Conventional Cardiovascular Research Articles

Lipoprotein (a) and the Occurrence of Lipid Disorders and Other Cardiovascular Risk Factors in Patients without Diagnosed Cardiovascular Disease.

Background: Elevated lipoprotein (a) [Lp(a)] concentrations are linked mainly to genetic factors. The relationship between Lp(a) and other lipid disorders or cardiovascular (CV) risk factors has been less investigated. The aim of this study was to assess the occurrence of lipid disorders and other CV risk factors according to Lp(a) concentrations. Methods: A cross-sectional analysis of 200 primary-care patients who had not been diagnosed with CV disease was conducted. The following risk factors were assessed: older age, history of hypertension, diabetes mellitus or dyslipidemia, smoking, lack of physical activity, body mass index (BMI), and waist circumference. The following lipid parameters were measured: total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and small, dense LDL (sdLDL-C). Patients were divided into two groups based on their Lp(a) concentrations: <30 mg/dL and ≥30 mg/dL. Results: In 70% of patients, the Lp(a) concentration was <30 mg/dL. The concentrations of lipid parameters did not differ between the groups. The rate of patients with sdLDL-C >1.0 mmol/L was higher in the low-Lp(a) group (10.0 vs. 1.7%, p = 0.04), with no significant differences regarding the other analyzed lipid disorders (p > 0.05). Both in the low- and high-Lp(a) group, most patients had two other abnormal lipid factors (45.0% and 60.0%, respectively). The distribution of impaired lipid parameters (p = 0.41) and other CV risk factors (p = 0.16) was similar in both groups. There was a lower rate of patients >60 years old (15.0% vs. 32.9%, p = 0.01) and with a BMI ≥ 25 kg/m2 (46.7% vs. 63.6%, p = 0.026) in the high-Lp(a) group, and previously diagnosed hyperlipidemia was more prevalent in this group (65.0% vs. 47.1%, p = 0.02). The occurrence of other cardiovascular risk factors did not differ significantly between the Lp(a) groups (p > 0.05). In the high-Lp(a) group, the highest proportion (25.0%) had two CV risk factors, and in the low-Lp(a) group, 31.4% had four CV risk factors. Conclusions: An elevated Lp(a) concentration is not related to the number of conventional CV risk factors or other impairment major lipid parameters.

Power-law properties of nocturnal arrhythmia avalanches: A novel marker for incident cardiovascular events

BackgroundBursting nonsustained cardiac arrhythmia events are a common observation during sleep. ObjectivesThe purpose of this study was to investigate the hypothesis that nocturnal arrhythmia episode durations could follow a power law, whose exponent could predict long-term clinical outcomes. MethodsWe defined “nocturnal arrhythmia avalanche” (NAA) as any instance of a drop in electrocardiographic (ECG) template-matched R-R intervals ≥30% of R-R baseline, followed by a return to 90% of baseline. We studied NAA in ECG recordings obtained from the Sleep Heart Health Study (SHHS), Osteoporotic Fractures in Men Study (MrOS) Study, and Multi-Ethnic Study of Atherosclerosis (MESA). The association of nocturnal arrhythmia durations with a power-law distribution was evaluated and the association of derived power-law exponents (α) with major adverse cardiovascular (CV) events and mortality assessed with multivariable Cox regression. ResultsA total of 9176 participants were studied. NAA episodes distribution was consistent with power-law vs comparator distributions in all datasets studied (positive log likelihood ratio of power-law vs exponential in MESA: 83%; SHHS: 69%; MrOS: 81%; power-law vs log-normal in MESA: 95%; SHHS: 35%; MrOS: 64%). The NAA power-law exponent (α) showed a significant association of with adverse CV outcomes (association with CV mortality: SHHS hazard ratio 1.39 [1.07–1.79], P = .012; MrOS hazard ratio 1.42 [1.02–1.94], P = .039; association with CV events: MESA HR 3.46 [1.46–8.21], P = .005) in multivariable Cox regression, after adjusting for conventional CV risk factors and nocturnal ectopic rate. ConclusionThe NAA power-law exponent is a reproducible, predictive marker for incident CV events and mortality.

Predicting cardiovascular events with fluoropyrimidine chemotherapy using a standard cardiovascular risk calculator.

Fluoropyrimidine chemotherapy is important for treatment of many solid tumours but is associated with cardiotoxicity. The relationship of fluoropyrimidine-associated cardiotoxicity (FAC) with conventional cardiovascular (CV) risk factors is poorly understood, and standard cardiovascular risk scores are not validated in this context. Single-centre retrospective study of patients treated with fluoropyrimidine chemotherapy using electronic health records for cardiovascular risk factors (and calculation of QRISK3 score), cancer treatment, and clinical outcomes. FAC was defined by cardiovascular events during or within 3months of fluoropyrimidine treatment, and Cox regression was used to assess associations of CV risk and cancer treatment with FAC. One thousand eight hundred ninety-eight patients were included (45% male; median age 64years), with median follow up 24.5 (11.5-48.3months); 52.7% of patients were at moderate or high baseline CV risk (QRISK3 score >10%) Cardiovascular events occurred in 3.1% (59/1898)-most commonly angina (64.4%, 38/59) and atrial fibrillation (13.6%, 8/59), with 39% events during cycle one of treatment. In univariable analysis, QRISK3 score >20% was significantly associated with incident FAC (HR 2.25, 95% CI 1.11-4.93, P=0.03). On multivariable analysis, beta-blocker use (HR 1.04, 95% CI 1.00-1.08, P=0.04) and higher BMI (HR 2.33, 95% CI 1.04-5.19, P=0.04) were independently associated with incident CV events. Thirty-two of the 59 patients with FAC were subsequently rechallenged with fluoropyrimidine chemotherapy, with repeat CV events in 6% (2/32). Incident FAC did not affect overall survival (P=0.50). High BMI and use of beta-blockers are associated with risk of CV events during fluoropyrimidine chemotherapy. QRISK3 score may also play a role in identifying patients at high risk of CV events during fluoropyrimidine chemotherapy. Re-challenge with further fluoropyrimidine chemotherapy can be considered in patients following CV events during prior treatment.

