Frontiers in Cardiovascular Medicine

BackgroundHypertension is a major cardiovascular risk factor in sub-Saharan Africa, particularly among people living with HIV (PLWH). The contributions of cardiac structural remodeling, metabolic factors, and the renin-angiotensin-aldosterone system (RAAS) to hypertension in this population remain incompletely understood. This study aimed to provide a detailed characterization of the clinical and echocardiographic determinants of hypertension in a cohort predominantly composed of people living with HIV. MethodsIn this cross-sectional study, 366 adults (70.2% female, 73.5% PLWH) attending a tertiary hospital in Zambia were enrolled. Hypertension was defined as systolic/diastolic blood pressure [&ge;]140/90 mmHg or current antihypertensive use. We collected sociodemographic, clinical, biochemical (lipid profile, RAAS markers, inflammatory cytokines), and echocardiographic data. Multivariable logistic regression models were used to identify independent predictors of hypertension, with statistical significance at p<0.05. ResultsHypertension prevalence was 24.3% (n=89). Hypertensive participants were older (median age 59 vs. 45 years, p<0.0001) and had higher BMI, cholesterol, triglycerides, and left ventricular mass index (all p<0.01). In adjusted Model 1 (controlling for age, BMI, waist circumference, HIV), left ventricular septal diameter (IVSD: AOR=25.2, 95% CI: 5.7-110.2), posterior wall diameter (LVPWD: AOR=22.9, 95% CI: 4.3-121.9) and age (AOR=1.08 per year, 95% CI: 1.05-1.11) were associated with hypertension. In Model 2, adjusting for RAAS components, cardiac structural parameters and age remained significant, while RAAS biomarkers showed no independent association. ConclusionIn this HIV-prevalent cohort, hypertension was independently associated with left ventricular structural remodeling and advancing age, but not with circulating RAAS components or HIV status. These findings underscore the importance of echocardiographic assessment in hypertension evaluation and suggest that non-RAAS pathways may contribute to hypertensive cardiac remodeling in this setting.

BackgroundThere is considerable focus on developing strategies for identifying subclinical cardiac decline prior to cardiac failure. Myocardial tissue elasticity changes may precede irreversible cardiac damage, providing promise for an early biomarker for cardiac decline. Biomarker strategies are of particular interest in cardio-oncology due to cardiotoxic effects of anti-neoplastic therapies, particularly anthracycline-based chemotherapeutics. Current clinical methods for diagnosing cardiotoxicity are too coarse to identify cardiac decline early enough for meaningful therapeutic intervention, or too cumbersome for clinical implementation. MethodsUtilizing changes in myocardial elasticity as a biomarker for subclinical cardiac decline, we developed a biomechanical model-based elasticity imaging methodology (BEIM) to estimate spatial maps of left ventricle (LV) myocardial elasticity. In this study, we employ this methodology to assess changes in LV elasticity in a non-human primate model of doxorubicin-induced cardiotoxicity. Cardiac magnetic resonance imaging of five African Green monkeys was acquired at baseline prior to doxorubicin administration, 6-weeks, and 15-weeks after final doxorubicin dose and histopathological samples of the LV were taken at 15-weeks after final doxorubicin dose. Spatial elasticity maps of the mid-short axis plane of the LV were estimated at each image acquisition. Global and regional LV elasticity were calculated and changes between imaging time points was assessed. LV elasticity at baseline and final time point were compared to cardiomyocyte size and collagen volume fraction measurements calculated from histopathological staining of archived tissue bank samples and study endpoint tissue samples utilizing Pearsons correlation coefficients. ResultsWe identify significant changes in LV elasticity between each imaging time point both globally and regionally. We also demonstrate strong correlation between LV elasticity and cardiomyocyte size and collagen volume fraction measurements. Results indicate that LV elasticity estimates calculated using BEIM correlate with histopathological changes that occur due to doxorubicin administration, validating LV elasticity solutions and providing significant promise for use of BEIM to non-invasively elucidate cardiac injury. ConclusionsThis methodology can show progressive changes in LV elasticity and has potential to be a more sensitive indicator of elasticity changes than current clinical measures of cardiotoxicity. LV elasticity may provide a valuable biomarker for cardiotoxic effects of anthracycline-based chemotherapeutics and cardiac disease detection.

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect (CHD), whereas hypoplastic left heart syndrome (HLHS) represents 2-3% of all CHDs. We analyzed the single-nucleus multiome profile of right ventricle samples obtained from children during routine cardiac surgery for correction of TOF or staged surgical palliation for HLHS to define cell types and characterize gene regulation states in different cell clusters. Data were integrated with pre-existing controls and analyzed using Scanpy to identify clusters and annotated using automated tool and manual curation, pycisTopic to identify cell stats and cis-regulatory topics, and SCENIC+ for enhancer-driven gene regulatory network (eRegulon). Integrated RNA-seq analysis identified 22 different cell subtypes, including five cardiomyocyte phenotypes. TOF samples showed involvement in pathway networks of the cell cycle, DNA repair, DNA replication, and RNA metabolism, whereas gene expression in HLHS samples was related to extracellular matrix organization, anatomical structure development, cell adhesion, actin-myosin filament sliding, and contractile muscle fiber pathways. In addition, the gene expression fingerprints of endothelial, fibroblast, pericyte, immune, and neuronal cell nuclei from TOF and HLHS samples exhibited nuclei-specific significant de-regulation compared to controls. We found considerable heterogeneity among the transcriptomes of TOF and HLHS, explaining the diverse clinical phenotypes. These findings can enable the development of new gene-based interventions for specific CHDs.

