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.Comment: 33 pages, 7 figures and 7 tables including appendices. Accepted in Statistics and Computin

Short-term Mortality and Postoperative Complications of Abdominal Aortic Aneurysm Repair in Obese versus Non-obese Patients

BACKGROUND: Obesity is a risk factor not only for abdominal aortic aneurysm (AAA) but also for complications after vascular surgery. This study was to determine the effect of obesity on short-term mortality and post-intervention complications after AAA repair. METHODS: A systematic review and meta-analysis were performed. A systematic search was performed in PubMed; the articles describing the differences in post-intervention complications after open or endovascular repair of an AAA between obese and non-obese patients were selected. The primary outcome was short-term mortality defined as in-hospital mortality or mortality within 30 days after AAA repair. The secondary outcomes were cardiac complications, pulmonary failure, renal failure, and wound infections. The meta-analysis was performed using OpenMeta. RESULTS: Four articles were included in the meta-analysis; these articles included 35,989 patients of which 10,917 (30.3%) were obese. The meta-analysis showed no significant differences for short-term mortality (odds ratio [OR], 0.85; 95% confidence interval [CI], 0.69–1.04). Also, no significant difference was found in pulmonary failure (OR, 1.09; 95% CI, 0.85–1.42). However, obese patients were less likely to suffer from cardiac complications (OR, 0.73; 95% CI, 0.55–0.96). Nevertheless, there was a significantly higher risk of renal failure (OR, 1.16; 95% CI, 1.05–1.30) and wound infections (OR, 1.92; 95% CI, 1.55–2.38) in obese patients. CONCLUSION: Obesity is not a risk factor for short-term mortality after AAA repair compared to non-obesity. Moreover, obese patients suffer less from cardiac complications than non-obese patients

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

Distribution of echocardiographic parameters and their associations with cardiovascular risk factors in the Rotterdam Study

Insight into echocardiographic parameters in the general population may facilitate early recognition of ventricular dysfunction, reducing the population morbidity and mortality of heart failure. We examined the distribution of structural, systolic and diastolic echocardiographic parameters and their associations with cardiovascular risk factors in the Rotterdam Study, a population-based cohort study in men and women aged ≥55 years. Participants with prevalent heart failure, myocardial infarction and atrial fibrillation and flutter were excluded. Echocardiographic parameters were assessed using two-dimensional, M-mode and Doppler echocardiography. Echocardiograms were available in 4,425 participants. Structural parameters were generally larger in men, and most consistently associated with age, body mass index and blood pressure in both sexes. Prevalence of moderate or poor left ventricular systolic function was 3.9% in men and 2.1% in women. Age, body mass index and blood pressure were most consistently associated with systolic function. E/A ratio was lower in women than in men. Age and diastolic blood pressure were most consistently associated with E/A ratio in both sexes. In conclusion, ventricular systolic and diastolic dysfunction is present in asymptomatic individuals. Selected established cardiovascular risk factors are associated with structural, systolic and diastolic parameters

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

Stent expansion in calcified coronary chronic total occlusions:The impact of different stent platforms

Objectives: To evaluate the stent expansion of the durable-polymer Zotarolimus-eluting stent (dp-ZES), the durable-polymer Everolimus-eluting stent (dp-EES), and the bioabsorbable-polymer Sirolimus-eluting stent (bp-SES) in calcified coronary chronic total occlusions (CTO). Background: The newer generation stents with ultrathin struts might raise concerns regarding reduced radial strength and higher stent recoil (SR) when implanted in calcified CTOs. Methods: Between January 2017 and June 2021 consecutive patients with CTO undergoing percutaneous coronary intervention with dp-ZES, dp-EES, or bp-SES were evaluated. The analysis was performed in calcific and in noncalcific CTOs. Quantitative coronary angiography analysis was used to assess diameter stenosis (DS), absolute and relative SR, absolute and relative focal SR, absolute and relative balloon deficit (BD), and absolute and relative focal BD. The primary endpoint was DS. Results: A total of 213 CTOs were evaluated, 115 calcific CTOs (dp-ZES:25, dp-EES:29, bp-SES:61) and 98 non-calcific CTOs (dp-ZES:41, dp-EES:11, bp-SES:46). In calcific CTOs, residual DS was lower in dp-ZES than in dp-EES and bp-SES (−1.00% [−6.50–6.50] vs. 13.00% [7.0–19.00] vs. 15.00% [5.00–20.00]; p &lt; 0.001). Dp-ZES was also an independent predictor of residual DS ≤ 10% (OR 11.34, 95% CI 2.6–49.43, p = 0.001). Absolute and relative focal SR and absolute and relative SR were similar between dp-ZES, dp-EES, and bp-SES (p = 0.913, p = 0.890, p = 0.518, p = 0.426, respectively). In noncalcified CTOs, the residual DS was similar in the three groups (p = 0.340). High relative focal SR was less frequent in dp-ZES than in dp-EES and in bp-SES (19.5% vs. 54.5% vs. 37.0%; p &lt; 0.048). Conclusions: The three stent platforms demonstrated an overall low residual DS when implanted in CTOs. However, dp-ZES was associated with the lowest residual DS and identified as independent predictor of residual DS ≤ 10% in patients with calcific CTOs. Dp-ZES was associated with a lower incidence of high relative focal stent recoil, in noncalcific CTOs. Balloon deficit might be considerate as a surrogate for stent expansion in calcified CTOs.</p

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