Graciela Delgado

Uric Acid and Cardiovascular Events: A Mendelian Randomization Study

Obesity and diets rich in uric acid-raising components appear to account for the increased prevalence of hyperuricemia in Westernized populations. Prevalence rates of hypertension, diabetes mellitus, CKD, and cardiovascular disease are also increasing. We used Mendelian randomization to examine whether uric acid is an independent and causal cardiovascular risk factor. Serum uric acid was measured in 3315 patients of the Ludwigshafen Risk and Cardiovascular Health Study. We calculated a weighted genetic risk score (GRS) for uric acid concentration based on eight uric acid-regulating single nucleotide polymorphisms. Causal odds ratios and causal hazard ratios (HRs) were calculated using a two-stage regression estimate with the GRS as the instrumental variable to examine associations with cardiometabolic phenotypes (cross-sectional) and mortality (prospectively) by logistic regression and Cox regression, respectively. Our GRS was not consistently associated with any biochemical marker except for uric acid, arguing against pleiotropy. Uric acid was associated with a range of prevalent diseases, including coronary artery disease. Uric acid and the GRS were both associated with cardiovascular death and sudden cardiac death. In a multivariate model adjusted for factors including medication, causal HRs corresponding to each 1-mg/dl increase in genetically predicted uric acid concentration were significant for cardiovascular death (HR, 1.77; 95% confidence interval, 1.12 to 2.81) and sudden cardiac death (HR, 2.41; 95% confidence interval, 1.16 to 5.00). These results suggest that high uric acid is causally related to adverse cardiovascular outcomes, especially sudden cardiac death.

Trans-fatty acids and mortality in patients referred for coronary angiography: the Ludwigshafen Risk and Cardiovascular Health Study

AIMS Trans-fatty acids (TFAs) are generated by the food industry and also occur naturally in trace amounts in dairy products. For the latter, beneficial health effects have been claimed, while there are numerous reports about TFA of industrial origin being hazardous to human health. Therefore, we aimed to investigate the association of TFA with mortality in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. METHODS AND RESULTS The fatty acid composition of erythrocyte membranes was analysed using the HS-Omega-3 Index(®) methodology in 3259 participants of the LURIC study at baseline. During a median of 10.0 years of follow-up, a total of 975 (29.9%) study participants died, 614 (18.8%) from cardiovascular causes including 254 (7.8%) sudden cardiac deaths (SCDs). Association of TFA with clinical outcome was investigated with Cox proportional hazards regression. Total TFAs were inversely associated with mortality due to cardiovascular causes or SCD. This was mainly driven by the naturally occurring TFA C16:1n-7t (trans-palmitoleic acid). The reduced risk of SCD associated with C16:1n-7t persisted after multivariate adjustment with a hazard ratio of 0.63 (0.46-0.86) for the third tertile compared with the first tertile. There was no association of any TFA subgroup with an increased risk of adverse outcomes. CONCLUSIONS In contrast to previous findings, the low concentrations of total TFAs found in LURIC were inversely associated with adverse cardiac outcomes. While the naturally occurring TFA C16:1n-7t was associated with reduced risk, no increased risk was found for industrially produced TFAs.

Galectin-3, Renal Function, and Clinical Outcomes: Results from the LURIC and 4D Studies

Galectin-3 has been linked to incident renal disease, experimental renal fibrosis, and nephropathy. However, the association among galectin-3, renal function, and adverse outcomes has not been described. We studied this association in two large cohorts of patients over a broad range of renal function. We measured galectin-3 concentrations in baseline samples from the German Diabetes mellitus Dialysis (4D) study (1168 dialysis patients with type 2 diabetes mellitus) and the Ludwigshafen Risk and Cardiovascular Health (LURIC) study (2579 patients with coronary angiograms). Patients were stratified into three groups: eGFR of ≥90 ml/min per 1.73 m(2), 60-89 ml/min per 1.73 m(2), and <60 ml/min per 1.73 m(2). We correlated galectin-3 concentrations with demographic, clinical, and biochemical parameters. The association of galectin-3 with clinical end points was assessed by Cox proportional hazards regression within 10 years (LURIC) or 4 years (4D) of follow-up. Mean±SD galectin-3 concentrations were 12.8±4.0 ng/ml (eGFR≥90 ml/min per 1.73 m(2)), 15.6±5.4 ng/ml (eGFR 60-89 ml/min per 1.73 m(2)), 23.1±9.9 ng/ml (eGFR<60 ml/min per 1.73 m(2)), and 54.1±19.6 ng/ml (dialysis patients of the 4D study). Galectin-3 concentration was significantly associated with clinical end points in participants with impaired kidney function, but not in participants with normal kidney function. Per SD increase in log-transformed galectin-3 concentration, the risks of all-cause mortality, cardiovascular mortality, and fatal infection increased significantly. In dialysis patients, galectin-3 was associated with the combined end point of cardiovascular events. In conclusion, galectin-3 concentrations increased with progressive renal impairment and independently associated with cardiovascular end points, infections, and all-cause death in patients with impaired renal function.