BackgroundCardiovascular diseases (CVD) prediction models for persons living with HIV (PLWH) depend on traditional CVD risk factors, but these underestimate true risk. We aimed to identify proteins and genetic variants and create proteo-genomic risk scores for CVD in PLWH. MethodsWe analyzed genetic and protein data from participants involved in trials for PLWH. We used state-of-the-art statistical methods for data integration, identified correlated signatures, and developed a protein score (PS) and a genetic score (GS) to predict CVD. We conducted functional enrichment analysis to explore biological functions of signatures identified in relation to CVD. ResultsA panel of 14 proteins and a set of 15 genetic variants were found to be better at distinguishing between CVD cases and controls than individual proteins or genetic variants. The PS or GS was each independently associated with a higher risk of CVD. Combining CVD-, HIV-related factors, genetics, and protein scores resulted in the most powerful discrimination. Functional enrichment analysis showed an upregulation of the cytokine tumor necrosis factor (TNF) and strong enrichment for inflammation related pathways such as the pathogen induced cytokine storm. ConclusionsA panel of protein biomarkers, some new (IGFBP7, HGF) and some previously known in PLWH (CLEC6A), could help identify PLWH at higher risk of developing CVD. If confirmed, these scores could be used with CVD and HIV-related factors to identify PLWH at risk for CVD who would benefit from proactive risk reduction strategies.

BackgroundPrevious studies have shown that acute myocardial infarction (AMI) may be associated with paroxysmal ventricular tachycardia (PVT). However, the causal effect between AMI and PVT, and whether cardiovascular proteins act as a mediator remain unclear. MethodsThe genetic data of AMI, 90 Cardiovascular proteins (CVPs) and PVT were obtained from large-scale genome-wide association studies (GWAS). The Mendelian randomization analysis was applied to evaluate the casual association among the AMI, CVPs and PVT. The inverse variance weighting casual effect was regarded as main statistical method. We further investigated whether CVPs take a mediating role in the pathway from AMI to PVT. ResultsThere were three positive, including ESM-1 (OR 1.139, 95%CI 1.034-1.255, P-FDR=0.014), GAL (OR 1.105,95%CI 1.025-1.191, P-FDR=0.015) and PRL (OR 1.084, 95%CI 1.004-1.170, P-FDR=0.038), and four negative, including FAS (OR 0.928, 95%CI 0.885-0.974, P-FDR=0.009), LEP (OR 0.938, 95%CI 0.891-0.987, P-FDR=0.018), TNF-R1 (OR 0.930, 95%CI 0.883-0.979, P-FDR=0.014) and TNF-R2 (OR 0.928, 95%CI 0.883-0.974, P-FDR=0.009), casual effects between genetic liability of AMI on CVPs. We identified two positive, including IL-27 (OR 1.371, 95%CI 1.010-1.861, P-FDR=0.045) and MMP-12 (OR 1.330, 95%CI 1.035-1.709, P-FDR=0.045), and two negative, including LEP (OR 0.614, 95%CI 0.384-0.981, P-FDR=0.045) and TF (OR 0.714, 95%CI 0.514-0.992, P-FDR=0.045), casual effects between genetic liability of CVPs on PVT. In addition, the AMI played a positive casual effect on PVT (OR 1.736, 95%CI 1.300-2.318, P-FDR<0.001) mediating by LEP with 5.71%. ConclusionsThe AMI was casually correlated to PVT, and LEP acted as a mediator in the pathway from AMI to PVT. Key MessagesO_ST_ABSWhat is already known on this topic?C_ST_ABSPrevious retrospective and prospective clinical studies have suggested that attention should be paid to the risk of subsequent malignant ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, in patients with acute myocardial infarction. What this study adds?We used Mendelian randomization to demonstrate the genetic relationship between acute myocardial infarction and paroxysmal ventricular tachycardia, and found that leptin mediated the occurrence of paroxysmal ventricular tachycardia in clinical patients with acute myocardial infarction for the first time. In addition, we also found a large number of cardiovascular proteins closely genetically related to acute myocardial infarction or paroxysmal ventricular tachycardia, How this study might affect research, practice or policy?Our research provides a new insight which means that appropriate serological detection or intervention for patients with acute myocardial infarction can predict or prevent the occurrence of secondary malignant ventricular arrhythmias and reduce the mortality of patients with acute myocardial infarction in the future. Also, the cardiovascular proteins detected by Mendelian randomization analysis are helpful for the diagnosis and prevention of the two. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/24314334v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1796215org.highwire.dtl.DTLVardef@166f34org.highwire.dtl.DTLVardef@dece5aorg.highwire.dtl.DTLVardef@1bda137_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract.C_FLOATNO C_FIG We carefully analyzed the causal relationship among AMI, 90 CVPs and PVT in the complicated MR analysis. We found three positive (ESM-1, GAL and PRL) and four negative casual effects (FAS, LEP, TNF-R1 and TNF-R2) between genetic liability of AMI on CVPs. There were two positive (IL-27 and MMP-12) and two negative (LEP and TF) casual effects between genetic liability of CVPs on PVT. The AMI played a positive casual effect on PVT mediating by LEP with 5.71%. We identified two positive (Dkk-1 and PDGF_subunit_B) and two negative (RAGE and SPON1) casual effects between genetic liability of CVPs on AMI, and thee positive (IL-1ra, MCP-1 and TIE2) casual effects between genetic liability of CVPs on PVT. AMI, acute myocardial infarction; PVT, paroxysmal ventricular tachycardia; CVPs, cardiovascular proteins; AGRP, agouti-related protein; ESM-1, endocan; FAS, tumor necrosis factor receptor superfamily member 6; GAL, galactose-alpha-1,3-galactose; LEP, leptin; PRL, placental growth factor; TNF-R1, tumor necrosis factor receptor 1; TNF-R2, tumor necrosis factor receptor 2; IL-27, interleukin-27; MMP-12, matrix metalloproteinase-12; TF, tissue factor; Dkk-1, dickkopf-related protein 1; PDGF_subunit_B, platelet-derived growth factor subunit B; RAGE, receptor for advanced glycosylation end products; SCF,stem cell factor; SPON1, spondin-1; IL-1ra, interleukin-1 receptor antagonist protein; MCP-1, monocyte chemotactic protein 1; TIE2, angiopoietin-1 receptor.

