Importance:Cardiovascular disease (CVD) is the leading cause of death among women worldwide. Pregnancy serves as a natural cardiovascular stress test and universal clinical encounter, yet few approaches leverage its insights to inform long-term cardiovascular risk. Objective:To determine whether clinical measures and biomarkers obtained during pregnancy may identify women at risk of long-term CVD. Design, Setting, and Participants:This was a registry-linked, population-based cohort study of all pregnancies reaching at least 22 weeks between June 2010 and October 2013 in Southern Denmark. Primary analyses were performed in a nested prospective subcohort of Odense Child Cohort participants with available pregnancy biomarker data. Women with preexisting CVD were excluded (n = 114). Follow-up was done through December 31, 2023. Among 38 455 eligible women, 2056 had biomarker data at week 12 or week 29. Analytic subsets with complete data were used for prognostic modeling at week 12 (n = 1379) and week 29 (n = 1389). Exposures:Clinical characteristics, obstetric outcomes, and pregnancy biomarkers including soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor, high-sensitivity cardiac troponin I (hs-cTnI), and N-terminal pro-B-type natriuretic peptide. Main Outcomes and Measures:Incident maternal CVD, evaluated using Cox proportional hazards models. Results:In the biomarker cohort (median [IQR] age, 30.4 [27.4-33.8] years), 28 women (1.4%) developed CVD during a median (IQR) follow-up of 11.9 (11.2-12.5) years. Maternal age, hypertensive disorders of pregnancy (HDPs), and third-trimester concentrations of hs-cTnI and sFlt-1 were each independently associated with higher long-term CVD risk. A combined model including age and sFlt-1 measured at week 29 improved discrimination for CVD compared with a base model of age alone (ΔAUC, 0.16; 95% CI, 0.02-0.30), whereas a clinical model consisting of age, systolic blood pressure, and non-high-density lipoprotein cholesterol did not. Results were consistent in women without prior hypertension or HDPs and in nulliparous women. CVD incidence and the predictive value of the base model were comparable between the biomarker and the contemporaneous background cohorts (n = 36 274). Conclusions and Relevance:These findings support pregnancy as an opportunistic window for sex-specific cardiovascular risk assessment and prevention throughout a woman's life course. Further studies are warranted to validate these findings.

Abstract Background While transcatheter aortic valve replacement (TAVR) has become an established alternative to surgical aortic valve replacement (SAVR), the comparative outcomes of balloon-expandable (BE) and self-expanding (SE) valve technologies remain an area of ongoing investigation. Methods Using the German DESTATIS database, we analyzed 48,565 transfemoral TAVR procedures performed between 2021 and 2022. Outcomes were compared between BE ( n = 23,412) and SE ( n = 25,153) valves using a double/debiased machine learning estimator to account for potential confounding. Key endpoints included in-hospital mortality, major bleeding, stroke, acute kidney injury, mechanical ventilation > 48 h, postoperative delirium, permanent pacemaker implantation (PPI), length of hospital stay, and reimbursement. Results Descriptively, SE valves were associated with significantly lower in-hospital mortality (1.6% vs. 2.0%, p < 0.001) and major bleeding (1.4% vs. 2.1%, p < 0.001) but a higher risk of stroke (2.4% vs. 1.9%, p < 0.001). A trend towards higher risk of PPI was observed ( p = 0.078). After adjustment, patients with SE valves are at lower risk for in-hospital mortality (RR 0.85, p = 0.049) and major bleeding (RR 0.78, p = 0.006), but had a higher risk of stroke (RR 1.35, p < 0.001) and permanent pacemaker implantation (RR 1.09, p = 0.028). Subgroup analysis indicated that older and high-risk patients, particularly those aged ≥ 85 years, showed a stronger association with lower in-hospital mortality for SE valves, whereas younger patients exhibited a trend favouring BE valves. BE valves were also associated with a modestly higher reimbursement (€209 per case, p = 0.004). Conclusion In this large, real-world cohort, self-expanding valves were associated with lower in-hospital mortality and major bleeding but a higher risk of stroke and permanent pacemaker implantation compared with balloon-expandable valves. Because prosthesis choice in routine practice is highly individualized and driven by anatomical and procedural factors not captured in administrative data, these associations are hypothesis-generating and cannot support device-selection recommendations.

