Live Cell Monitoring of Phosphodiesterase Inhibition by Sulfonylurea Drugs.

Sulfonylureas (SUs) are a class of antidiabetic drugs widely used in the management of diabetes mellitus type 2. They promote insulin secretion by inhibiting the ATP-sensitive potassium channel in pancreatic ß-cells. Recently, the exchange protein directly activated by cAMP (Epac) was identified as a new class of target proteins of SUs that might contribute to their antidiabetic effect, through the activation of the Ras-like guanosine triphosphatase Rap1, which has been controversially discussed. We used human embryonic kidney (HEK) 293 cells expressing genetic constructs of various Förster resonance energy transfer (FRET)-based biosensors containing different versions of Epac1 and Epac2 isoforms, alone or fused to different phosphodiesterases (PDEs), to monitor SU-induced conformational changes in Epac or direct PDE inhibition in real time. We show that SUs can both induce conformational changes in the Epac2 protein but not in Epac1, and directly inhibit the PDE3 and PDE4 families, thereby increasing cAMP levels in the direct vicinity of these PDEs. Furthermore, we demonstrate that the binding site of SUs in Epac2 is distinct from that of cAMP and is located between the amino acids E443 and E460. Using biochemical assays, we could also show that tolbutamide can inhibit PDE activity through an allosteric mechanism. Therefore, the cAMP-elevating capacity due to allosteric PDE inhibition in addition to direct Epac activation may contribute to the therapeutic effects of SU drugs.

Diagnostic accuracy of a machine learning algorithm using point-of-care high-sensitivity cardiac troponin I for rapid rule-out of myocardial infarction: a retrospective study.

BACKGROUND: Point-of-care (POC) high-sensitivity cardiac troponin (hs-cTn) assays have been shown to provide similar analytical precision despite substantially shorter turnaround times compared with laboratory-based hs-cTn assays. We applied the previously developed machine learning based personalised Artificial Intelligence in Suspected Myocardial Infarction Study (ARTEMIS) algorithm, which can predict the individual probability of myocardial infarction, with a single POC hs-cTn measurement, and compared its diagnostic performance with standard-of-care pathways for rapid rule-out of myocardial infarction. METHODS: We retrospectively analysed pooled data from consecutive patients of two prospective observational cohorts in geographically distinct regions (the Safe Emergency Department Discharge Rate cohort from the USA and the Suspected Acute Myocardial Infarction in Emergency cohort from Australia) who presented to the emergency department with suspected myocardial infarction. Patients with ST-segment elevation myocardial infarction were excluded. Safety and efficacy of direct rule-out of myocardial infarction by the ARTEMIS algorithm (at a pre-specified probability threshold of <0·5%) were compared with the European Society of Cardiology (ESC)-recommended and the American College of Cardiology (ACC)-recommended 0 h pathways using a single POC high-sensitivity cardiac troponin I (hs-cTnI) measurement (Siemens Atellica VTLi as investigational assay). The primary diagnostic outcome was an adjudicated index diagnosis of type 1 or type 2 myocardial infarction according to the Fourth Universal Definition of Myocardial Infarction. The safety outcome was a composite of incident myocardial infarction and cardiovascular death (follow-up events) at 30 days. Additional analyses were performed for type I myocardial infarction only (secondary diagnostic outcome), and for each cohort separately. Subgroup analyses were performed for age (<65 years vs ≥65 years), sex, symptom onset (≤3 h vs >3 h), estimated glomerular filtration rate (<60 mL/min per 1·73 m2vs ≥60 mL/min per 1·73 m2), and absence or presence of arterial hypertension, diabetes, a history of coronary artery disease, myocardial infarction, or heart failure, smoking, and ischaemic electrocardiogram signs. FINDINGS: Among 2560 patients (1075 [42%] women, median age 58 years [IQR 48·0-69·0]), prevalence of myocardial infarction was 6·5% (166/2560). The ARTEMIS-POC algorithm classified 899 patients (35·1%) as suitable for rapid rule-out with a negative predictive value of 99·96% (95% CI 99·64-99·96) and a sensitivity of 99·68% (97·21-99·70). For type I myocardial infarction only, negative predictive value and sensitivity were both 100%. Proportions of missed index myocardial infarction (0·05% [0·04-0·42]) and follow-up events at 30 days (0·07% [95% CI 0·06-0·59]) were low. While maintaining high safety, the ARTEMIS-POC algorithm identified more than twice as many patients as eligible for direct rule-out compared with guideline-recommended ESC 0 h (15·2%) and ACC 0 h (13·8%) pathways. Superior efficacy persisted across all clinically relevant subgroups. INTERPRETATION: The patient-tailored, medical decision support ARTEMIS-POC algorithm applied with a single POC hs-cTnI measurement allows for very rapid, safe, and more efficient direct rule-out of myocardial infarction than guideline-recommended pathways. It has the potential to expedite the safe discharge of low-risk patients from the emergency department including early presenters with symptom onset less than 3 h at the time of admission and might open new opportunities for the triage of patients with suspected myocardial infarction even in ambulatory, preclinical, or geographically isolated care settings. FUNDING: The German Center for Cardiovascular Research (DZHK).

