As promising compounds to lower Lipoprotein(a) (Lp(a)) are emerging, the need for a precise characterization and comparability of the Lp(a)-associated cardiovascular risk is increasing. Therefore, we ...aimed to evaluate the distribution of Lp(a) concentrations across the European population, to characterize the association with cardiovascular outcomes and to provide high comparability of the Lp(a)-associated cardiovascular risk by use of centrally determined Lp(a) concentrations.
Based on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE)-project, we analysed data of 56 804 participants from 7 prospective population-based cohorts across Europe with a maximum follow-up of 24 years. All Lp(a) measurements were performed in the central BiomarCaRE laboratory (Biokit Quantia Lp(a)-Test; Abbott Diagnostics). The three endpoints considered were incident major coronary events (MCE), incident cardiovascular disease (CVD) events, and total mortality. We found lower Lp(a) levels in Northern European cohorts (median 4.9 mg/dL) compared to central (median 7.9 mg/dL) and Southern European cohorts (10.9 mg/dL) (Jonckheere-Terpstra test P < 0.001). Kaplan-Meier curves showed the highest event rate of MCE and CVD events for Lp(a) levels ≥90th percentile (log-rank test: P < 0.001 for MCE and CVD). Cox regression models adjusted for age, sex, and cardiovascular risk factors revealed a significant association of Lp(a) levels with MCE and CVD with a hazard ratio (HR) of 1.30 for MCE 95% confidence interval (CI) 1.15‒1.46 and of 1.25 for CVD (95% CI 1.12‒1.39) for Lp(a) levels in the 67‒89th percentile and a HR of 1.49 for MCE (95% CI 1.29‒1.73) and of 1.44 for CVD (95% CI 1.25‒1.65) for Lp(a) levels ≥ 90th percentile vs. Lp(a) levels in the lowest third (P < 0.001 for all). There was no significant association between Lp(a) levels and total mortality. Subgroup analysis for a continuous version of cube root transformed Lp(a) identified the highest Lp(a)-associated risk in individuals with diabetes HR for MCE 1.31 (95% CI 1.15‒1.50) and for CVD 1.22 (95% CI 1.08‒1.38) compared to those without diabetes HR for MCE 1.15 (95% CI 1.08‒1.21; HR for CVD 1.13 (1.07-1.19) while no difference of the Lp(a)- associated risk were seen for other cardiovascular high risk states. The addition of Lp(a) levels to a prognostic model for MCE and CVD revealed only a marginal but significant C-index discrimination measure increase (0.001 for MCE and CVD; P < 0.05) and net reclassification improvement (0.010 for MCE and 0.011 for CVD).
In this large dataset on harmonized Lp(a) determination, we observed regional differences within the European population. Elevated Lp(a) was robustly associated with an increased risk for MCE and CVD in particular among individuals with diabetes. These results may lead to better identification of target populations who might benefit from future Lp(a)-lowering therapies.
Atherosclerotic cardiovascular disease (ACVD) is a lipid-driven inflammatory disease and one of the leading causes of death worldwide. Lipid deposits in the arterial wall lead to the formation of ...plaques that involve lipid oxidation, cellular necrosis, and complement activation, resulting in inflammation and thrombosis. The present study found that homozygous deletion of the CFHR1 gene, which encodes the plasma complement protein factor H-related protein 1 (FHR-1), was protective in two cohorts of patients with ACVD, suggesting that FHR-1 accelerates inflammation and exacerbates the disease. To test this hypothesis, FHR-1 was isolated from human plasma and was found to circulate on extracellular vesicles and to be deposited in atherosclerotic plaques. Surface-bound FHR-1 induced the expression of pro-inflammatory cytokines and tissue factor in both monocytes and neutrophils. Notably, plasma concentrations of FHR-1, but not of factor H, were significantly (p < 0.001) elevated in patients with ACVD, and correlated with the expression of the inflammation markers C-reactive protein, apolipoprotein serum amyloid protein A, and neopterin. FHR-1 expression also significantly correlated with plasma concentrations of low-density lipoprotein (LDL) (p < 0.0001) but not high-density lipoprotein (HDL). Taken together, these findings suggest that FHR-1 is associated with ACVD.
