Background:Data on sex-specific pharmacodynamic differences between prasugrel and ticagrelor in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) are limited. Background:This study aims to evaluate sex-specific differences in platelet inhibition with prasugrel and ticagrelor in ACS patients undergoing PCI. Materials and Methods:This prespecified ISAR-REACT (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment) 5 substudy included 598 P2Y12 inhibitor-naive patients (126 women, 472 men) undergoing PCI with one platelet function test within 24 hours after loading with prasugrel or ticagrelor. The primary endpoint was adenosine diphosphate (ADP)-induced platelet aggregation (PA) ≤24 hours post-loading. Ischemic events (death, myocardial infarction, or stroke) and major bleeding (Bleeding Academic Research Consortium [BARC] 3-5) were assessed at 12 months. Results:Baseline ADP-induced PA was higher in women. After loading, women had lower PA than men (median 92 vs. 122 aggregation units [AU] × min; p = 0.006). Multivariable analysis showed that male sex and ticagrelor were independently associated with higher PA, with a significant sex-by-treatment interaction (p = 0.031). Women had significantly lower PA than men with prasugrel (77 vs. 118 AU × min; p = 0.001), but similar PA with ticagrelor (136 vs. 138 AU × min; p = 0.787). Twelve-month ischemic outcomes were similar between sexes in both groups. Major bleeding was higher in women than men receiving prasugrel (13.6% vs. 5.6%; Hazard Ratio (HR) 2.61; p = 0.023), but similar with ticagrelor. Conclusion:In patients with ACS undergoing PCI, women exhibited higher baseline platelet reactivity than men. After loading with the study drug, women showed stronger platelet inhibition than men with prasugrel, but not with ticagrelor. A significant interaction between sex and treatment effect on ADP-induced PA was observed.

INTRODUCTION:The majority of clinical studies investigating patients with heart failure and a reduced ejection fraction (HFrEF) exclusively included patients with symptomatic heart failure. There is a paucity of information concerning the clinical characteristics, progression to symptomatic heart failure, heart failure hospitalization rates and survival in patients with asymptomatic systolic left ventricular dysfunction (ASLVD). We address this knowledge gap by describing the baseline characteristics of participants in the prospective observational TransitionCHF study of patients with reduced left ventricular Function in New York Heart Association (NYHA) functional Class I and comparing them to those of other recent trials in HFrEF. METHODS:In total, 1005 individuals with ASLVD NYHA I with an ejection fraction ≤ 40% were recruited. Patient characteristics were compared with other studies involving patients with symptomatic heart failure. Multivariable linear regression and Pearson coefficients were used to determine the association between quality of life, mental health, markers of organ function, N-terminal prohormone of brain natriuretic peptide (NT-proBNP) plasma levels, and exercise performance. RESULTS:The mean age of participants was 60 ± 14 years and 18% were women. The mean ejection fraction was 36% and the mean left ventricular end-diastolic diameter was 59 mm. When compared with studies involving patients with symptomatic heart failure, the age was ≈ 5 years younger and the frequency of comorbidities was lower. The Short Form Health Survey-36 physical functioning score was moderately correlated with the Maastricht Vital Exhaustion Questionnaire (MQ; r = -0.44 and weakly with 6-min walking distance (r = 0.32), peak VO2 at ergospirometry (r = 0.28), and Heart Focus Anxiety (HAF17; r = -0.34). NT-proBNP levels showed a weak association with peak VO2 (r = -0.29) and the 6-min walk distance (r = -0.21). CONCLUSIONS:Patients included in the TransitionCHF study are younger and suffer from fewer comorbidities as compared with symptomatic heart failure patients. Associations between NT-proBNP levels and markers of exercise performance were weak.