Sex differences in lipidomic and bile acid plasma profiles in patients with and without coronary artery disease.

BACKGROUND: Lipids, including phospholipids and bile acids, exert various signaling effects and are thought to contribute to the development of coronary artery disease (CAD). Here, we aimed to compare lipidomic and bile acid profiles in the blood of patients with and without CAD stratified by sex. METHODS: From 2015 to 2022, 3,012 patients who underwent coronary angiography were recruited in the INTERCATH cohort. From the overall cohort, subgroups were defined using patient characteristics such as CAD vs. no CAD, 1st vs. 3rd tertile of LDL-c, and female vs. male sex. Hereafter, a matching algorithm based on age, BMI, hypertension status, diabetes mellitus status, smoking status, the Mediterranean diet score, and the intake of statins, triglycerides, HDL-c and hs-CRP in a 1:1 ratio was implemented. Lipidomic analyses of stored blood samples using the Lipidyzer platform (SCIEX) and bile acid analysis using liquid chromatography with tandem mass spectrometry (LC‒MS/MS) were carried out. RESULTS: A total of 177 matched individuals were analyzed; the median ages were 73.5 years (25th and 75th percentile: 64.1, 78.2) and 71.9 years (65.7, 77.2) for females and males with CAD, respectively, and 67.6 years (58.3, 75.3) and 69.2 years (59.8, 76.8) for females and males without CAD, respectively. Further baseline characteristics, including cardiovascular risk factors, were balanced between the groups. Women with CAD had decreased levels of phosphatidylcholine and diacylglycerol, while no differences in bile acid profiles were detected in comparison to those of female patients without CAD. In contrast, in male patients with CAD, decreased concentrations of the secondary bile acid species glycolithocholic and lithocholic acid, as well as altered levels of specific lipids, were detected compared to those in males without CAD. Notably, male patients with low LDL-c and CAD had significantly greater concentrations of various phospholipid species, particularly plasmalogens, compared to those in high LDL-c subgroup. CONCLUSIONS: We present hypothesis-generating data on sex-specific lipidomic patterns and bile acid profiles in CAD patients. The data suggest that altered lipid and bile acid composition might contribute to CAD development and/or progression, helping to understand the different disease trajectories of CAD in women and men. REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT04936438 , Unique identifier: NCT04936438.

Sex-specific ventricular morphology, function, and tissue characteristics in arterial hypertension: a magnetic resonance study of the Hamburg city health cohort.

OBJECTIVE: To determine the influence of arterial hypertension (AHT), sex, and the interaction between both left- and right ventricular (LV, RV) morphology, function, and tissue characteristics. METHODS: The Hamburg City Health Study (HCHS) is a population-based, prospective, monocentric study. 1972 individuals without a history of cardiac diseases/ interventions underwent 3 T cardiac MR imaging (CMR). Generalized linear models were conducted, including AHT, sex (and the interaction if significant), age, body mass index, place of birth, diabetes mellitus, smoking, hyperlipoproteinemia, atrial fibrillation, and medication. RESULTS: Of 1972 subjects, 68% suffered from AHT. 42% with AHT and 49% controls were female. Females overall showed a higher ejection fraction (EF) (LV: regression coefficient +2.4% [95% confidence interval: 1.7; 3.1]), lower volumes and LV mass (-19.8% [-21.3; -18.5]), and prolonged native septal T1 (+22.1 ms [18.3; 25.9])/T2 relaxation times (+1.1 ms [0.9; 1.3]) (all p < 0.001) compared to males. Subjects with AHT showed a higher EF (LV: +1.2% [0.3; 2.0], p = 0.009) and LV mass (+6.6% [4.3; 9.0], p < 0.001) than controls. The interaction between sex and AHT influenced mapping. After excluding segments with LGE, males (-0.7 ms [-1.0; -0.3 | ) and females with AHT (-1.1 ms [-1.6; -0.6]) showed shorter T2 relaxation times than the sex-respective controls (p < 0.001), but the effect was stronger in females. CONCLUSION: In the HCHS, female and male subjects with AHT likewise showed a higher EF and LV mass than controls, independent of sex. However, differences in tissue characteristics between subjects with AHT and controls appeared to be sex-specific. CLINICAL RELEVANCE STATEMENT: The interaction between sex and cardiac risk factors is an underestimated factor that should be considered when comparing tissue characteristics between hypertensive subjects and controls, and when establishing cut-off values for normal and pathological relaxation times. KEY POINTS: There are sex-dependent differences in arterial hypertension, but it is unclear if cardiac MR parameters are sex-specific. Differences in cardiac MR parameters between hypertensive subjects and healthy controls appeared to be sex-specific for tissue characteristics. Sex needs to be considered when comparing tissue characteristics in patients with arterial hypertension to healthy controls.