BLOOD PRESSURE VARIABILITY AS PREDICTOR OF CANCER THERAPY-RELATED CARDIOVASCULAR TOXICITY IN PATIENTS WITH MULTIPLE MYELOMA

Objective: Blood pressure variability (BPV) is an independent predictor of cardiovascular (CV) events and overall mortality. The potential role of BPV in defining CV risk of patients undergoing anticancer therapy with a potential cancer therapy-related cardiovascular toxicity (CTR-CVT) is currently unknown. The aims of this study were: (i) to assess the predictive value of BPV indexes for CTR-CVT development and defining the corresponding cut-off values; (ii) to identify subgroups of subjects based on BPV, through clustering analysis. Design and method: Patients with Multiple Myeloma, who were eligible to anticancer therapy with Carfilzomib, were consecutively enrolled and underwent a baseline evaluation, including office blood pressure (BP) measurement, 24h-Ambulatory Blood pressure Monitoring (ABPM), PWV, and Echocardiography. Short-term BPV was assessed through standard deviation (SD), weighted standard deviation (wSD), coefficient of variation (CoV), average real variability (ARV), and variability independent of the mean (VIM), evaluated on ABPM measurements. Results: The study population included 124 patients (50% female). During follow-up, CTR-CVT occurred in 70 subjects (56.5% of the total population), including both BP and CV events. Night-time BPV was associated to CTR-CVT, independently by BP, age, smoking, and comorbidities as diabetes and renal dysfunction (night-time systolic CoV: adjusted OR 1.11 [1.01-1.22]; night-time systolic VIM adjusted OR 1.17 [1.03-1.35]; night-time diastolic VIM adjusted OR 1.18 [1.01-1.40]). Cut-off for these BPV parameters were identified as predictor of CTR-CVT occurrence: 10.5 for night-time systolic CoV (sensibility 73%, specificity 47%); 7.8 and 6.4 for systolic and diastolic night-time VIM (sensibility 85% for both; specificity 35% and 39%, respectively). Clustering analysis identified a subgroup of subjects characterized by the highest BPV, who had a greater prevalence of events during follow-up, but no differences in other conventional CV risk factors, as BP, dyslipidaemia, diabetes, renal function, and smoking habit, as well as left ventricular mass and global longitudinal strain. Conclusions: Short-term BPV is an independent predictor of CTR-CVT in patients with Multiple Myeloma undergoing therapy with Carfilzomib. The inclusion of these indexes improves CV risk prediction in these subjects and higher BPV is a distinctive feature predicting adverse events, on top of conventional CV risk factors.

Electrocardiography score based on the Minnesota code classification system predicts cardiovascular mortality in an asymptomatic low-risk population

Background The use of a single abnormal finding on electrocardiography (ECG) is not recommended for stratifying the risk of cardiovascular (CV) events in low-risk general populations because of its low discriminative power. However, the value of a scoring system containing multiple abnormal ECG findings for predicting CV death has not been sufficiently evaluated. Methods In a prospective community-based cohort study, 8417 participants without atherosclerotic CV diseases (ASCVDs) and any related symptoms were followed for 18 years. The standard 12-lead ECGs were recorded at baseline and the ECG findings were categorized using the Minnesota code classification. CV deaths were defined as death from myocardial infarction (MI), chronic ischemic heart disease, heart failure, fatal arrhythmia, cerebrovascular event, pulmonary thromboembolism, peripheral vascular disease and sudden cardiac arrest and identified using the Korean National Statistical Office (KOSTAT) database. Results In a multivariate Cox proportional hazard (CPH) model, major and minor ST-T wave abnormalities, atrial fibrillation (AF), Q waves in the anterior leads, the lack of Q waves in the posterior leads, high amplitudes of the left and right precordial leads, left axis deviation and sinus tachycardia were associated with higher risks of CV deaths. The ECG score consisted of these findings showed modest predictive values represented by C-statistics that ranged from 0.632 to 760 during the follow-up and performed better in the early follow-up period. The ECG score independently predicted CV death after adjustment for relevant covariates in a multivariate model, and improved the predictive performance of the 10-year ASCVD risk estimator and a model of conventional risk factors including age, diabetes and current smoking. The combined ECG score (Harrell’s C-index: 0.852, 95% confidence interval [CI], 0.828–0.876) composed of the ECG score and the conventional risk factors outperformed the 10-year ASCVD risk estimator (Harrell’s C-index: 0.806; 95% CI, 0.780–0.833) and the model of the conventional risk factors (Harrell’s C-index: 0.841, 95% CI, 0.817–0.865) and exhibited an excellent goodness of fit between the predicted and observed probabilities of CV death. Conclusions The ECG score could be useful to predict CV death independently and may add value to the conventional CV risk estimators regarding the risk stratification of CV death in asymptomatic low-risk general populations.