Aortic valve stenosis (AS) is one of the most frequent heart valve diseases in the western world, but aortic valve replacement (AVR) remains the only therapeutic option. While one of the most common complications of AS is heart failure, the early disease phase is asymptomatic with preserved cardiac function. Increased ventricular lymphatic vessel density is part of myocardial remodelling upon cardiac pressure overload and an important adaptation mechanism to maintain heart function after myocardial infarction, while in heart failure patients, circulating lymphatic growth factor levels and ventricular lymphatic vessel numbers are altered. Lymphangiogenesis is enhanced in endocardium of human stenotic aortic valves, however, ventricular lymphatic vessels have not been investigated in AS, yet. Therefore, aim of this study was to in a well-characterized mouse model of moderate AS analyse the link between density of ventricular lymphatic vessels, cardiac remodelling and function.

Post-exercise [V]O2 kinetics and [V]O2 recovery delay (RD) are clinical prognostic markers in cardiac patients, but have not been studied after exercise training in patients with coronary heart disease (CHD). We aimed to compare the effects of 12-weeks moderate-intensity continuous exercise training (MICET), low volume high-intensity interval training (LV-HIIT), or combined MICET/HIIT on O2 deficit, post-exercise [V]O2 kinetics, O2 debt and [V]O2 recovery delay (RD) in patients with CHD. MethodsPatients with CHD were randomised in MICET, LV-HIIT or combined MICET/HIIT group for 12 weeks. Cardiopulmonary exercise test (CPET) parameters were assessed, and key exercise variables were calculated during and after exercise. CPET post-exercise kinetics time constant (r) (for [V]O2, [V]CO2,[V] E and HR), O2 deficit, O2 debt and [V]O2 recovery delay (RD) were calculated before and after training. ResultsA significant time effect (training) for r [V]O2 (min) (p<0.05) was shown for all groups. Shorter r [V]O2 values with small effect size (ES: 0.21 to 0.4) were noted for the combined MICET/HIIT and MICET groups. A significant time effect (p<0.01) was noted for O2 debt that was increased after training (ES: 0.1 to 0.47). No significant statistical effect was shown for [V]O2 RD and r [V]CO2, r[V] E, r HR and O2 deficit in all groups. ConclusionsIn patients with CHD, exercise training improved post-exercise [V]O2 kinetic and the O2 debt, with a higher impact of exercise dose (combined MICET/HIIT). Exercise training did not improved the [V]O2 RD or other{tau} CPET recovery variables in CHD patients.

Epicardial delivery of human follistatin-like 1 protein (FSTL1) induces significant cardiac benefit following a myocardial infarction (MI). However, the optimal dosing regimen for maximal therapeutic benefit has not yet been elucidated. To investigate the impact of multiple FSTL1 doses, without the confounding effects of multiple surgical procedures for multidose delivery, alternative delivery strategies are needed. Here, we use an epicardial reservoir that allows non-invasive delivery of additional doses after implantation to investigate the impact of single, double, and triple FSTL1 dose regimens in a rat model of MI. Multidose delivery of FSTL1 improves ejection fraction (3 doses), fractional shortening (1, 2 and 3 doses), and chamber stiffness (2 doses) 28 days after MI. Histologically, multiple FSTL1 doses increase ventricular wall thickness (2 and 3 doses) and reduce infarct size (1, 2, and 3 doses). We also demonstrate a dose-dependent increase in blood vessel number and density in the infarct zone, with three FSTL1 doses leading to the highest improvements. This study shows that multidose delivery of FSTL1 improves cardiac function, healing, and angiogenesis following MI. The epicardial delivery platform used here may be essential in optimizing dosing regimens of various bioagent combinations for a range of clinical indications.