Prediction of cardiac worsening through to cardiogenic shock in patients with acute heart failure.

AIMS: Acute heart failure (AHF) can result in worsening of heart failure (WHF), cardiogenic shock (CS), or death. Risk factors for these adverse outcomes are not well characterized. This study aimed to identify predictors for WHF or new-onset CS in patients hospitalized for AHF. METHODS AND RESULTS: Prospective cohort study enrolling consecutive patients with AHF admitted to a large tertiary care centre with follow-up until death or discharge. WHF was defined by the RELAX-AHF-2 criteria. CS was defined as SCAI stages B-E. Potential predictors were assessed by fitting logistic regression models adjusted for age and sex. N = 233 patients were enrolled, median age was 78 years, and 80 were women (35.9%). Ischaemic cardiomyopathy was present in 82 patients (40.8%). Overall, 96 (44.2%) developed WHF and 18 (9.7%) CS. In-hospital death (8/223, 3.6%) was related to both events (WHF: OR 6.64, 95% CI 1.21-36.55, P = 0.03; CS: OR 38.27, 95% CI 6.32-231.81, P < 0.001). Chronic kidney disease (OR 2.20, 95% CI 1.25-3.93, P = 0.007), logarithmized serum creatinine (OR 2.90, 95% CI 1.51-5.82, P = 0.002), cystatin c (OR 1.86, 95% CI 1.27-2.77, P = 0.002), tricuspid valve regurgitation (OR 2.08, 95% CI 1.11-3.94, P = 0.023) and logarithmized pro-adrenomedullin (OR 3.01, 95% CI 1.75-5.38, P < 0.001) were significant predictors of WHF. Chronic kidney disease (OR 3.17, 95% CI 1.16-9.58, P = 0.03), cystatin c (OR 1.88, 95% CI 1.00-3.53, P = 0.045), logarithmized pro-adrenomedullin (OR 2.90, 95% CI 1.19-7.19, P = 0.019), and tricuspid valve regurgitation (OR 10.44, 95% CI 2.61-70.00, P = 0.003) were significantly with new-onset CS. CONCLUSIONS: Half of patients admitted with AHF experience WHF or new-onset CS. Chronic kidney disease, tricuspid valve regurgitation, and elevated pro-adrenomedullin concentrations predict these events. They could potentially serve as early warning signs for further deterioration in AHF patients.

Left atrial strain predicts the rhythm outcome in patients with persistent atrial fibrillation undergoing left atrial cryoablation during minimally invasive mitral valve repair.

Objectives: Patients with atrial fibrillation (AF) have lower left atrial (LA) strain, which is a predictor for LA function. Here, we evaluated the prognostic value of LA strain to predict the rhythm outcome in patients with persistent AF undergoing LA cryoablation concomitant to minimally invasive mitral valve repair. Methods: Between 01/2016 and 12/2020, 72 patients with persistent AF underwent LA cryoablation during minimally invasive mitral valve surgery. All patients received a complete LA lesion set and left atrial appendage (LAA) closure with a clip. All patients received preoperative transthoracic echocardiography (TTE) with LA and left ventricular strain measurements. Preoperative LA and LV strain analysis was correlated with postoperative rhythm outcome. Results: The mean age of the patients was 66.9 ± 7.2 years, of whom 42 (58%) were male patients. No major ablation-related complications occurred in any of the patients. Successful LAA closure was confirmed by intraoperative echocardiography in all patients. The 1-year survival rate was 97%. Freedom from AF at 12 months was 72% and 68% off antiarrhythmic drugs. Preoperative LA strain values were statistically significantly higher in patients with freedom from AF at 12 months of follow-up (12.7% ± 6.9% vs. 4.9% ± 4.1%, p = 0.006). Preoperative LV strain value was not associated with postoperative rhythm outcome. In multivariate logistic regression analysis, LA strain (p < 0.001) and AF duration (p = 0.017) were predictors for freedom from AF at 12 months of follow-up. Conclusions: In our study, LA strain analysis predicted the rhythm outcome in patients with persistent AF undergoing concomitant surgical AF ablation. In the future, LA strain might be a useful tool to guide decision-making on ablation strategies in patients with persistent AF.

New race-free creatinine- and cystatin C-based equations for the estimation of glomerular filtration rate and association with cardiovascular mortality in the AtheroGene study.