Background: To evaluate safety, technical success, and long-term outcomes of endovascular therapy (EVT) in severely calcified aortoiliac occlusive disease (AIOD), focusing on lesion characteristics and the presence of coral reef aorta (CRA). Patients and methods: This single-center retrospective study included 216 patients with angiographically confirmed calcified abdominal aortic stenosis (mean PACSS 3.7 ± 0.8) treated with EVT between 2005 and 2023. Of these, 33 patients had coral reef aorta (CRA). Patients were stratified by lesion location and CRA presence. Primary endpoints were 30-day adverse events and technical success (residual stenosis <30%). Secondary endpoints were major adverse cardiovascular events (MACE), major adverse limb events (MALE), and all-cause mortality. Cox regression identified predictors of outcome. Results: Technical success was achieved in 81.9%. Thirty-day mortality was 0.5%. At 10 years, freedom from MACE was significantly lower in patients with non-bifurcation abdominal aortic stenosis (56% vs. 76%; aHR 2.13, p < .05) and lowest in CRA (30% vs. 71%; aHR 3.17, p < .05). Independent predictors of MACE were CRA, chronic total occlusion (aHR 3.38, 95% CI 1.57-7.29), critical limb-threatening ischemia (aHR 3.67, 95% CI 1.74-7.75), and age (aHR 1.06 per year, 95% CI 1.01-1.11). MALE was more frequent in patients with peripheral arterial disease (aHR 2.07, 95% CI 1.12-3.81), CRA (aHR 2.51, 95% CI 1.17-5.40), and current smokers (aHR 5.10, 95% CI 1.23-21.0). Conclusions: CRA and non-bifurcation abdominal aortic stenosis are associated with reduced long-term freedom from MACE after EVT. These findings define high-risk subgroups within calcified AIOD and highlight the prognostic value of anatomical lesion characteristics for treatment planning and follow-up.

Cardiovascular (CV) disease remains the leading cause of death in women, yet risk is often recognized late. Pregnancy is a physiologically demanding, routinely monitored period with repeated health care contact, standardized clinical assessments and blood-based testing, creating a strategic window to capture early signals of CV vulnerability long before conventional midlife risk assessment. Research has largely focused on hypertensive pregnancy complications, but most future CV events occur in women without such complications. Emerging evidence indicates that blood pressure trajectories, angiogenic and cardiac biomarkers, and routinely assessed metabolic parameters are associated with long-term maternal hypertension, subclinical CV phenotypes, and clinical CV events, even in the absence of overt hypertensive pregnancy complications. This review summarizes data on soluble fms-like tyrosine kinase-1, placental growth factor, natriuretic peptides, cardiac troponins, blood pressure, and the metabolic parameters weight and glycemic status, and discusses limitations of the current evidence base and key priorities for translating pregnancy-derived signals into clinically actionable CV risk assessment.

CYP2C19 genetic polymorphisms impact the antiplatelet effect of clopidogrel and associate with ischemic and bleeding risk in patients undergoing percutaneous coronary intervention (PCI). This study aimed to evaluate the association of CYP2C19 and platelet reactivity (PR) with these risks, in atrial fibrillation (AF) patients undergoing PCI, treated with an oral anticoagulation (OAC) and clopidogrel. This two-center prospective cohort study included patients with AF and OAC undergoing PCI. Carriers of ≥ 1 loss-of-function (LOF) allele were classified as poor/intermediate metabolizers (PM/IM), whereas carriers of ≥ 1 gain-of-function allele without LOF alleles were classified as rapid metabolizers (RM). PR was assessed by thromboelastography (TEG) and/or multiple electrode aggregometry (MEA). The primary outcome included death, MI, or stroke at 6 months ±2 weeks; the secondary outcome consisted of non-major clinically relevant (NMCR) or major bleeding. Among 283 patients (median age 78 years; 72% male), 73 (26%) were PM/IM, 108 (38%) were NM, and 102 (36%) were RM. PM/IM status was not significantly associated with the primary ischemic outcome (PM/IM: 6 [8.2%] vs. NM + RM: 16 [7.6%], p = 0.869), but any bleeding rates were numerically lower. While there was a trend for association of high platelet reactivity (HPR) with the ischemic outcome (OR 2.005 [95% CI 0.820-4.902], p = 0.127), low platelet reactivity (LPR) was associated with major bleeding (OR 2.646 [95% CI 1.075-6.509], p = 0.034). PM/IM status did not detect an increased ischemic risk but might, however, protect from bleeding risk in AF patients undergoing PCI. HPR might indicate a higher ischemic risk, while LPR was associated with major bleeding.