Lipid Profile in Olympic Athletes: Proposal for a “Lipid Athlete Score” as a Clinical Tool to Identify High-Risk Athletes

Dyslipidemia is a major risk factor for atherosclerosis. Identification of dyslipidemia in athletes has raised interest in establishing preventive strategies and reducing cardiovascular (CV) events. Nowadays, targets or “scores” for athletes are undefined. The aim of our study was to create a “Lipid Athlete Score” based on lipid parameters and derive score indexes to identify high-risk athletes. We retrospectively enrolled 957 Olympic athletes practicing different sporting disciplines (power, skills, endurance, and mixed), analyzing their CV profiles and anthropometrics; 55.4% were male, the mean age was 27.1 ± 5 years, and the mean body mass index (BMI) was 23.1 ± 3.2 kg/m2. Three hundred and forty-three athletes (35.8%) were dyslipidemic (LDL ≥ 115 mg/dL or LDL/HDL ≥ 1.90). Multivariate analysis revealed the following: male p = 0.001, OR 1.88 [0.41–2.51], familiarity for dyslipidemia p = 0.001, OR 2.82 [1.72–4.59], BMI ≥ 30 kg/m2 p = 0.001, OR 2.53 [1.46–4.38], and fat mass p = 0.001, OR 2.29 [1.38–3.80] were significant. Endurance athletes presented the lowest CV risk. We proposed a lipid athlete score including major (LDL ≥ 115 mg/dL and LDL/HDL ≥ 1.90) and minor criteria (male, BMI &gt; 30 kg/m2 or fat mass &gt;22% for males and 32% for females, familiarity for dyslipidemia, and conventional CV risk factors). Twelve athletes (1.2%) were at high risk, 150 athletes (15.7%) at medium risk, 171 athletes (17.9%) at low risk, and 624 (65.2%) were at no risk. Dyslipidemia is very common in elite athletes. We have defined a specific lipid athlete score based on lipid parameters and derived score indexes for the stratification of risk. In accordance with this tool, a substantial proportion of athletes (16.9%) were at medium-to-high risk and need early preventive strategies to improve their lipid profiles and reduce the future development of atherosclerotic CV diseases.

Evaluation of a proactive cardiovascular risk screening program after preeclampsia: the Queen of Hearts study

Abstract Introduction: Despite the long-term risk for cardiovascular disease (CVD) after preeclampsia (PE), guidelines do not include specific recommendations on how to apply structural cardiovascular (CV) screening after complicated pregnancy. Insight in the prevalence of conventional CV risk factors at different age intervals may provide insight in the necessity of timely CV screening. Purpose Evaluate the prevalence of conventional CV risk factors in former pregnant women at different age intervals. Methods Data was used from the cross-sectional Queen of Hearts study, which includes relatively young women with a history of PE and a control group of women with a history of uncomplicated pregnancy. Based on history taking we established the prevalence of known diagnoses of hypertension, diabetes mellitus (DM) and hypercholesterolemia. Besides, a CV risk assessment was performed, including 30-minutes blood pressure (BP) measurement and venous blood sampling. De novo diagnosis of hypertension, DM and hypercholesterolemia were defined as systolic BP ≥140mmHg and/or diastolic BP ≥90mmHg, fasting glucose ≥7mmol/L, and Low Density Lipoprotein (LDL) &amp;gt;3.4mmol/L, respectively. Odds Ratio’s (ORs) with corresponding 95% confidence intervals (CI) were established, and survival analysis using Kaplan Meier curves and cox regression was performed. Results We included 1040 (39 ± 8 years) women who had suffered PE and 518 who experienced normotensive pregnancy (44 ± 8 years). In both groups, the prevalence of hypertension and hypercholesterolemia increased statistically significantly with advancing age (p-values trend &amp;lt;0.001), but this age-related increase seemed larger in former preeclamptic women. Across all age groups, former preeclamptic women suffered more often hypertension than controls whilst differences seemed most pronounced for younger individuals (&amp;lt;40 years: 12.4% vs. 2.1% respectively, OR 6.6 (95% CI 2.1-18.3); 40-49 years: 24.8% vs. 6.9% respectively, OR 4.5 (95% CI 2.4-8.3); ≥50 years: 38.2% vs. 15.7% respectively, OR 3.3 (95% CI 1.8-6.1)). A proportion of 33.5% former preeclamptic women and 23.9% controls suffered at least one CV risk factor (OR 1.6, 95% CI 1.3-2.0). This prevalence significantly increased with age, being 25.0% among former preeclamptic women aged &amp;lt;40 years and increasing up to 65.7% if aged ≥50 years. The age of CV risk diagnosis was on average 8 years younger in former preeclamptic women than controls, supported by survival analyses ((log rank p-value &amp;lt;0.001, Hazard Ratio 2.6 (95% CI 2.1-3.2)). Conclusions The prevalence of hypertension, DM and hypercholesterolemia is significantly higher in women with former PE compared to controls, already below the age of 40 and increasing with age. The age-related increase in risk was larger among former preeclamptic women than controls. Awareness on the high prevalence of CV risk factors at young age in former preeclamptic women should be taken into account when developing screening guidelines.Prevalence of CV risk factorsKaplan Meier curve CV risk factors