Adult height, coronary heart disease and stroke: a multi-locus Mendelian randomization meta-analysis

Abstract Background: We investigated causal effect of completed growth, measured by adult height, on coronary heart disease (CHD), stroke and cardiovascular traits, using instrumental variable (IV) Mendelian randomization meta-analysis. Methods: We developed an allele score based on 69 single nucleotide polymorphisms (SNPs) associated with adult height, identified by the IBCCardioChip, and used it for IV analysis against cardiovascular risk factors and events in 21 studies and 60 028 participants. IV analysis on CHD was supplemented by summary data from 180 height-SNPs from the GIANT consortium and their corresponding CHD estimates derived from CARDIoGRAMplusC4D. Results: IV estimates from IBCCardioChip and GIANT-CARDIoGRAMplusC4D showed that a 6.5-cm increase in height reduced the odds of CHD by 10% [odds ratios 0.90; 95% confidence intervals (CIs): 0.78 to 1.03 and 0.85 to 0.95, respectively],which agrees with the estimate from the Emerging Risk Factors Collaboration (hazard ratio 0.93; 95% CI: 0.91 to 0.94). IV analysis revealed no association with stroke (odds ratio 0.97; 95% CI: 0.79 to 1.19). IV analysis showed that a 6.5-cm increase in height resulted in lower levels of body mass index (P < 0.001), triglycerides (P < 0.001), non high-density (non-HDL) cholesterol (P < 0.001), C-reactive protein (P = 0.042), and systolic blood pressure (P = 0.064) and higher levels of forced expiratory volume in 1 s and forced vital capacity (P < 0.001 for both). Conclusions: Taller individuals have a lower risk of CHD with potential explanations being that taller people have a better lung function and lower levels of body mass index, cholesterol and blood pressure.

Omega-3 fatty acids and mortality in patients referred for coronary angiography. The Ludwigshafen Risk and Cardiovascular Health Study.

BACKGROUND AND AIMS There is an ongoing debate whether omega-3-fatty acids protect from cardiovascular disease mortality. We examined the associations of erythrocyte omega-3 fatty acids with mortality in patients referred for coronary angiography. METHODS Erythrocyte omega-3 fatty acid proportions were measured at baseline in 3259 participants of the Ludwigshafen Risk and Cardiovascular Health Study (LURIC) using the HS-Omega-3 Index method. Associations of omega-3 fatty acid proportions with mortality were investigated using Cox proportional hazards regression. RESULTS During a median follow-up of 9.9 years, 975 patients (29.9%) died, 614 patients (18.8%) from cardiovascular causes. Proportions of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were inversely associated with all-cause and cardiovascular mortality in models adjusted for conventional cardiovascular risk factors. The strongest association was observed for EPA with a hazard ratio (HR) of 0.89 (0.83-0.96) per increase of one standard deviation. Furthermore, we obtained evidence for a non-linear relation between EPA and mortality. CONCLUSIONS EPA and DHA were associated with reduced mortality in LURIC, independent of other risk factors, with the association of EPA with mortality being non-linear.

C‐reactive protein predicts mortality in patients referred for coronary angiography and symptoms of heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) has a different pathophysiological background compared to heart failure with reduced ejection fraction (HFrEF). Tailored risk prediction in this separate heart failure group with a high mortality rate is of major importance. Inflammation may play an important role in the pathogenesis of HFpEF because of its significant contribution to myocardial fibrosis. We therefore aimed to assess the predictive value of C‐reactive protein (CRP) in patients with HFpEF.

Fibroblast Growth Factor 23 Is an Independent and Specific Predictor of Mortality in Patients With Heart Failure and Reduced Ejection Fraction