Cardiogenic shock complicates takotsubo syndrome (TTS) in approximately 10

The 2024 hypertension guidelines from the European Society of Cardiology (ESC) introduce the category of 'elevated blood pressure' (120-139/70-89 mm Hg) and emphasise the importance of early prevention in individuals with such blood pressure levels and comorbid conditions. As blood pressure is recognised as a continuous risk factor, early initiation of antihypertensive treatment may be recommended even below the hypertensive range, depending on overall cardiovascular risk. All affected individuals should adopt a healthy lifestyle: regular exercise, balanced diet, reduced alcohol and salt intake, weight loss, and smoking cessation. If blood pressure remains > 130/80 mm Hg after three months and the patient has cardiovascular disease, heart failure, or a moderate to high risk, pharmacotherapy is advised. At ≥ 140/90 mm Hg, lifestyle measures and low-dose dual combination therapy should be initiated concurrently. The target systolic blood pressure is 120-129 mm Hg, with exceptions for individuals with frailty or those aged > 85 years. For resistant hypertension, spironolactone is the recommended pharmacological therapy, while renal denervation is listed as an interventional option.

Early detection of atrial fibrillation (AF) may reduce the risk of complications such as stroke. This study evaluated the diagnostic performance of a toilet seat-integrated electrocardiogram (TS-ECG) for AF detection under controlled clinical conditions. This prospective multicentre feasibility study included 83 participants (mean age 64 years, 55

AIMS:Acute myocardial infarction (MI) induces a systemic inflammatory response that usually resolves within days, but the prognostic impact of persistent inflammation is uncertain. We assessed whether sustained leukocytosis after ST-segment elevation myocardial infarction (STEMI) relates to infarct size, left ventricular function, and clinical outcomes. METHODS AND RESULTS:In >1,700 STEMI patients treated with primary percutaneous coronary intervention, leukocytes peaked on admission and typically normalized by day 3. Patients were stratified by leukocyte tertiles at admission and day 3. High day 3 leukocyte counts were associated with larger infarct size (scintigraphy; peak creatine kinase-myocardial band and troponin T), worse left ventricular function in hospital and at 6 months, and higher 1- and 5-year mortality. Patients whose leukocyte counts declined had better recovery, whereas persistent leukocytosis marked the poorest outcomes. Monocyte RNA sequencing showed post-MI transcriptomic reprogramming, and murine MI models recapitulated a similar systemic immune response. CONCLUSIONS:Persistent inflammation, particularly elevated leukocyte counts at day 3 post-MI, is associated with adverse remodeling and increased mortality after STEMI, identifying unresolved inflammation as a negative prognostic marker and potential therapeutic target.

In-stent restenosis (ISR) after percutaneous coronary intervention is a multi-factorial process. Specific morphological lesion characteristics were observed to contribute to the occurrence of ISR. Local mechanical factors, such as stresses and strains, are known to influence tissue adaptation after stent implantation. However, the influence of morphological features on those local mechanical states and, hence, on the occurrence of ISR remains understudied. This work explores how local mechanical quantities relate to ISR by evaluating the stress distributions in the artery wall during and after stent implantation for morphology-informed lesion examples. We perform computational simulations of the stenting procedure with physics-based patient-specific coronary artery models. Different morphologies are assessed using the spatial plaque composition information from high-resolution coronary computed tomography angiography data. In the sample cases, elevated local tensile stresses were consistently found at sites corresponding to ISR. We found that specific morphological characteristics like circumferential or asymmetric block calcifications result in higher stresses in the surrounding tissue. These findings show that for the observed connection between plaque morphology and ISR, the local mechanical state may represent a relevant link. This study provides a mechanistic, illustrative insight for the examined cases. Future work with larger cohorts and systematic follow-up can establish statistically robust associations.