Abstract 15806: An Age Index Derived From Heart Rate Metrics is Associated With Cardiovascular Risk Biomarkers

Introduction: Conventional cardiovascular (CV) risk scores depend on clinical and laboratory measurements, and therefore have limited accessibility in the general population. Consumer wearables provide heart rate measures which individually correlate with CV risk, but it is not known how well they align collectively with conventional clinical biomarkers. Objective: To demonstrate the alignment of a composite index based on heart rate metrics available from consumer wearables with clinical biomarkers and risk scores. Methods: As chronological age is a strong predictor of cardiovascular health, we trained a linear regression model on the UK Biobank (UKB) dataset to predict chronological age from sex, body mass index, resting heart rate (RHR), and mean HR, maximum HR, HR recovery and estimated VO2max during a cycle ergometry test. Data from 53,670 individuals aged 40-70 years were used: 30,247 for training and 23,423 for testing. A cardiovascular age (CVAge) index was obtained as the difference between chronological and predicted age of the individual: a positive/negative CVAge index indicates the CV health is better/worse than the age would suggest. Heart rate predictors and CVAge index were z-scored using age and sex data on the training set. Results: Individuals in the bottom quintile (“Poor CVAge index”) of the test set had higher systolic blood pressure (+5.0 mmHg), diastolic blood pressure (+3.0 mmHg), Framingham 10-year risk score (+1.8%) and ASCVD risk score (+0.8%), than those in the top quintile (“Very Good CVAge index”) - Figure 1. Conclusions: Continuous monitoring of heart rate metrics may help users track their heart health even in the absence of clinical and laboratory measurements.

Predictive value of the Framingham steatosis index for cardiovascular risk: a nationwide population-based cohort study.

Non-alcoholic fatty liver disease (NAFLD) is common and is associated with cardiovascular (CV) disease and mortality. The Framingham steatosis index (FSI) was recently proposed as a diagnostic marker of NAFLD and was calculated from age, body mass index, triglyceride, aspartate aminotransferase, alanine aminotransferase, diabetes history, and hypertension status. We aimed to evaluate the predictive ability of FSI for CV risk using a large-scale population dataset from the Korean National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS). Among 514,866 individuals in the NHIS-HEALS, we excluded those who died, had a history of admission due to a CV event, and were heavy drinkers. The final study cohort comprised 283,427 participants. We employed both unadjusted and covariate-adjusted models in Cox proportional hazards regression analyses to determine the association between FSI and major adverse cardiovascular events (MACEs), CV events, and CV mortality. During a median follow-up of 5.9 years, we documented 9,674, 8,798, and 1,602 cases of MACEs, CV events, and CV mortality, respectively. The incidence of MACEs was 1.28%, 2.99%, 3.94%, and 4.82% in the first to fourth quartiles of FSI, respectively. The adjusted hazard ratios (95% confidence interval) for MACEs gradually and significantly increased with the FSI quartiles [1.302 (1.215-1.395) in Q2, 1.487 (1.390-1.590) in Q3, and 1.792 (1.680-1.911) in Q4], following an adjustment for conventional CV risk factors, including age, sex, smoking, drinking, physical activities, low-density lipoprotein cholesterol, estimated glomerular filtration rate, and waist circumference. Participants in the higher quartiles of FSI exhibited a noteworthy increase in the occurrence of CV event. However, upon adjusting for relevant risk factors, the association between FSI and CV mortality did not reach statistical significance. Our study suggests that the FSI, which is a surrogate marker of NAFLD, has a prognostic value for detecting individuals at higher risk of CV events.

Biomarkers of Neutrophil Activation in Patients with Symptomatic Chronic Peripheral Artery Disease Predict Worse Cardiovascular Outcome

Neutrophils play a role in cardiovascular (CV) disease. However, relatively scant evidence exists in the setting of peripheral artery disease (PAD). The aims of this study were to measure biomarkers of neutrophil activation in patients with symptomatic chronic PAD compared with healthy controls, to assess their association with PAD severity, and to evaluate their prognostic value in patients with PAD. The following circulating markers of neutrophil degranulation were tested: polymorphonuclear neutrophil (PMN) elastase, neutrophil gelatinase-associated lipocalin (NGAL), and myeloperoxidase (MPO). Neutrophil extracellular traps (NETs) were quantified by measuring circulating MPO-DNA complexes. Patients with PAD underwent a comprehensive series of vascular tests. The occurrence of 6-month major adverse CV (MACE) and limb events (MALE) was assessed. Overall, 110 participants were included, 66 of which had PAD. After adjustment for conventional CV risk factors, PMN-elastase (adjusted odds ratio [OR]: 1.008; 95% confidence interval [CI]: 1.002-1.015; p = 0.006), NGAL (adjusted OR: 1.045; 95%CI: 1.024-1.066; p < 0.001), and MPO (adjusted OR: 1.013; 95%CI: 1.001-1.024; p = 0.028) were significantly associated with PAD presence. PMN-elastase (adjusted hazard ratio [HR]: 1.010; 95%CI: 1.000-1.020; p = 0.040) and MPO (adjusted HR: 1.027; 95%CI: 1.004-1.051; p = 0.019) were predictive of 6-month MACE and/or MALE. MPO displayed fair prognostic performance on receiver operating characteristic (ROC) curve analyses, with an area under the curve (AUC) of 0.74 (95%CI: 0.56-0.91) and a sensitivity and specificity of 0.80 and 0.65, respectively, for a cut-off of 108.37 ng/mL. MPO-DNA showed a weak inverse correlation with transcutaneous oximetry (TcPO2) on proximal foot (adjusted ρ -0.287; p = 0.032). In conclusion, in patients with symptomatic chronic PAD, enhanced neutrophil activity may be associated with an increased risk of acute CV events, rather than correlate with disease severity. Further research is needed to clarify the role of neutrophils in PAD natural history.