BackgroundReactive oxygen species (ROS) contribute to myocardial ischemia-reperfusion injury (IRI), but in-vivo data on the spatial myocardial distribution and systemic effects of ROS after IRI remain limited. This multimodal CMR and PET/CT study aimed to non-invasively image ROS activity in a clinically-relevant swine model of IRI using [18F]ROStrace, a fluorine-18-labeled analogue of dihydroethidium (DHE), and to investigate regional changes in ROS activity in the infarcted myocardium during the subacute post-IRI phase. MethodsIRI was induced by percutaneous occlusion of the left anterior descending artery for 90 minutes in swine (N=9). CMR and whole-body PET/CT imaging with [18F]ROStrace were performed before myocardial infarction (MI) and 3-5 days post-MI to assess ROS in non-infarct myocardium, lungs, bone marrow, spleen and skeletal muscle. Late gadolinium enhanced CMR was performed to structurally characterize infarct regions. Post-MI, in vivo [18F]ROStrace signal in infarcted myocardium was compared with remote, non-infarcted myocardium and validated via ex vivo DHE fluorescent imaging. Bulk RNA-sequencing (RNA-seq) and Gene Ontology pathway analysis were conducted on biopsies from infarct and remote myocardial tissue to identify differentially expressed genes and pathways connected to oxidative stress. ResultsDuring the subacute phase following MI, [18F]ROStrace fractional uptake rate (FUR; min-1) was significantly increased in skeletal muscle, compared to baseline (0.011{+/-}0.003 vs 0.016{+/-}0.005, p=0.04), with a trend toward increased FUR in bone marrow (0.046{+/-}0.009 vs 0.056{+/-}0.011, p=0.12) and the left ventricular free wall (0.067{+/-}0.007 vs 0.073{+/-}0.010, p=0.15). Within the myocardium, [18F]ROStrace FUR ((min-1)/(mL/min/g)) was significantly higher in infarcted compared to non-infarcted myocardium regions (0.110{+/-}0.034, vs 0.148{+/-}0.035, p=0.0005). DHE staining confirmed elevated ROS levels in the infarcted myocardium. RNA-seq identified 8,707 differentially expressed genes between infarct and remote myocardium, with downregulated pathways in the infarct associated with mitochondrial function, cellular respiration, and metabolic adaptation. ConclusionThis study demonstrated MI ROS imaging using [18F]ROStrace using a whole-body PET/CT scanner and structural assessment with CMR. Systemic and myocardial increases in ROS activity were observed post-MI, accompanied by substantial molecular alterations in infarcted tissue. These findings show potential imaging strategies to evaluate therapeutic targets that can mitigate oxidative stress after MI.

BackgroundAcute myocardial infarction (AMI) triggers local inflammation in the injured myocardium, followed by a systemic inflammatory response of lymphatic organs. This prospective trial investigated whether molecular imaging of lymphatic organs (spleen, bone marrow, and heart-draining lymph nodes (LN)) identifies individuals predisposed to functional recovery during follow-up after AMI. Methods41 timely re-perfused ST-elevation AMI patients received positron emission tomography (PET) using 68Ga-PentixaFor, a radiotracer targeting C-X-C motif chemokine receptor 4 (CXCR4) post-AMI. Patients were allocated to an early (2-4 days) or late PET imaging group (5-8 d) based on tracer availability. To determine left ventricular ejection fraction (LVEF) and infarct size, cardiac magnetic resonance imaging was conducted at baseline and repeated after six (follow-up (FU) 1, available in 38/41) and twelve months (FU 2, 36/41). As endpoint, an LVEF increase of [&ge;]5% relative to baseline was then defined as short- (at FU 1) and long-term functional (at FU 2) recovery. We also determined association of 68Ga-PentixaFor uptake in the infarct territory and lymphatic organs with outcome relative to established clinical and imaging biomarkers. ResultsAt FU 1, functional recovery was recorded in 21/38 patients. Univariate analysis identified baseline LVEF (Odds Ratio (OR), 0.80, P=0.002) and uptake derived from heart-draining LN (OR, 0.21, P=0.03) as predictor of functional recovery, while only LVEF reached significance at multivariate analysis (OR, 0.72, P=0.007). At FU 2, functional recovery was observed in 21/36 patients and LVEF (OR, 0.84, P=0.005) and splenic PET signal (OR, 2.46, P=0.04) provided prognostic value at univariate analysis. Both parameters remained significant at multivariate outcome analysis (LVEF: OR, 0.73, P=0.01; spleen: OR, 4.17, P=0.04), indicating that low baseline LVEF and high splenic tracer uptake are prognostic for improved long-term functional outcome. Established risk factors of cardiac damage (infarct size) or inflammation (C-reactive protein, white blood cell counts) failed to reach significance for functional recovery at FU 1 and FU 2. ConclusionsAlong with baseline EF, imaging of chemokine receptor expression in the spleen provides a complementary in-vivo biomarker for long-term functional recovery. Whole-body PET-based assessment of systemic inflammatory response in lymphatic organs may therefore open avenues for immune modulation strategies in patients after AMI.