Purpose: This study aims to determine if higher blood sugar, even within the prediabetes range, affects coronary lesion characteristicsMethods: Symptomatic patients with confirmed CAD on CCTA were stratified into three different groups based on their glycated-hemoglobin (HbA1c) levels: 1) Euglycemia, HbA1c below 5.7% (HbA1c<39mmol/mol) 2) Prediabetes, HbA1c-levels between 5.7% and 6.4% (HbA1c=39-46mmol/mol) 3) Diabetes, HbA1c-levels ≥6.5% (HbA1c≥48mmol/mol). A plaque analysis of culprit lesions on CCTA using a dedicated plaque analysis software was performed and findings between the three different groups were compared.Results: Overall 184 patients and 247 coronary lesions were analyzed. Coronary lesion length was significantly greater in prediabetic [(29.5 mm (12.7-50-4) versus 24.8 mm (11.4-51.1),p=0.025)] and diabetic individuals [(30.1 mm (16.7-50.2) versus 24.8 mm (11.4-51.1), p=0.005)] compared to those with normal HbA1c levels. In terms of plaque composition and volume, diabetics demonstrated a significantly higher amount of total lipid-rich plaque volume [(62.5 mm3 (38.1-93.7) versus 41.9 mm3 (22.4-66.7), p<0.001] and total fibrotic plaque volume [55.7 mm3 (37.1-92.2) versus 29.3 mm3 (16.9-61.2),p=0.004] compared to euglycemic patients. In multivariable adjusted logistic regression, there was a significant association between both prediabetes and diabetes and predominantly non-calcified plaques (odds ratio [OR] 2.124 [95% CI (1.016-4.437), p=0.045 and OR 2.505 (1.029-6.098),p=0.043].Conclusion: Poor glycemic control is associated with a higher prevalence of predominantly noncalcified plaques in symptomatic individuals. When compared to euglycemic individuals, prediabetic individuals demonstrate an extended coronary lesion length similar to diabetics. These factors may play a role in the poorer clinical outcomes even observed in patients with borderline diabetes

BACKGROUND AND AIMS:Familial hypercholesterolemia (FH), primarily caused by pathogenic LDLR, APOB, or PCSK9 variants, results in elevated LDL-C and increased cardiovascular risk. Genetic testing offers the definitive diagnosis, yet global approaches to FH genetic testing remain unstandardized. We investigate current testing practices worldwide and provide relevant recommendations. METHODS:A survey was distributed to national lead-investigators (NLIs) of 68 countries in the FH-Studies Collaboration, assessing referral criteria, assay methodologies, target genes, and pathogenicity interpretation methods. RESULTS:NLIs from centres in 55/68 countries (81%) responded, spanning Africa (N=2), Americas (N=6), Asia (N=20), Europe (N=26), and Oceania (N=1). DLCN scores were the most common reason for referral to genetic testing (adults:72%; children:57%). Simon Broome and MEDPED criteria were reported only by centres from high-income countries (adults: 7% and 2%; children: 12% and 2%). Methods for testing in index versus non-index cases were significantly different (p <0.001). Next-generation sequencing (NGS) was the predominant assay method for index cases (62%), while Sanger sequencing was favoured for non-index (71%). However, these testing techniques did not differ between centres from high- and non-high-income countries for index cases (p=0.74) and non-index cases (p=0.49). Copy-number variants (CNVs) were assessed by 65% of centres, with most integrating CNV analysis into NGS platforms (86%) and others (14%) using multiplex ligation-dependent probe-amplification (MLPA) or microarrays. Screening encompassed LDLR (100%), APOB (97%), PCSK9 (95%), and other genes. Most centres (96%) incorporated pathogenicity interpretation into their reports, adhering largely to American College of Medical Genetics and Genomics guidelines. CONCLUSIONS:FH genetic testing practices vary widely across countries surveyed, emphasizing the need for global standardization to enhance accuracy and comparability of FH diagnoses worldwide. We suggest that genetic testing should include the three FH-causing genes and ideally the five associated/phenocopy genes.