Background:Clinical risk factors identify subjects at risk of incident atrial fibrillation (AF) with only mediocre accuracy. Amplified P-wave duration (PWD) is a novel electrocardiographic (ECG) marker for conduction delay in atrial cardiomyopathy, which in turn is associated with AF. Objective:This study aimed to assess whether amplified PWD can predict incident AF in the general population. Methods:Amplified PWD was assessed manually on a signal-modified ECG in 2134 participants from the population-based Hamburg City Health Study. Incident AF during the 5-year follow-up was defined as the primary end point. Multivariable Cox regression models were constructed including significant clinical risk factors, ECG parameters, and transthoracic echocardiography parameters, and the predictive power for the primary end point was evaluated. Results:Over a median follow-up of 5.5 years, 102 participants (4.8%) developed incident AF. The upper tertile of amplified PWD was the only significant ECG-derived predictor for incident AF (hazard ratio [HR] 2.02; P = .010) in the multivariable ECG-based model, alongside age (HR 1.07; P = .013) and body mass index (HR 1.08; P = .003), after adjustment for significant clinical risk factors (concordance index 0.764). A comprehensive combined ECG/transthoracic echocardiography model achieved a concordance index of 0.770, with age (HR 1.07; P = .020) and left atrial volume (HR 1.02; P = .020) remaining significant predictors. Conclusion:Amplified PWD as a novel ECG-based marker predicts incident AF in a population-based cohort and may provide a pragmatic ECG-derived marker of atrial cardiomyopathy for risk assessment beyond conventional risk stratification. Clinical Trial Registration:NCT03934957 (https://www.clinicaltrials.gov).

Coronary computed tomography angiography (CCTA) as first-line diagnostic tool for suspected coronary artery disease (CAD) offers detailed assessment of coronary plaque, yet data on non-calcified components remain limited. This study aims to analyze total coronary plaque burden as well as non-calcified plaque characteristics in an ESC-guideline-selected cohort and to establish age- and sex-specific percentile distributions and benchmark values for quantitative plaque assessment. All patients undergoing CCTA for a clinical indication at a German outpatient institution between July 2017 and June 2020 were included. Plaque analysis using validated semi-automated software was performed on all coronary arteries; plaque burden was measured with differentiation among total, calcified, non-calcified, and low-attenuation components. Of 5412 patients, coronary plaques were present in 67.1

BACKGROUND:Approximately one half of patients undergoing transcatheter aortic-valve implantation (TAVI) have concomitant coronary artery disease. Although percutaneous coronary intervention (PCI) is often performed before TAVI, the preferred treatment strategy has not been established. METHODS:We conducted an international, open-label, randomized, noninferiority trial at 48 centers in Europe. Patients with severe aortic stenosis and coronary artery disease were randomly assigned in a 1:1 ratio to a strategy of either TAVI before PCI (TAVI-first group) or PCI before TAVI (PCI-first group). The primary end point was a composite of death from any cause; nonfatal myocardial infarction; ischemia-driven revascularization; rehospitalization related to the valve, procedure, or heart failure; or life-threatening, disabling, or major bleeding at 1 year after randomization. The noninferiority margin was 6.6 percentage points, with testing for noninferiority of TAVI first as compared with PCI first. RESULTS:A total of 986 patients underwent randomization: 498 were assigned to the TAVI-first group and 488 to the PCI-first group. A primary end-point event occurred in 105 patients (22.2%) in the TAVI-first group and in 112 patients (24.2%) in the PCI-first group (risk difference, -2.0 percentage points; 95% confidence interval, -7.4 to 3.4; P<0.001 for noninferiority). Serious adverse events occurred in 264 patients in the TAVI-first group and in 273 patients in the PCI-first group. CONCLUSIONS:Among patients with severe aortic stenosis and coronary artery disease, a strategy of TAVI before PCI was noninferior to a strategy of PCI before TAVI with respect to the primary end point at 1 year. (Funded by University Hospital Zurich and others; TAVI PCI ClinicalTrials.gov number, NCT04310046.).

