113 healthcare organizations worldwide with more than 100 million patients. Patients aged 18 years or older with prostate cancer documented up to 12 months before TAVR as well as controls undergoing TAVR without oncologic history before the proceeding were included. The survival analysis for 1 year and 3 years was performed with Kaplan Meier survival plots and log-rank test. Propensity score matching, using clinical and demographic variables, was performed to pair the cohorts. Results From a cohort of 26,656 men who had undergone TAVR, we identified 1,040 with prostate cancer diagnosed up to 1 year before TAVR ( prostate cancer group) and 20,231 patients without oncologic history before TAVI (control group). After propensity score matching, analyzing 1,040 patients in each group, the 1-year and 3-year survival probabilities were not different between the prostate cancer group versus the control group ( 89.5% vs 88.9%, log-rank test P=0.70 and 72.6% vs 68.7%, log-rank test P=0.22, respectively). Considering a subgroup of patients with metastatic prostate cancer ( n=229) under androgen deprivation therapy vs the control group ( n =229), we have also not observed a survival difference between the two groups at 1-year and 3-year follow-up ( 88.1 vs 89.1%, log-rank test P=0.69 and 58.7% vs 67.4%, log-rank test P=0.25). Conclusions In this real-world analysis, patients with prostate cancer and severe aortic stenosis who underwent TAVR, including patients with metastatic disease, the 1-year and 3-year survival rates were not significantly different when compared to patients without oncologic hystory who underwent TAVR.

Evaluation of myocardial work indexes in patients with cardiac sarcoidosis

Abstract Background Cardiac involvement is associated with worse prognosis and mortality in sarcoidosis. Diagnosis often requires expensive and less available tests. Purpose The aim of this study is to evaluate whether non-invasive measurement of myocardial work by transthoracic echocardiogram has incremental value in the diagnosis of cardiac involvement compared to left ventricular (LV) global longitudinal strain (GLS). Methods This is a cross-sectional, non-blinded, single-center pilot study. Patients of both genders > 18 years old, with confirmed diagnosis of cardiac sarcoidosis according to the Heart Rhythm Society criteria, and controls consisting of individuals diagnosed with systemic sarcoidosis without cardiac involvement, were included. Patients with obesity grade 2 or higher , moderate or severe primary heart valve disease, myocardial diseases of other etiologies, established coronary artery disease, and inadequate acoustic window were excluded. All patients underwent transthoracic echocardiography and non-invasive blood pressure measurement, followed by subsequent analysis involving the construction of a pression-strain curve. The following LV indexes were calculated: GLS, global work index, global constructive work, global wasted work, and global work efficiency. ROC curves were calculated for all variables using the EasyROC online tool (v 1.3.1), and these were later compared to GLS. Confidence intervals were established by the DeLong method, and curves were compared by the Bonferroni method. A two-tailed p value of 0.05 was considered significant. Results Twenty patients with cardiac involvement and twenty patients without cardiac involvement were evaluated. The results of the variables are presented in table 1. Conclusions With exception of wasted work, all other LV myocardial work variables showed statistical correlation with cardiac involvement in sarcoidosis patients. However, there was no incremental value of myocardial work indexes compared to the isolated use of GLS.

The association between exercise-induced ventricular premature contractions and long-term mortality in patients without coronary artery disease

Abstract Background/Introduction The treadmill exercise test is widely used clinical test to determine cardiovascular risk and mortality, regardless of clinical risk factors (1). ST-segment changes detected in the exercise test are shown to predict myocardial ischemia (2) and premature ventricular complexes (PVCs) are frequently observed during exercise stress testing (3). Exercise-related PVC is observed in 14% to 23% of healthy individuals without significant heart disease (4,5). The literature on the role of PVCs observed during treadmill exercise testing in predicting prognosis is controversial. Purpose Therefore, we aimed to evaluate the clinical results of PVCs seen during exercise testing in patients who had been diagnosed with non-obstructive coronary artery disease after coronary angiography. Methods The study population consisted of 1624 consecutive patients who were considered high risk according to the Duke treadmill risk score and had no significant stenosis on coronary angiogram from January 2016 to April 2021. Patients with previous history of coronary revascularization, previous myocardial infraction, heart failure, moderate or severe heart valve disease, congenital heart disease, cardiomyopathy, bundle branch block, and left ventricular hypertrophy were excluded from the study. The primary endpoints of the study were long-term all-cause mortality of patients who had PVCs during the exercise test or during the resting phase. Results The long-term mortality was observed in 53 patients out of 1624 patients in the mean follow-up of 47 months. PVCs was observed in 293 (18.7%) patients without long-term mortality, while PVCs was observed in 24 (45.3%) patients with long-term mortality (p<0.001). The model adjusted for all covariates showed that the presence of PVCs in the recovery phase (p<0.007, HR (95% CI) 2.244 (1.244 – 4.047)) and advanced age (p<0.001, HR (95% CI) 1.194 (1.143 – 1.247)) were associated with long-term all-cause mortality (Figure 1). Considering Kaplan-Meier curve, individuals with PVCs in recovery had significantly higher risk of long-term mortality compared with those with without PVCs (log-rank statistic: 22.47, p<0.001) (Figure 2). Conclusion(s) The study highlights that PVCs monitored in the recovery phase of the treadmill exercise test were associated with long -term mortality in patients without structural heart disease and coronary artery disease.Figure 2Figure 1