Effects of Long-term Use of Proton Pump Inhibitors on Systemic Arterial Stiffness and Pulse Wave Velocity.

Proton pump inhibitors (PPIs) are among the most widely prescribed agents. Although PPIs are widely regarded as harmlesss, long-term use of PPIs (LTUPPI) can have the potential to increase the risk of developing cardiovascular (CV) disease (CVD). Pulse wave velocity (PWV) is a good indicator of arterial stiffness. Several studies show a relationship between LTUPPI and CVD. However, the association between LTUPPI and PWV or arterial stiffness has not been reported. Patients (n=64) with LTUPPI and controls (n=91) were included. PWV, glucose, creatinine, total cholesterol, triglyceride, low-density lipoprotein cholesterol, cholesterol, highdensity lipoprotein cholesterol, and magnesium levels were measured. In the LTUPPI group, PWV was greater than in controls (9.08±2.04 vs. 7.77±1.52 m/s, respectively, p=0.01); 34.4% of patients and 8.8% of controls had PWV levels >10 m/s (p=0.000). Multiple logistic regression analysis showed age (p<0.001) and LTUPPI (p=0.024) as predictors of elevated PWV. PWV values are increased in patients with LTUPPI compared to controls independently of conventional CV risk factors. Measurement of PWV and other arterial stiffness parameters in cases with LTUPPI may be useful to predict possible CVD. Studies involving greater numbers are needed to confirm these findings.

High leptin status indicates an increased risk of mortality and heart failure in stable coronary artery disease

Background and aimsLeptin is an adipocyte-derived peptide involved in energy homeostasis and body weight regulation. The position of leptin in cardiovascular pathophysiology remains controversial. Some studies suggest a detrimental effect of hyperleptinemia on the cardiovascular (CV) system, while others assume the role of leptin as a neutral or even protective factor. We have explored whether high leptin affects the mortality and morbidity risk in patients with stable coronary heart disease. Methods and resultsWe followed 975 patients ≥6 months after myocardial infarction or coronary revascularization in a prospective study. All-cause or cardiovascular death, non-fatal cardiovascular events (recurrent myocardial infarction, stroke, or any revascularization), and hospitalizations for heart failure (HF) we used as outcomes.High serum leptin concentrations (≥18.9 ng/mL, i.e., 4th quartile) were associated with worse survival, as well as with a higher incidence of fatal vascular events or hospitalizations for HF. Even after full adjustment for potential covariates, high leptin remained to be associated with a significantly increased 5-years risk of all-cause death [Hazard risk ratio (HRR) 2.10 (95%CIs:1.29–3.42), p < 0.003], CV death [HRR 2.65 (95%CIs:1.48–4.74), p < 0.001], and HF hospitalization [HRR 1.95 (95% CIs:1.11–3.44), p < 0.020]. In contrast, the incidence risk of non-fatal CV events was only marginally and non-significantly influenced [HRR 1.27 (95%CIs:0.76–2.13), p = 0.359]. ConclusionsHigh leptin concentration entails an increased risk of mortality, apparently driven by fatal CV events and future worsening of HF, on top of conventional CV risk factors and the baseline status of left ventricular function.

Lipid Profile Is Negatively Associated with Uremic Toxins in Patients with Kidney Failure—A Tri-National Cohort

Patients with kidney failure (KF) have a high incidence of cardiovascular (CV) disease, partly driven by insufficient clearance of uremic toxins. Recent investigations have questioned the accepted effects of adverse lipid profile and CV risk in uremic patients. Therefore, we related a panel of uremic toxins previously associated with CV morbidity/mortality to a full lipid profile in a large, tri-national, cross-sectional cohort. Total, high-density lipoprotein (HDL), non-HDL, low-density lipoprotein (LDL), and remnant cholesterol, as well as triglyceride, levels were associated with five uremic toxins in a cohort of 611 adult KF patients with adjustment for clinically relevant covariates and other patient-level variables. Univariate analyses revealed negative correlations of total, non-HDL, and LDL cholesterol with all investigated uremic toxins. Multivariate linear regression analyses confirmed independent, negative associations of phenylacetylglutamine with total, non-HDL, and LDL cholesterol, while indole-3 acetic acid associated with non-HDL and LDL cholesterol. Furthermore, trimethylamine-N-Oxide was independently and negatively associated with non-HDL cholesterol. Sensitivity analyses largely confirmed findings in the entire cohort. In conclusion, significant inverse associations between lipid profile and distinct uremic toxins in KF highlight the complexity of the uremic milieu, suggesting that not all uremic toxin interactions with conventional CV risk markers may be pathogenic.