BackgroundComplete vessel reconstruction (CVR) with incorporation of side branches is essential for accurate evaluation of wall shear stress (WSS) distribution. However, CVR is time consuming and blood flow simulation is computationally expensive, while there is no evidence that WSS computed by CVR, enables better prediction of disease progression compared to WSS derived from the conventional single vessel reconstruction (SVR). We aim to compare the WSS in models reconstructed using the CVR and SVR methods and examine its ability to predict disease progression. MethodsPatients who had baseline and 13-months follow-up intravascular ultrasound (IVUS) imaging (n=19 vessels), and with neoatherosclerotic lesions (n=13 vessels) on optical coherence tomography (OCT) were included in the present analysis. All the studied vessels had at least one side branch with diameter >1mm. 3-dimensional (3D) CVR and SVR were performed and time averaged (TAWSS) and multidirectional WSS were computed using pulsatile blood flow simulation and the performance of both methods in predicting disease progression in IVUS and OCT models were assessed. ResultsThe incorporation of side branches in 3D geometry resulted in lower TAWSS in the IVUS (0.821 vs 1.698Pa, p<0.001) and OCT-based reconstructions (0.682 vs 1.325Pa, p<0.001) and influenced the multidirectional WSS distribution. In native segments, WSS metrics estimated by the CVR enabled better prediction of the lumen and plaque area and burden at follow-up than SVR and disease progression defined as decrease in lumen area and increase in plaque burden (AUC CVR 0.712 vs SVR 0.554). In stented segments, multidirectional WSS was associated with neointima area in both CVR and SVR methods, but TAWSS was only a predictor of neointima area in the CVR method. ConclusionsThe incorporation of side branches in vessel reconstruction influences WSS distribution and enables more accurate prediction of disease progression in native and stented segments than SVR modelling. HighlightsO_LIComplete vessel reconstruction (CVR) with incorporation of vessel side branches has been proposed for accurate evaluation of wall shear stress (WSS) distribution compared to the traditional single vessel reconstruction (SVR) method; however, there are no studies comparing the performance of the WSS metrics derived by these methods in predicting atherosclerotic evolution. C_LIO_LIIn vessels with large side branches, the incorporation of the side branches in the vessel geometry reconstructed from angiographic and intravascular imaging data resulted in lower time averaged wall shear stress (TAWSS) and influenced the multidirectional WSS estimations compared to the models reconstructed without the side branches. C_LIO_LIThe WSS metrics estimated in the CVR models enabled better prediction of atherosclerotic disease progression at 13-months follow-up on IVUS than the WSS derived by the SVR. C_LIO_LIIn stented vessels, all the WSS metrics in the CVR and the multidirectional WSS in SVR were associated with neointima tissue development; however, both approaches showed limited efficacy in predicting neointima proliferation. C_LI

Mammal cardiomyocytes lose their ability of regeneration shortly after birth. Reduced cardiomyocytes number caused by myocardial damage is unable to reverse in current clinical therapies. Therefore, it is important and urgent to find new approaches to stimulate cardiomyocytes regeneration. Here we design a recombinant protein IGF1-24 and show that it triggers cardiomyocytes proliferation in rat. 7 days after tail intravenous injection of IGF1-24, 6-7-weeks-old healthy rats showed marked improvements in cardiomyocytes proliferation. Next, we injured rats cardiac with isoproterenol and treated them with IGF1-24 injection. We found that it efficiently induced cell proliferation with significant improvements in heart histology. These results show that the recombinant IGF1-24 stimulates cardiomyocytes proliferation and can be used to achieve cardiac repair through stimulating endogenous cardiomyocyte proliferation in rats. The IGF 1-24 could be a prospective medicine to heart repair because it has high efficiency in triggering cell proliferation and it can be easily applied to heart by intravenous injection