Robotic-assisted percutaneous coronary interventions (rPCI) have proven feasible and safe while reducing radiation exposure for the operator. Recently, rPCI systems have been refined to facilitate ...the treatment of complex lesions. The aim of the current study was to evaluate challenges and opportunities of establishing an rPCI program at a tertiary referral center. rPCI was performed using the CorPath GRX Vascular Robotic System (Corindus Inc., a Siemens Healthineers Company, Waltham, USA). Baseline, procedural, and in-hospital follow-up data were prospectively assessed. rPCI success was defined as completion of the PCI without or with partial manual assistance. The safety endpoint was the composite of missing angiographic success or procedure-related adverse events during hospital stay. Overall, 86 coronary lesions were treated in 71 patients (28.2% female) from January to April 2021. Median age was 71.0 years (IQR 60.3; 79.8). Indications for rPCI were stable angina pectoris (71.8%), unstable angina (12.7%) and non-ST elevation myocardial infarction (15.5%). Most lesions were complex (type B2/C: 88.4%) and included 7 cases of rPCI for chronic total occlusions. Angiographic and rPCI success were achieved in 100.0% and 94.2%, respectively. Partial manual assistance was used in 25.6%. Conversion to manual PCI was required in 5.8%. The safety endpoint occurred in 7.0% of patients. rPCI when applied as clinical routine for complex coronary lesions is effective with good immediate angiographic and clinical results. Future investigations should focus on the identification of patients that particularly benefit from robotic-assisted vs. manual PCI despite higher resource utilization.
Chronic kidney disease has emerged as a strong cardiovascular risk factor, and in many current guidelines, it is already considered as a coronary heart disease (CHD) equivalent. Routinely, creatinine ...has been used as the main marker of renal function, but recently, cystatin C emerged as a more promising marker. The aim of this study was to assess the comparative cardiovascular and mortality risk of chronic kidney disease (CKD) using cystatin C-based and creatinine-based equations of the estimated glomerular filtration rate (eGFR) in participants of population-based and disease cohorts.
The present study has been conducted within the BiomarCaRE project, with harmonized data from 20 population-based cohorts (n = 76,954) from 6 European countries and 3 cardiovascular disease (CVD) cohorts (n = 4982) from Germany. Cox proportional hazards models were used to assess hazard ratios (HRs) for the various CKD definitions with adverse outcomes and mortality after adjustment for the Systematic COronary Risk Evaluation (SCORE) variables and study center. Main outcome measures were cardiovascular diseases, cardiovascular death, and all-cause mortality.
The overall prevalence of CKD stage 3-5 by creatinine- and cystatin C-based eGFR, respectively, was 3.3% and 7.4% in the population-based cohorts and 13.9% and 14.4% in the disease cohorts. CKD was an important independent risk factor for subsequent CVD events and mortality. For example, in the population-based cohorts, the HR for CVD mortality was 1.72 (95% CI 1.53 to 1.92) with creatinine-based CKD and it was 2.14 (95% CI 1.90 to 2.40) based on cystatin-based CKD compared to participants without CKD. In general, the HRs were higher for cystatin C-based CKD compared to creatinine-based CKD, for all three outcomes and risk increased clearly below the conventional threshold for CKD, also in older adults. Net reclassification indices were larger for a cystatin-C based CKD definition. Differences in HRs (between the two CKD measures) in the disease cohorts were less pronounced than in the population-based cohorts.
CKD is an important risk factor for subsequent CVD events and total mortality. However, point estimates of creatinine- and cystatin C-based CKD differed considerably between low- and high-risk populations. Especially in low-risk settings, the use of cystatin C-based CKD may result in more accurate risk estimates and have better prognostic value.
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.
Abstract 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.