BACKGROUND AND AIMS:The co-stimulatory signaling dyad of CD40 and CD40L is a potent inducer of cardiovascular inflammation and vulnerability of atherosclerotic plaques. A cytosine-to-thymidine transition (-1C > T) in the Kozak sequence of the CD40 gene (rs1883832) lowers CD40 protein expression. Here, we interrogate whether this CD40 gene variant correlates with recurrent cardiovascular events after acute coronary syndromes. METHODS:The Biomarkers in Acute Cardiac Care (BACC) cohort prospectively enrolled patients presenting to the emergency department with acute chest pain and suspected myocardial infarction. Genotype status (homozygous C/C or T/T, heterozygous: C/T) was determined by a TaqMan assay in 1298 patients with either confirmation of or ruled out acute myocardial infarction (AMI). The CD40 genotype-adjusted risk for major adverse cardiovascular events (MACE) during a median follow-up time of 5.2 years was studied by multivariate Cox regression. RESULTS:Relative abundances of the genotypes among all participants were 55.8% for C/C, 37.1% for C/T, and 7.2% for T/T. None of the genotype variants was associated with diabetes, hypertension, hyperlipoproteinemia, or a history of coronary artery disease (CAD). T/T carriers showed a strong trend towards an increased sex- and age-adjusted risk for AMI at admission (OR 1.58, 95% CI 0.95-2.64, p = 0.078) in logistic regression analysis. MACE occurred more often in patients with the T/T genotype (HR 1.46, 95% CI 1.01-2.11, p = 0.046) compared to C/T (HR 0.96, 95% CI 0.77-1.19, p = 0.70) and C/C (HR 0.94, 95% CI 0.76-1.16, p = 0.54) carriers. This effect was independent of age, sex, diabetes mellitus, hyperlipoproteinemia, arterial hypertension, smoking status and left ventricular ejection fraction in multivariable regression. CONCLUSIONS:Our data indicate that - unexpectedly - the T/T genotype of rs1883832 is associated with an enhanced risk for myocardial infarction and subsequent MACE. As this SNP impedes effective CD40 translation, our findings suggest a potentially protective role of CD40 in high-risk patients.

Elevated levels of oxidized phospholipids (OxPL) on plasminogen (OxPL-PLG) are associated with reduced time to fibrinolysis and reduced risk of cardiovascular events, but their effect on platelet function is unknown. We aimed to evaluate the association of OxPL-PLG with platelet surface marker expression, intrinsic and on‑dual anti-platelet (DAPT, aspirin plus clopidogrel)) platelet reactivity and cardiovascular events. OxPL-PLG levels were measured in pre-procedure blood samples in 2040 patients undergoing coronary angiography with or without PCI. The association of OxPL-PLG to pre-procedure and 24-hour platelet surface expression of CD62P, CD41 and PAC-1 and intrinsic and on-DAPT platelet reactivity in response to collagen and adenosine diphosphate (ADP) were assessed. The relationship of OxPL-PLG to myocardial infarction(MI)-free survival over a median 7-year follow-up was assessed using multivariable Cox regression models. Elevated levels of OxPL-PLG were significantly and inversely associated with age, male sex, severity of coronary obstruction, previous MI, PCI, and CABG. OxPL-PLG was inversely associated with platelet surface expression of CD41 (p < 0.001), CD62P (p = 0.0012) and PAC-1 (p < 0.001) at baseline and with CD41 (p = 0.001) and CD62P (p = 0.020) after DAPT. A significant inverse association was present between OxPL-PLG and intrinsic platelet reactivity in response to ADP (p < 0.001) at baseline but not after DAPT. OxPL-PLG was not associated with MI-free survival. In conclusion, elevated OxPL-PLG levels are independently associated with lower-risk clinical profile, less severe coronary disease, and reduced platelet activation and reactivity prior to DAPT. These findings suggest OxPL-PLG may modulate platelet activation and reactivity and warrant further mechanistic and clinical evaluation. EXCELSIOR study (Impact of Extent of Clopidogrel-Induced Platelet Inhibition during Elective Stent Implantation on Clinical Event Rate; ClinicalTrials.gov Identifier: NCT00457236). Elevated OxPL-PLG levels correlate with fewer high-risk clinical and angiographic features. OxPL-PLG levels are inversely associated with platelet activation markers CD41, CD62P, and PAC-1. Higher OxPL-PLG levels are linked to lower intrinsic platelet reactivity to ADP before DAPT. OxPL-PLG are not associated with MI-free survival at 7-year follow-up in EXCELSIOR. Findings suggest OxPL-PLG modulates platelet function and merits further mechanistic and clinical outcome studies.

