Inflammatory Markers and Genes: Epidemiologic Studies on their Roles in Cardiovascular Disease

Established cardiovascular risk factors such as hypertension, hyperlipidemia, diabetes mellitus and smoking do not fully explain the occurrence of cardiovascular disease; although the majority of patients have at least one of these risk factors, a substantial proportion of cases occurs in individuals that have none.1 As such, further insight is required into the pathophysiology of cardiovascular disease and in factors that may identify individuals at high risk. One of the most relevant insights in atherosclerosis of the past years is the recognition of the role of inflammation.2 Research on inflammatory markers, both experimental and epidemiological, has taken flight, and several of these markers have been implicated in cardiovascular disease.3 This development was accompanied by an expansion of research on genetic variation that may influence inflammatory processes. The field of genetics has rapidly evolved over the last years because of improved technology and methodology in combination with the emergence of large, publicly available genetic databases.4 The purpose of this thesis was to expand the knowledge on inflammatory markers and inflammatory genes that may play a part in the pathophysiology of cardiovascular disease. We focused on factors that have drawn increased attention in the recent years, such as C-reactive protein (CRP) and lipoprotein-associated phospholipase A2 (Lp-PLA2), and examined their roles in both atherothrombotic disease and in heart failure. Most studies were conducted within the Rotterdam Study, a population- based cohort study among 7983 men and women aged 55 years and over living in a well-defined suburb of Rotterdam, the Netherlands.5 During a visit of the participants to the research center, blood was drawn in order to assess inflammatory markers and genetic variation. Several measures of atherosclerosis were assessed at the research center, and furthermore, participants were followed-up for the occurrence of coronary events and heart failure. Specifically, the main research questions we examined were as follows. With regard to inflammation, atherosclerosis and coronary events: - Is CRP serum level associated with atherosclerosis and coronary events? - Is variation in the CRP gene and variation in the complement factor H gene associated with coronary events, and do these genes interact to predict disease? - Is Lp-PLA2 activity associated with atherosclerosis? With regard to inflammation and heart failure: - What is the distribution of echocardiographic parameters in an asymptomatic population, and do these parameters predict mortality? - Are the inflammatory markers CRP and Lp-PLA2 associated with the occurrence of heart failure

Joint models with multiple longitudinal outcomes and a time-to-event outcome: a corrected two-stage approach

Joint models for longitudinal and survival data have gained a lot of attention in recent years, with the development of myriad extensions to the basic model, including those which allow for multivariate longitudinal data, competing risks and recurrent events. Several software packages are now also available for their implementation. Although mathematically straightforward, the inclusion of multiple longitudinal outcomes in the joint model remains computationally difficult due to the large number of random effects required, which hampers the practical application of this extension. We present a novel approach that enables the fitting of such models with more realistic computational times. The idea behind the approach is to split the estimation of the joint model in two steps: estimating a multivariate mixed model for the longitudinal outcomes and then using the output from this model to fit the survival submodel. So-called two-stage approaches have previously been proposed and shown to be biased. Our approach differs from the standard version, in that we additionally propose the application of a correction factor, adjusting the estimates obtained such that they more closely resemble those we would expect to find with the multivariate joint model. This correction is based on importance sampling ideas. Simulation studies show that this corrected two-stage approach works satisfactorily, eliminating the bias while maintaining substantial improvement in computational time, even in more difficult settings

Spatial QRS-T angle predicts cardiac death in a general population

AIMS: The aim of this study was to assess the prognostic importance of the spatial QRS-T angle for fatal and non-fatal cardiac events. METHODS AND RESULTS: Electrocardiograms (ECGs) were recorded in 6134 men and women aged 55 years and over from the prospective population-based Rotterdam Study. Spatial QRS-T angles were categorized as normal, borderline or abnormal. Using Cox's proportional hazards model, abnormal angles showed increased hazard ratios of cardiac death (age-and sex-adjusted hazard ratio 5.2 (95% CI 4.0-6.8)), non-fatal cardiac events (2.2 (1.5-3.1)), sudden death (5.6 (3.7-8.5)) and total mortality (2.3 (2.0-2.7)). None of the classical cardiovascular and ECG predictors provided larger hazard ratios. After adjustment for these predictors, the association of abnormal spatial QRS-T angles with all fata