Background Coronary heart disease is a leading cause of mortality worldwide. Iron deficiency, a frequent comorbidity of coronary heart disease, causes an increased expression of transferrin receptor ...and soluble transferrin receptor levels (sTfR) levels, while iron repletion returns sTfR levels to the normal physiological range. Recently, sTfR levels were proposed as a potential new marker of iron metabolism in cardiovascular diseases. Therefore, we aimed to evaluate the prognostic value of circulating sTfR levels in a large cohort of patients with coronary heart disease. Methods and Results The disease cohort comprised 3423 subjects who had angiographically documented coronary heart disease and who participated in the AtheroGene study. Serum levels of sTfR were determined at baseline using an automated immunoassay (Roche Cobas Integra 400). Two main outcomes were considered: a combined end point of myocardial infarction and cardiovascular death and cardiovascular death alone. During a median follow-up of 4.0 years, 10.3% of the patients experienced an end point. In Cox regression analyses for sTfR levels, the hazard ratio (HR) for future cardiovascular death and/or myocardial infarction was 1.27 (95% CI, 1.11-1.44,
<0.001) after adjustment for sex and age. This association remained significant (HR, 1.23; 95% CI, 1.03-1.46,
=0.02) after additional adjustment for body mass index, smoking status, hypertension, diabetes mellitus, dyslipidemia, C-reactive protein, and surrogates of cardiac function, size of myocardial necrosis (hs-Tnl), and hemoglobin levels. Conclusions In this large cohort study, sTfR levels were strongly associated with future myocardial infarction and cardiovascular death. This implicates a role for sTfR in secondary cardiovascular risk prediction.
Background The association between high-sensitivity troponin T (hsTnT) and high-sensitivity troponin I (hsTnI) and outcome when adjusted for confounders including the angiographical severity of ...coronary artery disease (CAD) remains largely unknown. We therefore aimed to explore whether hsTnT and hsTnI blood levels increase with CAD severity and add independent predictive information for future major adverse cardiovascular events and all-cause mortality in stable patients. Methods and Results Patients from the INTERCATH cohort with available coronary angiography and hsTnT and hsTnI concentrations were included. Troponin concentrations were quantified via hsTnT (Roche Elecsys) and hsTnI (Abbott ARCHITECT STAT). To investigate the association of hsTnT and hsTnI with outcome, a multivariable analysis adjusting for classical cardiovascular risk factors, low-density lipoprotein cholesterol, estimated glomerular filtration rate, hs-CRP (high-sensitivity C-reactive protein), NT-proBNP (N-terminal pro-brain natriuretic peptide), and Gensini score was carried out. Of 1829 patients, 27.9% were women, and the mean age was 68.6±10.9 years. Troponin blood concentrations were higher in patients with diagnosed CAD compared with those without. Using a linear regression model current smoking, arterial hypertension, estimated glomerular filtration rate, hs-CRP, NT-proBNP, and CAD severity as graded by the Gensini and SYNTAX scores were associated with high-sensitivity troponin levels. Patients were followed for 4.4 years (25th and 75th percentiles: 4.3, 4.4). After multivariable adjustment, all-cause mortality was predicted by hsTnT (hazard ratio HR, 1.7 95% CI, 1.5-2.2,
<0.001) as well as hsTnI (HR, 1.5 95% CI, 1.2-1.8,
<0.001). However, only hsTnI (HR, 1.2 95% CI, 1.0-1.4,
=0.032) remained as an independent predictor of major adverse cardiovascular events after adjusting for most possible confounders, including CAD severity (hsTnT: HR, 1.0 95% CI, 0.9-1.2,
=0.95). Conclusions After adjusting for classical cardiovascular risk factors, low-density lipoprotein cholesterol, estimated glomerular filtration rate, hs-CRP, NT-proBNP, and CAD severity, hsTnT and hsTnI were independently associated with all-cause mortality, but only hsTnI was associated with major adverse cardiovascular events in stable patients undergoing coronary angiography. Registration URL: https://clinicaltrials.gov/; Unique identifier: NCT04936438.
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