BACKGROUND AND AIMS:Atrial fibrillation (AF) is a well-known risk factor for ischemic stroke. Emerging evidence suggests that atrial cardiomyopathy (AtCM), independent of AF, may be a key contributor to stroke risk. We aimed to evaluate whether non-invasive AtCM markers assessed by electrocardiography (ECG), transthoracic echocardiography (TTE), and blood-based biomarkers provide incremental diagnostic value beyond established clinical risk factors for identifying cerebral stroke lesions on magnetic resonance imaging (MRI). METHODS:We analyzed 1,794 Hamburg City Health Study participants who underwent cerebral MRI with available baseline 12-lead ECG and TTE in sinus rhythm. Logistic regression analyses were performed to identify associations between non-invasive AtCM markers and stroke lesions. The incremental discriminatory performance of these markers beyond clinical risk factors was assessed. RESULTS:Stroke lesions were present in 152 participants (8.5%). Male sex, history of prior AF and higher CHA₂DS₂-VA score were significantly associated with stroke lesions. Among AtCM markers, amplified P-wave duration, P-wave area in lead II, PR interval, left atrial volume index, left atrial ejection fraction, and NT-proBNP were also significant. Combining both clinical and AtCM markers, only CHA₂DS₂-VA score (OR:1.95 per point, 95%CI:1.49-2.55, p<0.001) and P-wave area in lead II (OR:0.99 per 100µV·ms, 95%CI:0.98-1.00, p=0.031) remained independent predictors. However, this resulted in only marginal improvement in discrimination (ΔAUC:0.03, 95%CI: 0.0001-0.0594) compared with the clinical risk factor model alone. CONCLUSION:The incremental diagnostic value of AtCM markers beyond clinical risk factors for MRI-defined cerebral lesions is limited, likely reflecting the heterogeneous etiology of stroke lesions in a general population cohort.

BACKGROUND:The cardiovascular-kidney-metabolic syndrome (CKM) is a multisystem disorder increasingly recognized for its association with adverse outcomes. The incidence and prognostic relevance of CKM in patients undergoing transcatheter aortic valve implantation (TAVI) has not been investigated. METHODS AND RESULTS:A double center, retrospective analysis of patients undergoing TAVI from 2011 to 2024 was performed. CKM syndrome was diagnosed and quantified using a simplified definition based on the presence of atherosclerotic cardiovascular diseases (ASCVD), chronic kidney disease (CKD), and diabetes mellitus (DM). The prevalence of CKM and its association with procedural success, bleeding events, permanent pacemaker implantation and 1-year mortality was evaluated.Among 5,834 TAVI patients, 5,280 (90%) fulfilled criteria for CKM. The overall prevalence remained stable. Procedural success was highest in patients with no CKM conditions, followed by patients with 1 and 2 CKM conditions. Patients with 3 CKM conditions had the worst procedural success (p=0.002). Patients with 2 and 3 CKM conditions had higher probability of death within 1 year as compared to patients with no CKM conditions and 1 CKM condition (HR for 2 CKM conditions 1.40, p=0.030, HR for 3 CKM conditions 1.88, p<0.001). Patients with 3 CKM conditions had higher rates of permanent pacemaker implantation (OR 1.45, p=0.02), but not of major bleeding (HR 1.24, p=0.328). After adjustment for baseline differences in comorbidities and patient characteristics, 3/3 CKM conditions remained associated with increased all-cause mortality at 1, 2 and 5 years. CONCLUSION:CKM is highly prevalent in patients undergoing TAVI. Higher CKM condition burden was associated with adverse outcomes.