REDUCE-HF: a stronger heart go a long way

Abstract Introduction/Purpose Heart failure (HF) is a serious cardiovascular condition with a significant global health concern. The risk of heart failure rehospitalisation is high globally and locally, the 30-day HF readmission was about 32% from a local study (1). The study aims to adopt an intensive treatment strategy similar to Strong-HF trial (2) and evaluate rapid up-titration of guideline directed medical therapy (GDMT) and close follow-up will improve patients' outcomes after acute heart failure (AHF). Objectives The Reduction of Decompensation and Unnecessary Cardiac failure Emergency admissions: ambulatory Heart Failure service model (REDUCE-HF) is a non-randomised prospective study evaluating clinical outcome of patients discharged from AHF. Exclusion criteria included primary valvular disorders, end-stage renal failure and metastatic cancer. After HF discharge, eligible patients were recruited into our REDUCE-HF program irrespective of LVEF. They were subsequently managed in our ambulatory HF centre within two weeks, where intensive up-titration of GDMT and close follow-up would be proceeded. The data of our service model will be compared with our 5-year historical cohort. Primary outcome comprised of all-cause mortality and heart failure hospitalisation. Secondary outcome will be comparison of clinical and functional status at baseline and 3-month on follow up. Results Between October 2022, and December 2023, 245 patients were successfully recruited into our REDUCE-HF service model. Historical cohort of 6867 patients with primary diagnosis of acute heart failure were served as control (usual care pathway), data extracted from 2018 to 2022. Their mean age was 67.8+/-12.2 and 72.2%were male. 60% of them were HFrEF (EF<=40%) and 28% were ischaemic cardiomyopathy. The mean follow up period was 3 months. At 90 days, REDUCE-HF cohort group has shown much lower all-cause mortality than usual care group (2.5% vs 9.3%, HR 0.26, 95% CI 0.18-0.41, p<0.001). There was a much lower incidence of heart failure hospitalisation in REDUCE-HF group as compared to control (8.6% vs 13.1%, HR 0.65; 95% CI 0.55 to 0.74, p<0.01). In secondary outcome, there was significant reduction of NT-ProBNP of 45.2% (from 4229 to 2319pg/m, p<0.001), tremendous increment of 6-minute walk test (from 211 to 250m, p<0.001) and remarkable improvement of KCCQ score from 55.1 to 86.7, p<0.001. The overall LVEF was significantly increased from 39% to 44%, p<0.05. The positive outcome were attributed to good adherence to GDMT: ACEi/ARB/ARNI 91%, Betablocker 90.3%, MRA 72.4% and SGLT2i 95.5%. Conclusion The REDUCE-HF ambulatory service model has been proven effective in reducing mortality, decompensation and preventing unnecessary heart failure hospitalisation in this prospective study. By intervening proactively, this model not only enhances the quality of life but also hold promise in alleviating the burden of in-patient services on heart failure.

Characteristics and predictors of persistent somatic symptoms in patients with cardiac disease

Persistent somatic symptoms (PSS) are a diagnostic core criterion of the somatic symptom disorder. This longitudinal study aims to determine the frequency of PSS in patients with cardiac disease, identify potential predictive factors, and investigate its impact on healthcare utilization. Somatic symptoms were assessed with the Somatic Symptom Scale-8 four times over the course of three months in consecutively approached cardiac outpatients. Patients were grouped having PSS vs. not having PSS following a psychometric-driven approach based on the SSS-8 cut-off score and a data-driven approach applying cluster analysis. T-tests were performed to compare the characteristics between patients having vs. not having PSS. To identify predictors of group affiliation, we conducted multivariable logistic regressions. Additionally, analyses of covariance were used to further examine associations between healthcare utilization and group affiliation. The study included 95 patients (30.5% female) with a mean age of 60.5 years (SD = 8.7). All patients had at least one of the following cardiac diseases recorded in their medical history: coronary heart disease (n = 51), myocardial infarction (n = 21), valve disease (n = 22), cardiomyopathy (n = 15), cardiac dysrhythmia (n = 43), and heart failure (n = 12). 30 (32%) were grouped having PSS according to the psychometric-driven approach and 27 (28%) according to the data-driven approach. For both approaches, patients with PSS were more likely to be female, unemployed, reporting angina pectoris, having higher depression, and higher anxiety severity (for all: p ≤ 0.05). Predictors of PSS group affiliation were female gender, higher age, depression severity, and angina pectoris (for all: p ≤ 0.015). Patients with PSS more frequently visited general practitioners and cardiologists compared to patients without PSS (p ≤ 0.013). Enhancing our knowledge of PSS in patients with cardiac disease could help to improve identification of patients’ specific needs and the factors to consider in diagnosis and individualized treatment.