Renal function is associated with cardiovascular outcomes and mortality. Among equations used to eGFR, CKD-EPI equations show more accurate association with cardiovascular risk and mortality than MDRD. Recently, new CKD-EPI equations were proposed which do not include race and would be considered sufficiently accurate to estimate eGFR in clinical practice. It is unknown if these new race-free equations are comparably well associated with cardiovascular outcomes in high-risk individuals. The analysis was performed in the AtheroGene Study cohort including patients at high cardiovascular risk. eGFR was determined using the established as well as the recently developed formulas which are calculated without the otherwise existing coefficient for black race. The outcome was cardiovascular death. Analyses included Cox-proportional hazard regression and area-under-the-curve calculation. The analysis included 2089 patients followed up for a median of 3.8 years with a maximum of 6.9 years, corresponding to an overall period of 7701 patient-years. Cardiovascular death occurred in 93 (4.45%), corresponding to an annualized rate of 1.2/100 person-years. In all Cox regression analyses, the estimated adjusted GFR was an independent predictor of cardiovascular death. The equations which included cystatin C showed higher C-index compared to those which did not include cystatin C (0.75-0.76 vs. 0.71, respectively). The equations for the estimation of eGFR which include cystatin C are better associated with cardiovascular death compared to the race-free equations which include only creatinine. This finding adds on the related literature which supports the elimination of race in GFR-estimating equations, and promotion of the use of cystatin C.

Procedural and one-year outcomes of robotic-assisted versus manual percutaneous coronary intervention.

BACKGROUND: Robotic-assisted percutaneous coronary intervention (rPCI) has proven to be feasible and safe. Comparative analyses of rPCI versus manual PCI (mPCI) are scarce. AIMS: We aimed to investigate procedural aspects and outcomes of rPCI using the second-generation CorPath GRX Vascular Robotic System compared with mPCI in patients with chronic coronary syndrome and non-ST-segment elevation myocardial infarction acute coronary syndrome. METHODS: From January to April 2021, 70 patients underwent rPCI at the University Heart & Vascular Center Hamburg-Eppendorf and were recruited into the INTERCATH study. By propensity score matching, a control cohort of 210 patients who underwent mPCI from 2015-2021 was identified. Co-primary endpoints were one-year all-cause mortality and major adverse cardiovascular events (MACE) as a composite of cardiovascular death, unplanned target lesion revascularisation, myocardial infarction, and stroke. RESULTS: The median age of the patients (n=280) was 70.7 (25th percentile-75th percentile: 62.0-78.0) years, and 24.6% were female. The Gensini score (28.5 [16.2-48.1] vs 28.0 [15.5-47.0]; p=0.78) was comparable between rPCI versus mPCI. During the PCI procedure, total contrast fluid volume did not differ, whilst longer fluoroscopy times (20.4 min [13.8-27.2] vs 14.4 min [10.4-24.3]; p=0.001) were documented in the rPCI versus mPCI cohort. After 12 months of follow-up, neither all-cause mortality (p=0.22) nor MACE (p=0.25) differed between the groups. CONCLUSIONS: rPCI was associated with longer fluoroscopy times compared with mPCI, though without increased use of contrast medium. One-year follow-up revealed no differences in all-cause mortality or MACE, supporting the safety of a robotic-assisted approach.

Balloon-expandable transcatheter heart valves for treatment of aortic valve stenosis in patients with large aortic annuli: Evaluation of deployment balloon overfilling strategies.

OBJECTIVES: Transcatheter aortic valve implantation (TAVI) using balloon-expandable (BE) transcatheter heart valves (THV) in aortic annuli above 29 mm includes particular procedural steps, mainly involving overfilling of the deployment balloon. Data on overfilling strategies in clinical daily practice is scarce. We herein aimed for a retrospective description of utilized overfilling strategies in those patients. METHODS: Between January 2016 and December 2022, 45 patients (100% male, 76.9 ± 6.1 years) received TAVI in aortic annuli above 29 mm using a BE THV. Overfilling volumina of the deployment balloon were left to operators' discretion. Clinical and multislice computed tomography data were retrospectively collected. Clinical endpoints were adjudicated in accordance with the updated standardized VARC-3 definitions. RESULTS: Profound overfilling (+4/5 mL) was used in patients with a mild calcium burden (˂750 mm³) even in aortic annuli of 29.0-30.0 mm. Nominal/slight overfilling (+1 mL) was used in aortic annuli up to 32.5 mm but an intermediate to severe calcific burden (>750-3200 mm³). Accordingly, a low calcification group (˂750 mm³, n = 17) compared to a significant calcification group (≥750 mm³, n = 28), presented with higher overfilling volumina (2.1 ± 1.4 vs. 0.8 ± 1.0; p ˂ 0.001), although aortic annulus diameter was not different (29.8 ± 0.8 vs. 29.9 ± 0.9 mm; p = 0.7). All-cause 30-day mortality was 0%. Device success was 97.8%. Transvalvular mean pressure gradient at discharge was 9.5 ± 3.6 mmHg. No case of PVL >mild was documented. CONCLUSION: Extent of overfilling of the deployment balloon largely depends on calcification burden in addition to aortic annulus diameter with significant and profound overfilling particularly in patients with a calcification burden of the aortic valve complex ˂750 mm³.