Association of the atherogenic index of plasma with cardiovascular risk beyond the traditional risk factors: a nationwide population-based cohort study

BackgroundThe atherogenic index of plasma (AIP) is composed of triglycerides and high-density lipoprotein cholesterol and is a novel marker for assessing the risk of atherogenicity and cardiometabolic health. An association between AIP and greater frequency of major adverse cardiovascular events (MACEs) in patients with type 2 diabetes mellitus and high cardiovascular (CV) disease risk has been reported. However, only few studies have examined the correlation between AIP and CV risk in general populations. We thus aimed to evaluate the relationship between AIP and CV diseases using a large-scale population dataset from the Korean National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS).MethodsA total of 514,866 participants were enrolled from the NHIS-HEALS and classified according to the AIP quartiles. We performed univariate and multivariate Cox proportional hazards regression analyses to determine the association between AIP and MACEs, CV events, and CV mortality.ResultsDuring follow-up, we documented 12,133, 11,055, and 1942 cases of MACEs, CV events, and CV mortality, respectively. The multivariate-adjusted hazard ratios [HRs; 95% confidence interval (CI)] for MACEs gradually and significantly increased with the AIP quartiles [1.113 (1.054–1.175) in Q2, 1.175 (1.113–1.240) in Q3, and 1.278 (1.209–1.350) in Q4], following an adjustment for the conventional CV risk factors, including age, sex, body mass index, smoking, alcohol drinking, physical activities, household income, fasting glucose, systolic blood pressure, low-density lipoprotein cholesterol, and estimated glomerular filtration rate. In subgroup analyses, the association of AIP with MACEs and CV events was particularly outstanding in patients with diabetes.ConclusionsAIP was significantly associated with CV risks after adjusting for the traditional risk factors. Therefore, it may be used as an effective mass screening method to identify patients at a high risk of CV events.

Rheumatoid arthritis, as a clinical disease, but not rheumatoid arthritis-associated autoimmunity, is linked to cardiovascular events

BackgroundRheumatoid arthritis (RA) is characterized by increased cardiovascular (CV) mortality. CV events are particularly high in patients with RA-specific autoimmunity, including rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA), raising the question whether RA-specific autoimmunity itself is associated with CV events.MethodsNew CV events (myocardial infarction, stroke or death by CV cause) were recorded in 20,625 subjects of the Electricité de France – Gaz de France (GAZEL) cohort. Self-reported RA cases in the GAZEL cohort were validated by phone interview on the basis of a specific questionnaire. In 1618 subjects, in whom plasma was available, RF and ACPA were measured. A piecewise exponential Poisson regression was used to analyze the association of CV events with presence of RA as well as RA-specific autoimmunity (without RA).ResultsCV events in GAZEL were associated with age, male sex, smoking, hypertension, hyperlipidemia, and diabetes mellitus (HR from 1.06 to 1.87, p < 0.05). Forty-two confirmed RA cases were identified. Confirmed RA was significantly associated with CV risk increase (HR of 3.03; 95% CI: 1.13–8.11, p = 0.03) independently of conventional CV risk factors. One hundred seventy-eight subjects showed RF or ACPA positivity without presence of RA. CV events were not associated with ACPA positivity (HR: 1.52, 95% CI: 0.47–4.84, p = 0.48) or RF positivity (HR: 1.15, 95% CI: 0.55–2.40, p = 0.70) in the absence of RA.ConclusionsRA, as a clinical chronic inflammatory disease, but not mere positivity for RF or ACPA in the absence of clinical disease is associated with increased CV risk.

Abstract 8902: The High Circulating Leptin is Associated With Increased Mortality Risk in Stable Coronary Heart Disease Patients

Introduction: Leptin is an adipocyte-derived peptide, involved in energy homeostasis and regulation of body weight. The position of leptin in cardiovascular pathophysiology remained controversial, some studies suggest a detrimental effect of hyperleptinemia on the cardiovascular (CV) system, while others assume the role of leptin as protective. Hypothesis: We explore whether high leptin status affects the mortality/ morbidity risk in stable patients with coronary heart disease. Methods: 975 patients, ≥6 months after myocardial infarction (EUROASPIRE cohort) were followed in a prospective study. All-cause or CV death, non-fatal events (myocardial infarction, stroke or any revascularization) and hospitalizations for heart failure (HF) were registered as outcomes Results: High serum leptin concentrations (≥18.9 ng/mL, i.e. 4 th quartile) indicate inferior survival, as well as a higher incidence of fatal vascular event or hospitalizations for HF ( see Figure). Even after full adjustment for potential covariates, high leptin was associated with significantly increased 5-years risk of all-cause death [HRR 2.10 (95%CIs:1.29-3.42), p&lt;0.003], CV death [HRR 2.65 (95%CIs:1.48-4.74), p&lt;0.001] and HF hospitalization [HRR 1.95 (95%CIs:1.11-3.44), p&lt;0.020]. In contrast, the incidence risk of non-fatal CV events was only marginally and non-significantly influenced [HRR 1.27 (95%CIs:0.76-2.13), p=0.359] Conclusions: High leptin concentration entails an increased risk of mortality (apparently driven by fatal CV events) and future worsening of HF, on top of conventional CV risk factors and the baseline status of left ventricular function.