The expanding use of bioprosthetic aortic valve replacements has raised concerns regarding the long-term durability of bioprosthetic valve prostheses. While lipoprotein(a) [Lp(a)] is implicated in the pathogenesis of native aortic valve stenosis, its impact on bioprosthetic valve degeneration leading to reintervention remains unclear. To evaluate the association between Lp(a) levels and structural degeneration of aortic bioprosthetic valves in patients undergoing secondary aortic valve procedure. We retrospectively analyzed 389 patients with available Lp(a) values who underwent replacement of a degenerated aortic bioprosthetic valves between February 2001 and September 2024. Endpoint was the interval from initial surgical aortic valve replacement (SAVR) to the second aortic valve procedure either as transvascular or surgical replacement. Patients were stratified by Lp(a) levels into low (< 105 nmol/L) and high (≥ 105 nmol/L) Lp(a) groups. Associations between Lp(a) levels and time-to-reintervention were assessed using Kaplan–Meier survival analysis. Out of an initial cohort of 909 patients, 389 met the inclusion criteria. Of these, 296 patients showed low and 93 high Lp(a) levels. Baseline characteristics were comparable between both groups. The median time from initial valve implantation to the second aortic valve intervention did not differ significantly by Lp(a) group. Kaplan–Meier analysis demonstrated no significant association between elevated Lp(a) and time-to-reintervention (hazard ratio [HR] 0.81; 95

BACKGROUND:Clinical and angiographic outcomes after chronic total occlusion (CTO) percutaneous coronary intervention (PCI) remain incompletely investigated, whereas direct comparisons with non-CTO-PCI are missing. In this study we aimed to compare the midterm clinical and angiographic outcomes following successful CTO-PCI and non-CTO-PCI. METHODS:This study included consecutive patients from the Intracoronary Stenting and Angiographic Results-Chronic Total Occlusion (ISAR-CTO) Registry undergoing successful CTO recanalization as well as all successful non-CTO-PCI procedures from our institutional database. Propensity score matching (PSM) with a 1:3 matching ratio was performed. The primary endpoint was the incidence of major adverse cardiac events (MACEs) at 12-month follow-up. The secondary angiographic endpoint was in-segment binary restenosis at surveillance angiography. RESULTS:Overall, 453 CTO-PCI patients (472 lesions) and 14,733 non-CTO-PCI patients (23,458 lesions) were analyzed. After PSM, a total of 1812 patients were included in the study (CTO-PCI: n = 453 patients [472 lesions]; non-CTO-PCI: n = 1359 patients [1424 lesions]). There were no significant differences in terms of MACEs (adjusted hazard ratio [HRadj] = 1.26, 95% confidence interval [CI] 0.95-1.66) between CTO-PCI and non-CTO-PCI at 12-month follow-up. CTO-PCI independently correlated with a higher risk of target lesion revascularization (TLR) (HRadj = 1.66, 95% CI 1.21-2.27) and a significantly lower risk of myocardial infarction (MI) (HRadj = 0.231, 95% CI 0.06-0.98). CTO-PCI independently correlated with occurrence of binary restenosis (adjusted odds ratio = 1.86, 95% CI 1.38-2.51) at surveillance angiography. CONCLUSIONS:CTO-PCI was independently associated with significantly higher rates of TLR as well as a significantly lower incidence of MI at 12-month follow-up. Quantitative coronary angiography analysis of surveillance angiography showed superior angiographic outcomes after non-CTO-PCI.

Abstract Mitral valve prolapse (MVP) is the most common cause of primary mitral regurgitation and is associated with the development of malignant arrhythmias, often in the context of myocardial fibrosis. The genetic architecture of MVP, and whether there are genetic factors explaining why only some individuals with MVP have adverse outcomes, remains poorly understood. We performed a meta-analysis of genome-wide association studies (GWAS) for MVP encompassing 21,517 cases among a total sample size of over 2.2 million individuals. We discovered 89 genomic risk loci for MVP, of which 72 were novel findings. Prioritization of causal genes and pathways using epigenetic and transcriptomic data from mitral valve and extra-valvular tissues replicated known gene associations to MVP including those involved in TGF-β signaling and extracellular matrix biology, but additionally emphasized a role in MVP for biological pathways relevant to cardiomyocyte biology. Accordingly, we identified several MVP risk loci with pleiotropy to cardiomyopathies, especially hypertrophic cardiomyopathy, and demonstrated a significant genetic correlation between MVP and hypertrophic cardiomyopathy. Finally, we interrogated snRNA-seq data in human papillary muscle tissue from two individuals with severe MVP, characterizing genes associated with both risk of papillary muscle fibrosis and MVP.