High-Sensitivity Cardiac Troponin I Enhances Preeclampsia Prediction Beyond Maternal Factors and the sFlt-1/PlGF Ratio.

BACKGROUND: Preeclampsia shares numerous risk factors with cardiovascular diseases. Here, we aimed to assess the potential utility of high-sensitivity cardiac troponin I (hs-cTnI) values during pregnancy in predicting preeclampsia occurrence. METHODS: This study measured hs-cTnI levels in 3721 blood samples of 2245 pregnant women from 4 international, prospective cohorts. Three analytical approaches were used: (1) a cross-sectional analysis of all women using a single blood sample, (2) a longitudinal analysis of hs-cTnI trajectories in women with multiple samples, and (3) analyses of prediction models incorporating hs-cTnI, maternal factors, and the sFlt-1 (soluble fms-like tyrosine kinase 1)/PlGF (placental growth factor) ratio. RESULTS: Women with hs-cTnI levels in the upper quarter had higher odds ratios for preeclampsia occurrence compared with women with levels in the lower quarter. Associations were driven by preterm preeclampsia (odds ratio, 5.78 [95% CI, 2.73-12.26]) and remained significant when using hs-cTnI as a continuous variable adjusted for confounders. Between-trimester hs-cTnI trajectories were independent of subsequent preeclampsia occurrence. A prediction model incorporating a practical hs-cTnI level of detection cutoff (≥1.9 pg/mL) alongside maternal factors provided comparable performance with the sFlt-1/PlGF ratio. A comprehensive model including sFlt-1/PlGF, maternal factors, and hs-cTnI provided added value (cross-validated area under the receiver operator characteristic, 0.78 [95% CI, 0.73-0.82]) above the sFlt-1/PlGF ratio alone (cross-validated area under the receiver operator characteristic, 0.70 [95% CI, 0.65-0.76]; P=0.027). As assessed by likelihood ratio tests, the addition of hs-cTnI to each prediction model significantly improved the respective prediction model not incorporating hs-cTnI, particularly for preterm preeclampsia. Net reclassification improvement analyses indicated that incorporating hs-cTnI improved risk prediction predominantly by correctly reclassifying women with subsequent preeclampsia occurrence. CONCLUSIONS: These exploratory findings uncover a potential role for hs-cTnI as a complementary biomarker in the prediction of preeclampsia. After validation in prospective studies, hs-cTnI, alongside maternal factors, may either be considered as a substitute for angiogenic biomarkers in health care systems where they are sparce or unavailable, or as an enhancement to established prediction models using angiogenic markers.

Inflammatory burden, lifestyle and atherosclerotic cardiovascular disease: insights from a population based cohort study.

The inflammatory burden as measured by high-sensitivity C-reactive Protein (hsCRP) is recognized as a cardiovascular risk factor, which can however be affected by lifestyle-related risk factors (LRF). Up-to-date the interplay between hsCRP, LRF and presence and extent of atherosclerotic disease is still largely unknown, which we therefore sought to investigate in a contemporary population-based cohort. We included participants from the cross-sectional population-based Hamburg City Health Study. Affected vascular beds were defined as coronary, peripheral, and cerebrovascular arteries. LRF considered were lack of physical activity, overweight, active smoking and poor adherence to a Mediterranean diet. We computed multivariable analyses with hsCRP as the dependent variable and LRF as covariates according to the number of vascular beds affected. In the 6765 individuals available for analysis, we found a stepwise increase of hsCRP concentration both according to the number of LRF present as well as the number of vascular beds affected. Adjusted regression analyses showed an independent association between increasing numbers of LRF with hsCRP levels across the extent of atherosclerosis. We demonstrate increasing hsCRP concentrations according to both the number of LRF as well as the extent of atherosclerosis, emphasizing the necessity of lifestyle-related risk factor optimization.

Valve-in-valve procedures for degenerated surgical and transcatheter aortic valve bioprostheses using a latest-generation self-expanding intra-annular transcatheter heart valve.