MO455LIPID PROFILE AND UREMIC RETENTION SOLUTES IN PATIENTS WITH END-STAGE KIDNEY DISEASE

Abstract Background and Aims Patients with end-stage kidney disease (ESKD) have an extremely high incidence of cardiovascular (CV) diseases, partly driven by insufficient clearance of uremic toxins. ESKD patients have a characteristically adverse lipid profile, however data investigating the relationship between uremic toxins and lipid profile, potentially contributing to increased CV risk, is scarce. To determine if uremic retention solutes (URS) associate with an adverse lipid profile in ESKD, we studied a large, trinational cohort with a detailed lipid profile, as well as a comprehensive panel of uremic toxins. Method Total, high density lipoprotein (HDL), non-HDL, low density lipoprotein (LDL), and remnant cholesterol, as well as triglyceride, levels were associated with a panel of 15 uremic retention solutes in a combined cohort of 591 European, adult patients with advanced chronic kidney disease (CKD) from UZ Leuven, Belgium (n=150), Karolinska Hospital, Stockholm, Sweden (n=235) or University of Leipzig Medical Center, Leipzig, Germany (n=226). Total and HDL cholesterol, as well as triglycerides, were quantified at each study center, whereas non-HDL cholesterol, LDL cholesterol, and remnant cholesterol were calculated. In all subjects of this trinational study, a selected panel of solutes, including CMPF, TMAO, aromatic amino acids and corresponding end-products of endogenous and microbial metabolism, was centrally quantified in a single lab by liquid chromatography - tandem mass spectrometry. Univariate correlations were assessed using non-parametric Spearman’s rank correlation method. To identify independent associations between solutes and lipid profile, multivariate linear regression models were used with adjustment for age, sex, as well as markers of inflammation, protein energy wasting, renal function, diabetes and dialysis. Results In total, 189 patients in CKD stage 3-5 not on renal replacement therapy (RRT), as well as 402 subjects on RRT, were included. All URS except phenylalanine significantly differed between patients on RRT vs. not on RTT. In univariate analyses, URS negatively correlated with most lipid markers, including LDL and HDL cholesterol. In contrast, the amino acids tryptophan, phenylalanine, and tyrosine were positively correlated with a large majority of lipid markers. After combining URS concentrations based on molecule size, similar associations were observed for the respective groups, i.e. small water-soluble molecules, protein-bound molecules, and amino acids. After adjustment for age, sex, presence of diabetes, dialysis treatment, inflammation, protein energy wasting, and renal function, significant associations were lost for URS and total cholesterol or HDL cholesterol, excluding total cholesterol and phenylacetyl glutamine. However, high triglyceride levels were independently predicted by p-cresyl sulphate, tryptophan, indole-3 acetic acid, phenylalanine, TMAO, small water-soluble molecules combined, and protein-bound molecules combined. Non-HDL cholesterol was independently predicted by phenyl glucuronide, TMAO, phenylacetyl glutamine and small water-soluble molecules combined, while remnant cholesterol was independently associated with 10 out of the 15 URS, as well as small water-soluble molecules combined and amino acids combined. Furthermore, LDL cholesterol independently associated with tryptophan, TMAO, phenylacetyl glutamine and protein-bound molecules combined. Conclusion Significant inverse associations between lipid profile and small water-soluble or protein-bound uremic toxins in advanced CKD highlight the complexity of the uremic environment. Our data suggest that not all URS interactions with conventional CV risk markers may be pathogenic.