Background: Perivascular fat attenuation index (FAI) derived from coronary CT angiography (CCTA) has emerged as a quantitative biomarker of vascular inflammation, with potential to improve risk stratification in coronary artery disease (CAD) patients. This study aimed to evaluate plaque characteristics of coronary atherosclerotic lesions in patients with high (≥-70.1 HU) or low FAI of pericoronary adipose tissue. Methods: In a retrospective analysis, patients with suspected or confirmed CAD who underwent coronary CTA were included. Coronary lesions were classified into two groups based on their perivascular inflammation as assessed by CCTA: high perivascular FAI phenotype (≥-70.1 HU) versus low FAI phenotype (<-70.1 HU). Both groups were compared with respect to various patient- and lesion-specific characteristics. Results: A total of 247 coronary lesions were analyzed in this study. Of these, 36 (14.6%) lesions were associated with high perivascular inflammation (high FAI phenotpye) and 211 (85.4%) were associated with low perivascular inflammation (low FAI phenotype). Lesions with a high FAI phenotype demonstrated a significantly higher amount of non-calcified plaque volume (NCPV) compared to lesions with a low FAI phenotype [(111.8 mm3 (69.4-184.2) versus 87.7 mm3 (44.6-143.0), p < 0.003]. NCPV emerged as a consistent and significant predictor of fat attenuation positive plaque in both univariate (OR 1.030 [95% CI, 1.010-1.050], p = 0.003); and multivariate logistic regression analyses (OR 1.028 [95% CI, 1.008-1.050]. p = 0.007). Additionally, lesions with a high FAI phenotype less frequently exhibited homogeneous calcification than their low FAI phenotype counterparts (25% versus 46.9%, p = 0.014). Conclusions: Coronary lesions associated with a high FAI phenotype on coronary CCTA consist predominantly of non-calcified plaques. Conversely, lesions characterized by a low perivascular FAI phenotype are primarily calcified and seem to be more homogeneous by visual assessment. Further prospective studies are warranted to validate these associations and explore the underlying pathophysiological mechanisms.

Objective: One of the strongest genetic associations with coronary artery disease (CAD) risk maps to the metalloproteinase 'a disintegrin and metalloproteinase with thrombospondin motifs 7' (ADAMTS-7) locus. The protein was shown to promote plaque formation and instability. We aimed to generate and evaluate an antibody-based strategy targeting ADAMTS-7 therapeutically to reduce atherosclerotic plaque formation. Approach and Results: A truncated form of human ADAMTS-7 was produced in Nicotiana benthamiana and used as antigen for antibody generation by hybridoma technology. Eight monoclonal antibodies (mAbs) were screened, among which ADAMTS-7-mAb32 (mAb32) demonstrated the highest affinity, as confirmed by surface plasmon resonance analyses and immunoblotting against full-length ADAMTS-7. In vitro, mAb32 inhibited interactions of ADAMTS-7 with its substrates TIMP-1 and SVEP1 in a dose- and time-dependent manner, as assessed by time-resolved Forster resonance energy transfer assays. To assess therapeutic efficacy in vivo, Apoe-/- mice were fed a Western diet for ten weeks and treated with weekly injections of mAb32 or control IgG over the last six weeks. En face aortic Oil Red O staining revealed significantly reduced plaque area in the treatment group, without changes in plasma cholesterol levels or body weight. No evidence of liver or kidney toxicity was observed. Conclusion: Monoclonal antibody-based inhibition of ADAMTS-7 reduced atherosclerotic burden in vivo without affecting lipid metabolism, supporting ADAMTS-7 as a viable therapeutic target in CAD. Further development of mAb32 may provide a cholesterol-independent treatment strategy for atherosclerosis.