Background: Valve-in-valve (ViV) transfemoral transcatheter aortic valve implantation (TAVI) for failing aortic surgical bioprostheses or transcatheter heart valves (THV) has demonstrated a reasonable clinical and hemodynamic efficacy. Traditionally, self-expanding (SE) supra-annular THV are considered to result in superior hemodynamics compared with balloon-expandable intra-annular THV after ViV. However, so far no data are found on latest-generation intra-annular SE THV for aortic ViV procedures which might be superior with regard to coronary access or subsequent valve reintervention. Aim: We herein aim to evaluate a latest-generation SE intra-annular THV for aortic ViV procedures. Materials and methods: Between May 2022 and November 2022, five consecutive patients (4/5 female with mean age of 76.2 years and mean Society of Thoracic Surgeons predicted risk of mortality score of 2.9%) received ViV TAVI using the Navitor system (Abbott, Chicago, IL, USA) for treatment of failing surgical bioprostheses or THV. Data were retrospectively analyzed according to updated Valve Academic Research Consortium 3 (VARC-3) definitions. Results: At 30 days, absence of mortality and VARC-3 adjudicated clinical endpoints were documented. Echocardiography at 30 days revealed complete absence of paravalvular leakage and single-digit mean transvalvular gradients (mean of 6.0 mmHg) in all patients. Conclusion: The investigated intra-annular SE THV results in excellent 30-day outcomes for aortic ViV procedures for failing surgical bioprostheses or THV. Despite the intra-annular design, hemodynamic results were excellent, even in small bioprostheses. Ease of use of this valve platform is reflected by only two cycles of resheathing in five ViV procedures with hemodynamic stability during all steps of valve deployment.

Sex differences in clinical characteristics and outcomes in patients undergoing heart transplantation.

AIMS: Whether sex affects selection for and outcomes after heart transplantation (HTx) remains unclear. We aimed to show sex differences in pre-transplant characteristics and outcomes after HTx. METHODS AND RESULTS: From 1995 to 2019, 49 200 HTx recipients were prospectively enrolled in the Organ Procurement and Transplantation Network. Logistic regression models were used to evaluate clinical characteristics by sex. Multivariable Cox regression models were fitted to assess sex differences in all-cause mortality, cardiovascular mortality, graft failure, cardiac allograft vasculopathy (CAV), and malignancy. In 49 200 patients (median age 55 years, interquartile range 46-62; 24.6% women), 49 732 events occurred during a median follow-up of 8.1 years. Men were older than women, had more often ischaemic cardiomyopathy (odds ratio [OR] 3.26, 95% confidence interval [CI] 3.11-3.42; P < 0.001), and a higher burden of cardiovascular risk factors, whereas women had less malignancies (OR 0.47, CI 0.44-0.51; P < 0.001). Men were more often treated in intensive care unit (OR 1.24, CI 1.12-1.37; P < 0.001) with a higher need for ventilatory (OR 1.24, CI 1.17-1.32; P < 0.001) or VAD (OR 1.53, CI 1.45-1.63; P < 0.001) support. After multivariable adjustment, men had a higher risk for CAV (hazard ratio [HR] 1.21, CI 1.13-1.29; P < 0.001) and malignancy (HR 1.80, CI 1.62-2.00; P < 0.001). There were no differences in all-cause mortality, cardiovascular mortality, and graft failure between sexes. CONCLUSIONS: In this US transplant registry, men and women differed in pre-transplant characteristics. Male sex was independently associated with incident CAV and malignancy even after multivariable adjustment. Our results underline the need for better personalized post-HTx management and care.

Differential effects of anaemia and iron deficiency on long-term outcomes following transcatheter edge-to-edge repair in degenerative vs. secondary mitral regurgitation: results from a large single-center study.

BACKGROUND: Anaemia and iron deficiency (ID) are independently associated with adverse outcomes in patients with cardiovascular diseases, especially in those with heart failure. Here, we aimed to clarify the long-term effect of anaemia and ID on outcomes in patients undergoing transcatheter mitral edge-to-edge repair (TEER) for relevant mitral regurgitation (MR) as well as to relate these to the underlying MR aetiology. METHODS: 833 patients (median age 77.1 years, 40.7% women, 63.3% secondary MR) treated by TEER between 09/2008 and 07/2019 were included and stratified according to baseline anaemia (hemoglobin < 12 g/dL in women and < 13 g/dL in men) or ID. RESULTS: Anaemia and ID were frequent with 61.6% and 68.1%, respectively. Anaemic patients had a lower functional status at baseline and were less likely to improve after TEER. In addition, anaemia was associated with all-cause mortality (hazard ratio [HR] = 1.68, 95% confidence interval [CI] 1.36-2.07, p < 0.001) and the composite endpoint of death or heart failure (HF) rehospitalization (HR = 1.30, 95% CI 1.10-1.54, p = 0.002). In contrast, ID was not associated with either all-cause mortality or the composite endpoint of death or HF rehospitalization. CONCLUSION: Patients undergoing TEER have high rates of both anaemia and ID. However, anaemia is associated with worse functional baseline status and post-interventional improvements compared to ID. Furthermore, anaemia is linked to higher rates of mortality and HF rehospitalization, particularly in those with secondary MR.