POS0205 AMELIORATION OF ENDOTHELIAL DYSFUNCTION WITH JAK INHIBITION IN RHEUMATOID ARTHRITIS: JAK CV-RISK REDUCTION STUDY

Background:Cardiovascular (CV) disease is the leading cause of premature mortality and sudden death in Rheumatoid Arthritis (RA). Conventional CV risk factors and disease specific risk factors are responsible for endothelial dysfunction (ED) in RA. ED is the barometer of CV health and key initial event in atherosclerosis. Tofacitinib, a JAK inhibitor, is in clinical use since 2012 and has had the most extensive development program in RA, but its impact on ED has not yet been explored in humans.Objectives:To investigate the impact of tofacitinib on endothelial dysfunction in RAMethods:40 RA patients fulfilling the 2010 Rheumatoid Arthritis classification criteria with active disease (DAS28&gt;3.2) were randomized to receive 24 weeks of treatment with Tofacitinib (5mg bd, n=20) and placebo (n=20) as an adjunct to existing stable antirheumatic drugs. Primary endpoints included endothelial dysfunction assessed by FMD using Angiodefender and lipids were estimated at baseline and after 12 weeks of treatment. The secondary end points included: DAS28, ESR, CRP, HAQ-DI and cardiovascular risk using SCORE chart assessed at week 0 and 12.Results:At baseline, endothelial function was impaired and levels of inflammatory measures were elevated in both groups. CV risk SCORE was high and HAQ-DI was impaired at baseline. After treatment, FMD improved significantly in the tofacitinib group from (8.16±1.38% to 10.98±2.33%, p≤0.05) as compared to placebo (7.12±0.25% to 8.04±0.30%, p=0.35) (Fig. 1A). DAS28 (Fig. 1B), ESR and CRP (Fig. 1C) levels improved significantly in tofacitinib group as compared to placebo (p≤0.05). Tofacitinib significantly decreased HAQ-DI and SCORE (Fig. 1D) values as compared to placebo. There was significant increase in HDL (p≤0.05) after treatment with tofacitinib as compared to placebo. After 12 weeks of treatment, FMD and HDL increased by 34.55% and 13.58% respectively where as DAS28, ESR and CRP decreased by 37.40%, 36.10% and 76.59% respectively in the tofacitinib group. Significant negative correlation was observed between FMD and DAS28 (r= -0.50, p≤0.05) and CRP (r= -52, p≤0.05) after treatment with tofacitinib where as no such correlation was found in placebo group.Figure 1.Impact of Tofacitinib on FMD, DAS 28, CRP &amp; SCOREConclusion:First study to show that tofacitinib, apart from its anti inflammatory activity, improves endothelial dysfunction and cardiovascular risk in RA. Thus, JAK inhibition with tofacitinib has vasculoprotective and cardioprotective effect mediated through anti-inflammatory and probably other mechanisms. This study would stimulate further research in exploring the vasculoprotective and cardioprotective potential of tofacitinib in RA.

ASYMPTOMATIC HYPERURICEMIA AS A POTENTIAL METABOLIC RISK FACTOR FOR CORONARY ARTERY CALCIFICATION IN PATIENTS WITH ATRIAL FIBRILLATION OR HEART FAILURE

Purpose: To assess the role of asymptomatic hyperuricemia for the presence and severity of coronary arterial calcium (CAC) in adults with different cardiovascular (CV) pathology and its association with conventional CV risk factors. Material/Methods: Adults (n=81) of both genders were divided into controls: with moderate- to high risk without known CVD; AF-group: CVD-patients with paroxysmal or persistent atrial fibrillation in sinus rhythm, HF–group: heart failure subjects with preserved ejection fraction. A structured interview was performed at admittance for evaluation of the classical CVD risk factors. CAC score (CACS) was determined by multislice computed tomography. Routine laboratory parameters, including uric acid (UA), were extracted from medical documentation. Descriptive statistics, Mann-Whitney U-test, one-way ANOVA, chi-square test, Spearman's correlation, and multiple linear regression analysis were applied. The predictive power of serum UA was evaluated using receiver operating characteristic (ROC) analysis. Statistical significance was considered at p&lt;0.05. Results: Serum UA was significantly higher in subjects with CACS=1-99AU (p=0.030), and with CACS≥100AU (p=0.067) vs. patients without CACS. Within the UA tertiles, highest CACS was found in the tertile with highest serum UA. UA revealed positive relation with CACS (r=0.35, p=0.002), age (r=0.25, p=0.027), body mass index (0.27, p=0.017), waist circumference (r=0.44, p&lt;0.0001), triglycerides (r=0.29, p=0.001), and creatinine (r=0.54, p&lt;0.0001). Multiple linear regression analysis revealed significant association between UA as dependent variable and waist circumference (β=0.63, p=0.061), serum triglycerides (β=0.37, p=0.028), creatinine levels (β=0.45, p&lt;0.0001). Conclusions: Asymptomatic hyperuricaemia could be an important metabolic factor negatively affecting the chronic cardio-vascular pathology besides the conventional risk factors.

Association of fatal myocardial infarction with past level of physical activity: a pooled analysis of cohort studies

To assess the association between past level of physical activity (PA) and risk for death during the acute phase of myocardial infarction (MI) in a pooled analysis of cohort studies. European cohorts including participants with a baseline assessment of PA, conventional cardiovascular (CV) risk factors, and available follow-up on MI and death were eligible. Patients with an incident MI were included. Leisure-time PA was grouped as sedentary (<7 MET-hours), low (7-16 MET-hours), moderate (16.1-32 MET-hours), or high (>32 MET-hours) based on calculated net weekly energy expenditure. The main outcome measures were instant and 28-day case fatality of MI. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using multivariate random-effects models. Adjustments for age, sex, CV risk factors, alcohol consumption, and socioeconomic status were made. From 10 cohorts including a total of 1 495 254 participants, 28 140 patients with an incident MI comprised the study population. A total of 4976 (17.7%) died within 28 days-of these 3101 (62.3%) were classified as instant fatal MI. Compared with sedentary individuals, those with a higher level of PA had lower adjusted odds of instant fatal MI: low PA [OR, 0.79 (95% CI, 0.60-1.04)], moderate PA [0.67 (0.51-0.89)], and high PA [0.55 (0.40-0.76)]. Similar results were found for 28-day fatal MI: low PA [0.85 (0.71-1.03)], moderate PA [0.64 (0.51-0.80)], and high PA [0.72 (0.51-1.00)]. A low-to-moderate degree of heterogeneity was detected in the analysis of instant fatal MI (I2 = 47.3%), but not in that of 28-day fatal MI (I2 = 0.0%). A moderate-to-high level of PA was associated with a lower risk of instant and 28-day death in relation to a MI.