Anti-oxidized LDL antibodies and coronary artery disease: a systematic review

Antibodies to oxidized LDL (oxLDL) may be associated with improved outcomes in cardiovascular disease. However, analysis is restricted by heterogenous study design and endpoints. Our objective was to conduct a comprehensive systematic review assessing anti-oxLDL antibodies in relation to coronary artery disease (CAD). Through a systematic literature search, we identified all studies assessing the relationship of either, IgG or IgM ox-LDL/ copper-oxLDL/ malondialdehyde-LDL, with coronary atherosclerosis or cardiovascular events in populations with, and without, established CAD. Systematic review best practices were adhered to and study quality was assessed. An initial electronic database search identified 2059 records, which was subsequently followed by abstract and full-text review. Finally, we included 18 studies with over 1811 patients with CAD. The studies varied according to populations studied, conventional cardiovascular risk factors and interventional modalities used to assess CAD. IgM anti-oxLDL antibodies were found to indicate protection from more severe CAD and possibly cardiovascular events, whilst the relationship with IgG is more complex and difficult to elucidate, with studies reporting divergent results. In this systematic review, there is evidence that suggests a relationship between anti-oxLDL antibodies and CAD, especially for the IgM subclass. However, further studies, with well-characterized prospective cohorts, will be important to clarify these associations

Optimized electrocardiographic criteria for the detection of left ventricular hypertrophy in obesity patients

Background: Despite a generally high specificity, electrocardiographic (ECG) criteria for the detection of left ventricular hypertrophy (LVH) lack sensitivity, particularly in obesity patients. Objectives: The aim of the study was to evaluate the accuracy of the most commonly used ECG criteria (Cornell voltage and Sokolow-Lyon index), the recently introduced Peguero-Lo Presti criteria and the correction of these criteria by body mass index (BMI) to detect LVH in obesity patients and to propose adjusted ECG criteria with optimal accuracy. Methods: The accuracy of the ECG criteria for the detection of LVH was retrospectively tested in a cohort of obesity patients referred for a transthoracic echocardiogram based on clinical grounds (test cohort, n = 167). Adjusted ECG criteria with optimal sensitivity for the detection of LVH were developed. Subsequently, the value of these criteria was prospectively tested in an obese population without known cardiovascular disease (validation cohort, n = 100). Results: Established ECG criteria had a poor sensitivity in obesity patients in both the test cohort and the validation cohort. The adjusted criteria showed improved sensitivity, with optimal values for males using the Cornell voltage corrected for BMI, (RaVL+SV3)*BMI ≥700 mm*kg/m2; sensitivity 47% test cohort, 40% validation cohort; for females, the Sokolow-Lyon index corrected for BMI, (SV1 + RV5/RV6)*BMI ≥885 mm*kg/m2; sensitivity 26% test cohort, 23% validation cohort. Conclusions: Established ECG criteria for the detection of LVH lack sufficient sensitivity in obesity patients. We propose new criteria for the detection of LVH in obesit

Immediate versus staged revascularisation of non-culprit arteries in patients with acute coronary syndrome: a systematic review and meta-analysis

Although there is robust evidence that revascularisation of non-culprit vessels should be pursued in patients presenting with an acute coronary syndrome (ACS) and multivessel coronary artery disease (MVD), the optimal timing of complete revascularisation remains disputed. In this systematic review and meta-analysis our results suggest that outcomes are comparable for immediate and staged complete revascularisation in patients with ACS and MVD. However, evidence from randomised controlled trials remains scarce and cautious interpretation of these results is recommended. More non-biased evidence is necessary to aid future decision making on the optimal timing of complete revascularisation

República: Año III Número 387 - (14/11/33)

PURPOSE OF REVIEW: The purpose of this study was to investigate the association of 26 inflammatory biomarkers (acute phase proteins, cytokines, chemokines) and renal markers with coronary lipid core burden index (LCBI) assessed by near-infrared spectroscopy (NIRS) imaging, as well as the association of these biomarkers with long-term cardiovascular outcome. RECENT FINDINGS: NIRS-derived LCBI has recently been shown to be an independent predictor of major adverse cardiac events (MACE). However, studies on the association between circulating biomarkers and NIRS-derived characteristics have not yet been performed. Between 2008 and 2011, 581 patients underwent diagnostic coronary angiography or percutaneous coronary intervention for stable angina pectoris or acute coronary syndrome (ACS). NIRS of a non-culprit vessel was performed in a subset of 203 patients. In multivariable analyses, TNF-alpha tended to be associated with higher LCBI (beta 0.088 ln (pg/ml) increase per unit LCBI; 95% CI 0.000-0.177, p = 0.05) after adjustment for clinical characteristics. However, this association did not persist after Bonferroni correction (statistical threshold 0.0019). Major adverse cardiac events (MACE) were registered in 581 patients during a median follow-up time of 4.7 years (IQR: [4.2-5.6] years). After adjustment for clinical characteristics and Bonferroni correction, IL-8 (HR 1.60; 95% CI [1.18-2.17] per ln (pg/ml), p = 0.002) was borderline associated with MACE and significantly associated with all-cause mortality or ACS (HR 1.75; 95% CI [1.24-2.48] per ln (pg/ml), p = 0.0015). In conclusion, we found that IL-8 was independently associated with clinical outcome, but altogether, the multiplex panel we investigated here did not render a useful blood biomarker of high LCBI