Aims:Cardiogenic shock carries high early mortality. Combined veno-arterial extracorporeal membrane oxygenation and Impella support (ECPELLA) may improve outcomes but is costly and unevenly available across Europe. Its incremental clinical and economic value compared with guideline-directed medical therapy (GDMT) remains uncertain. Methods:We developed a calibrated partitioned-survival model comparing ECPELLA with GDMT over a 10-year horizon from a statutory health insurance payer perspective (2024€ reference costing environment). Costs, utilities, and survival inputs were derived from contemporary randomized trials and multinational registries. Uncertainty was assessed using probabilistic, deterministic, scenario, and value-of-information analyses. European cost-environment scenarios were explored to assess transferability. Results:ECPELLA yielded 4.05 quality-adjusted life-years (QALYs) at €195 000 vs. 3.10 QALYs at €95 000 for GDMT (incremental cost €100 000; incremental QALY 0.95), resulting in an incremental cost-effectiveness ratio (ICER) of €105 263 per QALY. Device and intensive care unit (ICU) costs and early survival effects were the main drivers of uncertainty. Cost-effectiveness improved in patients younger than 60 years, those with reversible myocardial dysfunction, early cannulation, and treatment in high-volume centres (ICER €60 000-80 000 per QALY), whereas neutral survival effects produced ICERs exceeding €300 000 per QALY. Value-of-information analysis indicated residual decision uncertainty. Conclusion:ECPELLA increased quality-adjusted survival at higher cost. In the base-case analysis, the ICER was €105 263 per QALY gained. In predefined scenario analyses, ICERs were lower in younger patients, those with recovery potential, early cannulation, and high-volume centres. Residual decision uncertainty was observed in value-of-information analyses.

Background Contrast-associated nephropathy is a complication of cardiovascular procedures. Although contrast volume is a risk factor for acute kidney injury, its impact on medium- to long-term renal function remains unknown. This study aimed to investigate this association in patients undergoing repeated percutaneous coronary interventions (PCI). Methods This retrospective single-centre study included patients undergoing repeated PCIs between 2003 and 2023, with intervals of ≥7 and ≤ 365 days between procedures. Renal function was classified by “Kidney Disease: Improving Global Outcomes” (KDIGO) staging system. The maximum allowable contrast dose (MACD) was retrospectively calculated as individual threshold. Primary endpoint was progression to a higher KDIGO stage at readmission. Secondary endpoints included changes in estimated glomerular filtration rate (eGFR). Results In total 6714 patients were included (mean age 67.2 years; 80.2% male; KDIGO stage analysis available for 6611; median interval between procedures 127 days). Baseline mean eGFR was 74.4 mL/min/1.73 m2. Median contrast volume was 220 mL, and median MACD 300 mL. At readmission, mean eGFR was 72.2 mL/min/1.73 m2, 1700 Patients (25.7%) showed KDIGO stage progression. Neither contrast volume nor MACD exceedance was associated with renal deterioration. However, predispositions (diabetes mellitus, arterial hypertension, age), clinical presentation (STEMI, NSTEMI) and the vascular access route were significantly associated with adverse renal outcomes. Conclusions Contrast volume and MACD exceedance during PCI was not associated with deterioration of medium- to long-term renal function. Abbreviations PCI:Percutaneous coronary interventioneGFR:Estimated glomerular filtration rateKDIGO:Kidney Disease: Improving Global OutcomesMACD:Maximum allowable contrast doseCA-AKI:Contrast-associated acute kidney injuryBMI:Body mass indexHR:Hazard ratioCI:Confidence intervalNSTEMI:Non-ST-segment elevation myocardial infarctionSTEMI:ST-segment elevation myocardial infarction