Coffee consumption and associations with blood pressure, LDL-cholesterol and echocardiographic measures in the general population.

Coffee, next to water the most widespread beverage, is attributed both harmful and protective characteristics concerning cardiovascular health. This study aimed to evaluate associations of coffee consumption with cardiac biomarkers, echocardiographic, electrocardiographic parameters and major cardiovascular diseases. We performed a cross-sectional analysis of 9009 participants of the population-based Hamburg City Health Study (HCHS), enrolled between 2016 and 2018 median age 63 [IQR: 55; 69] years. Coffee consumption was classified into three groups: < 3 cups/day (low), 3-4 cups/day (moderate), > 4 cups/day (high). In linear regression analyses adjusted for age, sex, body mass index, diabetes, hypertension, smoking, and additives, high coffee consumption correlated with higher LDL-cholesterol (ß = 5.92; 95% CI 2.95, 8.89; p < 0.001). Moderate and high coffee consumption correlated with lower systolic (ß = - 1.91; 95% CI - 3.04, - 0.78; p = 0.001; high: ß = - 3.06; 95% CI - 4.69, - 1.44; p < 0.001) and diastolic blood pressure (ß = - 1.05; 95% CI - 1.67, - 0.43; p = 0.001; high: ß = - 1.85; 95% CI - 2.74, - 0.96; p < 0.001). Different levels of coffee consumption did neither correlate with any investigated electrocardiographic or echocardiographic parameter nor with prevalent major cardiovascular diseases, including prior myocardial infarction and heart failure. In this cross-sectional analysis, high coffee consumption correlated with raised LDL-cholesterol levels and lower systolic and diastolic blood pressure. However, major cardiovascular diseases including heart failure and its diagnostic precursors were not associated with coffee consumption, connoting a neutral role of coffee in the context of cardiovascular health.

Cross-Sectional Association of Dietary Patterns and Supplement Intake with Presence and Gray-Scale Median of Carotid Plaques-A Comparison between Women and Men in the Population-Based Hamburg City Health Study.

This population-based cross-sectional cohort study investigated the association of the Mediterranean and DASH (Dietary Approach to Stop Hypertension) diet as well as supplement intake with gray-scale median (GSM) and the presence of carotid plaques comparing women and men. Low GSM is associated with plaque vulnerability. Ten thousand participants of the Hamburg City Health Study aged 45-74 underwent carotid ultrasound examination. We analyzed plaque presence in all participants plus GSM in those having plaques (n = 2163). Dietary patterns and supplement intake were assessed via a food frequency questionnaire. Multiple linear and logistic regression models were used to assess associations between dietary patterns, supplement intake and GSM plus plaque presence. Linear regressions showed an association between higher GSM and folate intake only in men (+9.12, 95% CI (1.37, 16.86), p = 0.021). High compared to intermediate adherence to the DASH diet was associated with higher odds for carotid plaques (OR = 1.18, 95% CI (1.02, 1.36), p = 0.027, adjusted). Odds for plaque presence were higher for men, older age, low education, hypertension, hyperlipidemia and smoking. In this study, the intake of most supplements, as well as DASH or Mediterranean diet, was not significantly associated with GSM for women or men. Future research is needed to clarify the influence, especially of the folate intake and DASH diet, on the presence and vulnerability of plaques.

Editor's Choice - Prevalence of Peripheral Arterial Disease, Abdominal Aortic Aneurysm, and Risk Factors in the Hamburg City Health Study: A Cross Sectional Analysis.

OBJECTIVE: There is a paucity of current figures on the prevalence of carotid and lower extremity peripheral arterial disease (PAD) and abdominal aortic aneurysm (AAA) as well as the associated cardiovascular risk factors to support considerations on screening programmes. METHODS: In the population based Hamburg City Health Study, participants between 45 and 74 years were randomly recruited. In the current cross sectional analysis of the first 10 000 participants enrolled between February 2016 and November 2018, the prevalence of carotid artery disease (intima-media thickness ≥ 1 mm), lower extremity PAD (ankle brachial index ≤ 0.9), and AAA (aortic diameter ≥ 30 mm) was determined. Multivariable logistic regression models were applied to determine the association between vascular diseases and risk factors. To account for missing values, multiple imputation was performed. RESULTS: A total of 10 000 participants were analysed (51.1% females, median age 63 years, median body mass index 26.1 kg/m2). In medians, the intima media thickness was 0.74 mm (interquartile range [IQR] 0.65 - 0.84), the ankle brachial index 1.04 (IQR 0.95 - 1.13), and the aortic diameter 17.8 mm (IQR 16.1 - 19.6). Concerning risk factors, 64% self reported any smoking, 39% hypertension, 5% coronary artery disease, 3% congestive heart failure, 5% atrial fibrillation, and 3% history of stroke or myocardial infarction, respectively. In males, the prevalence of carotid artery disease, lower extremity PAD, and AAA were 35.3%, 22.7%, and 1.3%, respectively, and in females, 23.4%, 24.8%, and 0.2%, respectively. Higher age and current smoking were likewise associated with higher prevalence while the impact of variables varied widely. CONCLUSION: In this large population based cohort study of 10 000 subjects from Hamburg, Germany, a strikingly high prevalence of PAD was revealed. Almost 45% suffered from any index disease, while AAA was only diagnosed in 1.3% of males and 0.2% of females. The high prevalence of atherosclerotic disease and associated cardiovascular risk factors underline that it is essential to increase awareness and fuel efforts for secondary prevention.

