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

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

Renal sympathetic denervation in patients with vasospastic angina

Background. Sympathetic overactivity has been linked to vasospastic angina (VSA), although the exact pathophysiology of VSA is poorly understood. The purpose of this study is to assess if renal sympathetic denervation (RDN) reduces cardiac sympathetic nerve activity with a subsequent beneficial effect on angina relief in patients with refractory VSA. Methods and results. Cardiac sympathetic nerve activity was assessed prior to procedure and at 6 months post-procedure using iodine-123 labeled meta-iodobenzylguanidine ( 123I-MIBG) imaging. The Seattle Angina questionnaire (SAQ) was used to assess the degree to which the disease impacts quality of life. No significant change was observed in early HMR (pre-RDN: 2.74 [2.10 to 3.21] vs 6 months post-RDN: 2.57 [2.20 to 3.00]; P = 0.76), and late HMR (pre-RDN: 2.56 [2.18 to 3.20] vs 6 months post-RDN: 2.36 [2.13 to 3.22]; P = 0.22). Additionally, no change was seen in WR (P = 0.22). SAQ results revealed significant improvements in perceived physical limitation, angina frequency, and quality of life at 6 months (P < 0.05 for all). Conclusion. RDN resulted in improvements in angina class and quality of life at 6 months in patients with refractory VSA. RDN, however, did not result in significant changes in cardiac sympathetic nerve activity as measured using 123I-MIBG. The latter observation should be considered with caution given the small sample size of this study. Larger studies are needed to assess this further

Outcomes of Atrial Arrhythmia Surgery in Patients With Congenital Heart Disease: A Systematic Review

BACKGROUND: The improved life expectancy of patients with congenital heart disease is often accompanied by the development of atrial tachyarrhythmias. Similarly, the number of patients requiring redo operations is expected to continue to rise as these patients are aging. Consequently, the role of arrhythmia surgery in the treatment of atrial arrhythmias is likely to become more important in this population. Although atrial arrhythmia surgery is a well-established part of Fontan conversion procedures, evidence-based recommendations for arrhythmia surgery for macroreentrant atrial tachycardia and atrial fibrillation in other patients with congenital heart disease are still lacking. METHODS AND RESULTS: Twenty-eight studies were included in this systematic review. The median reported arrhythmia recurrence was 13% (interquartile range, 4%–26%) during follow-up ranging from 3 months to 15.2 years. A large variation in surgical techniques was observed. Based on the acquired data, biatrial lesions are more effective in the treatment of atrial fibrillation than exclusive right-sided lesions. Right-sided lesions may be more appropriate in the treatment of macroreentrant atrial tachycardia; evidence for the superiority of additional left-sided lesions is lacking. There are not enough data to support the use of exclusive left-sided lesions. Theoretically, prophylactic atrial arrhythmia surgery may be beneficial in this population, but evidence is currently limited

Incidence of end-stage renal disease after heart transplantation and effect of its treatment on survival

Aims: Many heart transplant recipients will develop end-stage renal disease in the post-operative course. The aim of this study was to identify the long-term incidence of end-stage renal disease, determine its risk factors, and investigate what subsequent therapy was associated with the best survival. Methods and results: A retrospective, single-centre study was performed in all adult heart transplant patients from 1984 to 2016. Risk factors for end-stage renal disease were analysed by means of multivariable regression analysis and survival by means of Kaplan–Meier. Of 685 heart transplant recipients, 71 were excluded: 64 were under 18 years of age and seven were re-transplantations. During a median follow-up of 8.6 years, 121 (19.7%) patients developed end-stage renal disease: 22 received conservative therapy, 80 were treated with dialysis (46 haemodialysis and 34 peritoneal dialysis), and 19 received a kidney transplant. Development of end-stage renal disease (examined as a time-dependent variable) inferred a hazard ratio of 6.45 (95% confidence interval 4.87–8.54, P < 0.001) for mortality. Tacrolimus-based therapy decreased, and acute kidney injury requiring renal replacement therapy increased the risk for end-stage renal disease development (hazard ratio 0.40, 95% confidence interval 0.26–0.62, P < 0.001, and hazard ratio 4.18, 95% confidence interval 2.30–7.59, P < 0.001, respectively). Kidney transplantation was associated with the best median survival compared with dialysis or conservative therapy: 6.4 vs. 2.2 vs. 0.3 years (P < 0.0001), respectively, after end-stage renal disease development. Conclusions: End-stage renal disease is a frequent complication after heart transplant and is associated with poor survival. Kidney transplantation resulted in the longest survival of patients with end-stage renal disease

The Association Between Cytomegalovirus Infection and Cardiac Allograft Vasculopathy in the Era of Antiviral Valganciclovir Prophylaxis

Background. Previous studies on the association between cytomegalovirus (CMV) infection and cardiac allograft vasculopathy (CAV) were conducted on patients transplanted in the prevalganciclovir prophylaxis era. The aim of our study is to evaluate this relation in heart transplantation (HTx) recipients treated according to current prophylactic and immunosuppressive regimens. Methods. This single-center retrospective study included all consecutive adult patients that underwent HTx between January 1, 2000, and May 31, 2018. Clinically relevant CMV infection was defined as either plasma CMV DNAemia ≥ 1000 IU/mL with/without clinical symptoms or <1000 IU/mL with symptoms. The primary endpoint was first manifestation of CAV diagnosed by coronary angiography. For statistical analysis, the cause-specific hazard regression model was applied, with clinically relevant CMV infection and any CMV infection as time-dependent variables. Results. In total, 260 patients were included in the analysis. The median (interquartile range) follow-up was 7.88 (4.21–12.04) years. During the follow-up, clinically relevant CMV infection was diagnosed in 96 (37%) patients and CAV in 149 (57%) patients. In the multivariate regression analysis, independent predictors of CAV were: number of rejection episodes (cause-specific hazard ratio [95% confidence interval]: 1.18 [1.04-1.34], P = 0.01), hypertension (1.61 [1.11-2.34], P = 0.01), treatment with mycophenolate mofetil (0.68 [0.47-0.97], P = 0.03). No significant association was observed between CMV infection and CAV, except for patients who experienced a breakthrough CMV infection (n = 24) during prophylaxis (1.94 [1.11-3.40], P = 0.02). Conclusions. In the era of contemporary immunosuppression and valganciclovir prophylaxis, a signifi