BackgroundStudies have reported that 5hmC features in cell-free DNA (cfDNA) could serve as early warning biomarkers for the occurrence and progression of COVID-19, as well as myocardial injury. However, its roles in the occurrence and progression of acute coronary syndrome (ACS) following COVID-19 infection have not been fully studied. MethodsFirstly, we used the 5hmC-Seal technique to obtain genome-wide 5hmC profiles from plasma cfDNA of 24 ACS2N patients (individuals experiencing ACS onset within 2 months after COVID-19 infection), 28 ACS2W patients (individuals experiencing ACS onset beyond 2 months after COVID-19 infection), and 16 ACS patients (patients with ACS without COVID-19 infection). Secondly, we performed GO, KEGG analysis on the differentially expressed genes and identified a series of immune and inflammation related genes. Thirdly, the distribution of immune cells in different groups of patients was studied by immune infiltration analysis. Finally, we performed PPI network analysis on these genes to identify potential key target genes. ResultsIn this study, we firstly found that there was a significant difference in 5hmC levels between ACS2N patients and ACS patients, while the difference between ACS2W and ACS was not significant. Secondly, it was found that neutrophils were abnormally activated in the ACS2N group. Finally, a target gene phosphodiesterase 4D (PDE4D) was found to be highly expressed in the ACS2N group by PPI network analysis of the differential genes and validated with external datasets. ConclusionsOur study suggested that 5hmC markers extracted from plasma cfDNA could differentiate between ACS2N and ACS patients. In addition, we observed that neutrophils exhibited abnormal activation in ACS2N patients. Further analysis showed that COVID-19 infection may affect the occurrence and development of ACS by abnormally up-regulating PDE4D gene expression.

BACKGROUNDIn women, risk stratification for a major adverse coronary event (MACE) is complex, and moreover women have often been underrepresented in cardiovascular studies. This study aims to establish a COronary Risk Score in WOmen (CORSWO) to predict MACE. METHODSFrom a cohort of 25,943 consecutive patients referred for clinical gSPECT-MPI (gated single-photon emission computed tomography myocardial perfusion imaging), 2,226 women (aged 66.7{+/-}11.6 years) were included. During the follow-up (mean 4{+/-}2.7 years) post gSPECT-MPI, MACE (unstable-angina requiring hospitalization, non-fetal myocardial infarction, coronary revascularization, cardiac death) was assessed. The patients were divided into training (n=1460) and validation (n=766) groups. To obtain the predictor model, LASSO-regression analysis with 10-fold cross-validation was used. RESULTSIn training group, 148 women had MACE (0.026/patient/year). The best model (ROC area:0.8, Brier score:0.0777) to stratify women included: age >69 years (OR:1.6); diabetes mellitus (OR:2); angina-history (OR:1.6); nitrate (OR:1.5); left bundle branch block (OR:1.2); pharmacological test (OR:1.6); ST-segment-depression ([&ge;]1mm) (OR:2); stress angina (OR:1.3); myocardial ischemia >5% (OR:2.6); perfusion defect at rest >9% (OR:2.4); perfusion defect at stress >6% (OR:1.7); end-systolic volume index >15 ml (OR:1.6); and left ventricular ejection fraction <50% (OR:1.2). This model was validated (validation group) with a strong prediction (ROC area:0.8, Brier score:0.0747). The CORSWO obtained from these variables allows the stratification of women into five risk levels: very low (score:0,HR:1), low (score:1-2,HR:1.5), moderate (score:3-6,HR:2.7), high (score:7-10,HR:6.9) and very high (score:[&ge;]11,HR:21.7). CONCLUSIONSIn a clinical practice setting we can obtain an excellent coronary risk stratification in women, however at the expense of multiple variables. CLINICAL PERSPECTIVEO_ST_ABSWhat Is New?C_ST_ABSThe coronary risk stratification of women depends on of the multiple clinical, exercise and imaging variables. This new risk score allows the risk to be calculated for individual women in a simple way with a mean of a 4-year follow-up. What Are the Clinical Implications?CORSWO is an effective tool to stratify the risk for major adverse coronary event in 5 risk levels, very low, low, moderate, high and very high risk with a good accuracy.

BackgroundMyocardial ischemia leads to a decrease in the speed and intensity of myocardial tissue contraction. In the early stages, this cardiac dysfunction is difficult to be detected by conventional echocardiography methods. ObjectiveFirst-phase left ventricular ejection fraction (LVEF-1) serves as a sensitive indicator for evaluating myocardial contractility. The aim of this study was to assess the decreased cardiac function caused by myocardial ischemia and its improvement following interventional treatment, as measured by LVEF-1. Methods207 patients were enrolled. Based on the results of the angiography, they were categorized into three groups: mild, moderate, and severe. The LVEF-1, Gensini score and other clinical data were compared among these groups. Furthermore, logistic regression analysis was used to analyze the relationship between LVEF-1 and coronary artery stenosis, as well as factors associated with improvement in LVEF-1 following interventional treatment using linear regression. ResultsThe LVEF-1 of patients in the 3 groups were 29.6 (28.2, 31.7) %, 27.8 (27.0, 28.6) %, and 25.2 (23.6, 26.5) % (p<0.001). There was a negative relationship between LVEF-1 and the Gensini score (r=-0.694, p<0.001), as well as between LVEF-1 and BNP (r=-0.244, p<0.001). LVEF-1 was identified as an independent predictor for coronary artery stenosis [&ge;]50% or [&ge;]70%. A cutoff value of 26.9% for LVEF-1 had a sensitivity of 89.5% and specificity of 83.9% for predicting the coronary artery stenosis [&ge;]70%. Following intervention, LVEF-1 increased from 24.70 (23.30, 26.32) % to 28.10 (26.80, 29.92) % in 82 patients. Stent diameter was identified as an independent factor influencing the improvement in LVEF-1 post-intervention. ConclusionsLVEF-1 is negatively correlated with the severity of coronary artery stenosis, and it increases after receiving coronary artery intervention therapy, suggesting that LVEF-1 can serve as a new indicator to evaluate the severity of coronary artery stenosis and the efficacy of interventional treatment.