Exploring the incremental utility of circulating biomarkers for robust risk prediction of incident atrial fibrillation in European cohorts using regressions and modern machine learning methods.

AIMS: To identify robust circulating predictors for incident atrial fibrillation (AF) using classical regressions and machine learning (ML) techniques within a broad spectrum of candidate variables. METHODS AND RESULTS: In pooled European community cohorts (n = 42 280 individuals), 14 routinely available biomarkers mirroring distinct pathophysiological pathways including lipids, inflammation, renal, and myocardium-specific markers (N-terminal pro B-type natriuretic peptide [NT-proBNP], high-sensitivity troponin I [hsTnI]) were examined in relation to incident AF using Cox regressions and distinct ML methods. Of 42 280 individuals (21 843 women [51.7%]; median [interquartile range, IQR] age, 52.2 [42.7, 62.0] years), 1496 (3.5%) developed AF during a median follow-up time of 5.7 years. In multivariable-adjusted Cox-regression analysis, NT-proBNP was the strongest circulating predictor of incident AF [hazard ratio (HR) per standard deviation (SD), 1.93 (95% CI, 1.82-2.04); P < 0.001]. Further, hsTnI [HR per SD, 1.18 (95% CI, 1.13-1.22); P < 0.001], cystatin C [HR per SD, 1.16 (95% CI, 1.10-1.23); P < 0.001], and C-reactive protein [HR per SD, 1.08 (95% CI, 1.02-1.14); P = 0.012] correlated positively with incident AF. Applying various ML techniques, a high inter-method consistency of selected candidate variables was observed. NT-proBNP was identified as the blood-based marker with the highest predictive value for incident AF. Relevant clinical predictors were age, the use of antihypertensive medication, and body mass index. CONCLUSION: Using different variable selection procedures including ML methods, NT-proBNP consistently remained the strongest blood-based predictor of incident AF and ranked before classical cardiovascular risk factors. The clinical benefit of these findings for identifying at-risk individuals for targeted AF screening needs to be elucidated and tested prospectively.

Mechanical thrombectomy in ischemic stroke after cardiovascular procedures: a propensity-matched cohort analysis.

BACKGROUND: Stroke after a cardiovascular procedure (CVP) is a devastating complication adversely affecting outcome. Mechanical thrombectomy (MT) has not been investigated systematically in this population. OBJECTIVE: To carry out a retrospective study in patients undergoing MT for early stroke after CVP, aiming to further characterize this cohort of patients, and to evaluate the efficacy, safety, procedural characteristics, and outcome of MT. METHODS: A single-center stroke registry of patients who received MT was analyzed. Baseline and procedural parameters, mortality, functional outcome, recanalization rates, and complications were evaluated. Propensity score matching was carried out, identifying a control cohort with non-periprocedural large vessel occlusion (LVO). RESULTS: Overall 913 patients were included (mean age 73.0 (±13.0) years, 52.5% female, median National Institutes of Health Stroke Scale score 15 (10-19)). Eleven patients with a LVO after a recent (<30 days postoperatively) CVP were identified (n=3 transcatheter aortic valve and n=1 surgical aortic valve replacements (SAVR), n=3 coronary bypass grafting (CABG) surgeries, n=2 SAVR+CABG, and n=2 aortic surgeries). After matching, 8 patients in the CVP group were compared with 16 patients in the matched cohort. Comparable rates of reperfusion were achieved. Time from symptom onset to groin puncture (171.5 min (136.3, 178.3) vs 284.0 min (215.0, 490.5); p=0.039), as well as recanalization (195.0 min (146.0, 201.0) vs 419.0 min (274.0, 613.0); p=0.028) was faster in the CVP group. However, this was not reflected by an improved outcome (modified Rankin Scale score after 90 days: 5.5 (3.3, 6.0) vs 5.0 (4.0, 6.0), mortality after 90 days 50.0% vs 37.5%). Complications did not differ between the groups. CONCLUSIONS: Use of MT for LVO stroke in patients after a recent CVP is a safe and efficient treatment in comparison with patients with a non-periprocedural LVO undergoing MT.