Relation of Iron Status to Prognosis After Acute Coronary Syndrome

Iron deficiency has been extensively researched and is associated with adverse outcomes in heart failure. However, to our knowledge, the temporal evolution of iron status has not been previously investigated in patients with acute coronary syndrome (ACS). Therefore, we aimed to explore the temporal pattern of repeatedly measured iron, ferritin, transferrin, and transferrin saturation (TSAT) in relation to prognosis post-ACS. BIOMArCS (BIOMarker study to identify the Acute risk of a Coronary Syndrome) is a prospective, multicenter, observational cohort study conducted in The Netherlands between 2008 and 2015. A total of 844 patients with post-ACS were enrolled and underwent high-frequency (median 17) blood sampling during 1 year follow-up. Biomarkers of iron status were measured batchwise in a central laboratory. We analyzed 3 patient subsets, including the case-cohort (n = 187). The primary endpoint (PE) was a composite of cardiovascular mortality and repeat nonfatal ACS, including unstable angina pectoris requiring revascularization. The association between iron status and the PE was analyzed using multivariable joint models. Mean age was 63 years; 78% were men, and >50% had iron deficiency at first sample in the case-cohort. After adjustment for a broad range of clinical variables, 1 SD decrease in log-iron was associated with a 2.2-fold greater risk of the PE (hazard ratio 2.19, 95% confidence interval 1.34 to 3.54, p = 0.002). Similarly, 1 SD decrease in log-TSAT was associated with a 78% increased risk of the PE (hazard ratio 1.78, 95% confidence interval 1.17 to 2.65, p = 0.006). Ferritin and transferrin were not associated with the PE. Repeated measurements of iron and TSAT predict risk of adverse outcomes in patients with post-ACS during 1 year follow-up. Trial Registration: The Netherlands Trial Register. Unique identifiers: NTR1698 and NTR1106. Registered at https://www.trialregister.nl/trial/1614 and https://www.trialregister.nl/trial/1073

Insights in a restricted temporary pacemaker strategy in a lean transcatheter aortic valve implantation program

OBJECTIVES: To study the safety and feasibility of a restrictive temporary‐RV‐pacemaker use and to evaluate the need for temporary pacemaker insertion for failed left ventricular (LV) pacing ability (no ventricular capture) or occurrence of high‐degree AV‐blocks mandating continuous pacing. BACKGROUND: Ventricular pacing remains an essential part of contemporary transcatheter aortic valve implantation (TAVI). A temporary‐right‐ventricle (RV)‐pacemaker lead is the standard approach for transient pacing during TAVI but requires central venous access. METHODS: An observational registry including 672 patients who underwent TAVI between June 2018 and December 2020. Patients received pacing on the wire when necessary, unless there was a high‐anticipated risk for conduction disturbances post‐TAVI, based on the baseline‐ECG. The follow‐up period was 30 days. RESULTS: A temporary‐RV‐pacemaker lead (RVP‐cohort) was inserted in 45 patients, pacing on the wire (LVP‐cohort) in 488 patients, and no pacing (NoP‐cohort) in 139 patients. A bailout temporary pacemaker was implanted in 14 patients (10.1%) in the NoP‐cohort and in 24 patients (4.9%) in the LVP‐cohort. One patient in the LVP‐cohort needed an RV‐pacemaker for incomplete ventricular capture. Procedure time was significantly longer in the RVP‐cohort (68 min [IQR 52–88.] vs. 55 min [IQR 44–72] in NoP‐cohort and 55 min [IQR 43–71] in the LVP‐cohort [p < 0.005]). Procedural high‐degree AV‐block occurred most often in the RVP‐cohort (45% vs. 14% in the LVP and 16% in the NoP‐cohort [p ≤ 0.001]). Need for new PPI occurred in 47% in the RVP‐cohort, versus 20% in the NoP‐cohort and 11% in the LVP‐cohort (p ≤ 0.001). CONCLUSION: A restricted RV‐pacemaker strategy is safe and shortens procedure time. The majority of TAVI‐procedures do not require a temporary‐RV‐pacemaker