Background and aimLay people and medical professionals have suggested a link between (mRNA) COVID-19 vaccination and a purported increase in sudden cardiac arrest (SCA) and death (SCD) among athletes. We aimed to compare the athlete death rate in 2021-2022 with pre-pandemic estimates and investigate the role of vaccination. MethodsA comprehensive, much referenced, publicly available list of health issues, emergencies, and SCA/SCD in athletes from January 2021 to December 2022 was analysed. Demographic data, country, type of sport, vaccination status, and possible association between reported medical events and vaccination were evaluated for the complete set of athletes. The following data were specifically assessed for cases of SCD in young US athletes and compared to matched data from pre-pandemic studies: average annual SCD number, mean age, male/female ratio, sports with highest death toll, cause and scene of death, and relation to exercise. Descriptive statistics were used. ResultsThe list contained 1653 entries. (Former) athletes, aged 5-86 years, from 99 countries, participated in 61 different sports. In multiple cases, causes of and circumstances surrounding medical events were irretrievable. Many cases involved non-cardiovascular, exercise-unrelated aetiologies. Vaccination details were scarce. In 63 (3.8%) cases, including 9 fatal events, there was a plausible association with COVID-19 vaccination. In US athletes aged 9-40 (mean 22.7) years, 166 SCD cases were identified (average 83/year), mainly in males (83%) and in football (39.8%) and basketball (16.9%). Main causes of death were non-cardiovascular exercise-unrelated (22.9%) or unknown (50.6%). Deaths primarily occurred at rest (32.5%) or under unknown circumstances (38.6%). SCD characteristics were similar to those of two pre-pandemic studies with comparable datasets. ConclusionSCD rate among young US athletes in 2021-2022 was comparable to pre-pandemic estimates. There is currently no evidence to substantiate a link between (mRNA) COVID-19 vaccination and SCD in (young) athletes.

AimArtificial intelligence applied to electrocardiography (AI-ECG) can derive a heart age or ECG-age, potentially reflecting waveform patterns that indicate cumulative myocardial stress. The heart age gap (HA-gap, {Delta}age) is defined as the difference between a persons ECG-age and chronological age. Former studies suggest a threshold of {Delta}age > 8 yrs as a biomarker for accelerated biological age, associated with higher risk for cardiovascular events. In this study, we investigate whether {Delta}age differentiates training-induced physiological from pathological left ventricular remodeling. MethodsAn AI-ECG was applied to 162 resting 12-lead ECGs of each professional footballers, population controls without cardiovascular disease, and patients with systolic heart failure (HF). Explainable AI identified contributing leads and waveforms, and results were compared with established ECG voltage criteria for left ventricular hypertrophy (Sokolow-Lyon, Cornell) and low QRS voltage (LQRSV). ResultsAccelerated HA ({Delta}age,+) was present in 38.9% of athletes, 35.8% of community controls, and 96.9% of HF patients. As a diagnostic criterion, accelerated HA achieved 96.9% sensitivity and 62.7% specificity for distinguishing diseased from healthy cohorts. In contrast, classical ECG voltage criteria showed lower sensitivity (6-17%) but higher specificity (85-100%). Correlation analyses confirmed significant associations of HA-gap with Cornell voltage ({rho} = 0.25, p < 0.001) and LQRSV (limb:{rho} = -0.43, p < 0.001; precordial:{rho} = -0.32, p < 0.001). ConclusionsThe AI-based HA-gap is a multi-factorial marker of ventricular remodeling beyond mass and can separate benign athletic hypertrophy from pathological remodeling with high sensitivity. Incorporating athlete and youth cohorts into model development could further improve specificity to enable future application in preventive and sports cardiology.

ObjectivesThis study aimed to explore the linkage between intra-left ventricular (LV) diastolic hemodynamics and coronary endothelial function, utilizing four-dimensional (4D) flow magnetic resonance imaging (MR) and myocardial flow reserve (MFR) through simultaneous acquisition using hybrid PETMR system in patients with ischemic heart disease (IHD). MethodsSixty-eight patients (mean 66 {+/-} 15 years, male 55) with IHD who underwent rest-pharmacological stress 13N-ammonia PET/MR were included. MFR and summed defect score (SSS and SRS for stress and rest) were obtained thorough rest-stress PET images. MR acquisition was performed simultaneously during PET scan to obtain rest-stress 4D flow datasets and followed by cine-MRI for the LV volume measurement. LV diastolic inflow(mL/s), peak velocity(cm/s), and averaged diastolic kinetic energy (KE)(J/mL) indexed with endo-diastolic volume were computed. ResultsDiastolic LV inflow parameters and KE significantly increased in stress scan compared to the rest (74.8 {+/-} 17.5 cm/s vs. 64.5 {+/-} 14.4 cm/s, p<0.0001; 10.1 {+/-} 5.2 vs. 13.3 {+/-} 7.8, p=0.0004 for peak velocity and KE, respectively). Stress KE showed a significant and weak correlation to MFR and SSS (r = 0.3, p=0.004; r=-0.4, p=0.002 for MFR and SSS, respectively). In patients with MFR above median value (1.76), stress KE significantly elevated from rest KE, while no significant change was observed for the patients with MFR below median (11.0 {+/-} 4.6 vs. 16.2 {+/-} 8.8, p=0.0002; 9.7 {+/-} 5.4 vs. 10.3 {+/-} 5.1 for rest vs. stress, respectively). ConclusionNon-invasive assessment of intra-LV diastolic hemodynamics derived from 4D flow MRI demonstrated significant alterations under stress, and was found to have a notable association with the extent of ischemia and coronary endothelial dysfunction.

BackgroundActive myocardial fibrosis plays a pivotal role in valvular heart disease (VHD) progression. While conventional imaging modalities primarily detect established fibrosis, the detection of active fibroblast activation remains challenging. 99mTc-FAPI SPECT/CT, offering advantages of wider availability and lower cost compared to PET imaging, represents a promising tool for evaluating active myocardial fibrosis. MethodsWe conducted a prospective study of 30 VHD patients who underwent 99mTc-FAPI SPECT/CT imaging with comprehensive clinical evaluation. Patients were categorized into FAPI-positive (n=24) and FAPI-negative (n=6) groups based on myocardial tracer uptake patterns. Thirteen FAPI-positive patients completed a three-month follow-up to assess therapeutic response. ResultsFAPI uptake parameters showed robust correlations with established myocardial injury markers (Hs-cTnI vs SUVmax: r=0.831, p<0.001; vs SUVmean: r=0.795, p<0.001) and disease severity indices (VHD staging: r=0.812, p<0.001). FAPI-positive patients demonstrated significantly higher atrial fibrillation prevalence (54.2% vs 0%, P=0.024). Post-treatment follow-up revealed significant improvements in FAPI parameters (SUVmax: 2.8{+/-}0.4 to 1.9{+/-}0.3, p<0.0001; SUVmean: 2.3{+/-}0.3 to 1.6{+/-}0.2, p<0.0001), accompanied by enhanced left ventricular ejection fraction (45.3{+/-}5.2% to 52.1{+/-}4.8%, p=0.0176) and NYHA functional status (p=0.0011), despite unchanged structural parameters. ConclusionsThis study demonstrates that 99mTc-FAPI SPECT/CT enables non-invasive visualization and quantification of active myocardial fibrosis in VHD patients. The strong associations between FAPI parameters and clinical indices, coupled with its ability to monitor therapeutic response, suggest its potential as a valuable tool for risk stratification and treatment optimization in VHD management. Trial registrationChiCTR2400094867. Registered 30 December 2024. Public site: https://www.chictr.org.cn/index.html.

BackgroundCurrent risk stratification tools for acute myocardial infarction (AMI) have limitations, particularly in predicting mortality. This study utilizes cardiac ultrasound radiomics (i.e., ultrasomics) to risk stratify AMI patients when predicting all-cause mortality. MethodsThe study included 197 patients: a) retrospective internal cohort (n=155) of non-ST-elevation myocardial infarction (n=63) and ST-elevation myocardial infarction (n=92) patients, and b) external cohort from the multicenter Door-To-Unload in ST-segment-elevation myocardial infarction [DTU-STEMI] Pilot Trial (n=42). Echocardiography images of apical 2, 3, and 4-chamber were processed through an automated deep-learning pipeline to extract ultrasomic features. Unsupervised machine learning (topological data analysis) generated AMI clusters followed by a supervised classifier to generate individual predicted probabilities. Validation included assessing the incremental value of predicted probabilities over the Global Registry of Acute Coronary Events (GRACE) risk score 2.0 to predict 1-year all-cause mortality in the internal cohort and infarct size in the external cohort. ResultsThree phenogroups were identified: Cluster A (high-risk), Cluster B (intermediate-risk), and Cluster C (low-risk). Cluster A patients had decreased LV ejection fraction (P=0.004) and global longitudinal strain (P=0.027) and increased mortality at 1-year (log rank P=0.049). Ultrasomics features alone (C-Index: 0.74 vs. 0.70, P=0.039) and combined with global longitudinal strain (C-Index: 0.81 vs. 0.70, P<0.001) increased prediction of mortality beyond the GRACE 2.0 score. In the DTU-STEMI clinical trial, Cluster A was associated with larger infarcts size (>10% LV mass, P=0.003), compared to remaining clusters. ConclusionsUltrasomics-based phenogroup clustering, augmented by TDA and supervised machine learning, provides a novel approach for AMI risk stratification.