Background—Strategies to improve risk prediction are of major importance in patients with heart failure (HF). Fibroblast growth factor 23 (FGF-23) is an endocrine regulator of phosphate and vitamin D homeostasis associated with an increased cardiovascular risk. We aimed to assess the prognostic effect of FGF-23 on mortality in HF patients with a particular focus on differences between patients with HF with preserved ejection fraction and patients with HF with reduced ejection fraction (HFrEF). Methods and Results—FGF-23 levels were measured in 980 patients with HF enrolled in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study including 511 patients with HFrEF and 469 patients with HF with preserved ejection fraction and a median follow-up time of 8.6 years. FGF-23 was additionally measured in a second cohort comprising 320 patients with advanced HFrEF. FGF-23 was independently associated with mortality with an adjusted hazard ratio per 1-SD increase of 1.30 (95% confidence interval, 1.14–1.48; P<0.001) in patients with HFrEF, whereas no such association was found in patients with HF with preserved ejection fraction (for interaction, P=0.043). External validation confirmed the significant association with mortality with an adjusted hazard ratio per 1 SD of 1.23 (95% confidence interval, 1.02–1.60; P=0.027). FGF-23 demonstrated an increased discriminatory power for mortality in addition to N-terminal pro–B-type natriuretic peptide (C-statistic: 0.59 versus 0.63) and an improvement in net reclassification index (39.6%; P<0.001). Conclusions—FGF-23 is independently associated with an increased risk of mortality in patients with HFrEF but not in those with HF with preserved ejection fraction, suggesting a different pathophysiologic role for both entities.

Von Willebrand Factor Improves Risk Prediction in Addition to N-Terminal Pro–B-type Natriuretic Peptide in Patients Referred to Coronary Angiography and Signs and Symptoms of Heart Failure and Preserved Ejection Fraction

Background—Heart failure with preserved ejection fraction (HFpEF) represents a growing health burden associated with substantial mortality and morbidity. Consequently, risk prediction is of highest importance. Endothelial dysfunction has been recently shown to play an important role in the complex pathophysiology of HFpEF. We therefore aimed to assess von Willebrand factor (vWF), a marker of endothelial damage, as potential biomarker for risk assessment in patients with HFpEF. Methods and Results—Concentrations of vWF were assessed in 457 patients with HFpEF enrolled as part of the LUdwigshafen Risk and Cardiovascular Health (LURIC) study. All-cause mortality was observed in 40% of patients during a median follow-up time of 9.7 years. vWF significantly predicted mortality with a hazard ratio (HR) per increase of 1 SD of 1.45 (95% confidence interval, 1.26–1.68; P<0.001) and remained a significant predictor after adjustment for age, sex, body mass index, N-terminal pro–B-type natriuretic peptide (NT-proBNP), renal function, and frequent HFpEF-related comorbidities (adjusted HR per 1 SD, 1.22; 95% confidence interval, 1.05–1.42; P=0.001). Most notably, vWF showed additional prognostic value beyond that achievable with NT-proBNP indicated by improvements in C-Statistic (vWF×NT-proBNP: 0.65 versus NT-proBNP: 0.63; P for comparison, 0.004) and category-free net reclassification index (37.6%; P<0.001). Conclusions—vWF is an independent predictor of long-term outcome in patients with HFpEF, which is in line with endothelial dysfunction as potential mediator in the pathophysiology of HFpEF. In particular, combined assessment of vWF and NT-proBNP improved risk prediction in this vulnerable group of patients.

Serum Uromodulin and Mortality Risk in Patients Undergoing Coronary Angiography

The mucoprotein uromodulin is the most abundant protein in mammalian urine and has important roles in ion transport, maintenance of water and electrolyte balance, and clearance of bacteria from the urinary tract. Low urinary uromodulin concentrations have been associated with increased mortality risk. However, measuring uromodulin in urine has several preanalytic drawbacks, and sensitive assays for the detection of uromodulin in blood have become available. In this study, we investigated the association of serum uromodulin concentration with cardiovascular biomarkers and mortality risk in a large cohort of patients referred for coronary angiography. Uromodulin concentrations were available in 3057 of 3316 participants of the Ludwigshafen Risk and Cardiovascular Health Study. Higher serum uromodulin concentration associated with a favorable metabolic profile, lower prevalence rates of comorbidities (arterial hypertension, diabetes mellitus, and heart failure), and a lower risk for 10-year mortality, with hazard ratios (95% confidence intervals) of 0.65 (0.54 to 0.78), 0.71 (0.58 to 0.88), and 0.57 (0.45 to 0.73) in the second, third, and fourth quartiles, respectively, compared with the first quartile. The association with reduced mortality was independent of other cardiovascular risk factors, including eGFR, and stronger after adjustment for the genotype of the rs12917707 polymorphism at the UMOD locus. Adding serum uromodulin concentration to established cardiovascular risk prediction scores improved risk prediction. Uromodulin may, therefore, be a useful marker for cardiovascular and renal health.

Soluble klotho and mortality: The Ludwigshafen Risk and Cardiovascular Health Study

BACKGROUND Experimental evidence suggests that soluble klotho (s-klotho), a co-receptor for fibroblast growth factor 23 (FGF23), may modulate cardiovascular risk through multiple mechanisms. However, the predictive value of s-klotho in patients remains unclear. Therefore, the present study examined in a large cohort of patients referred for coronary angiography whether s-klotho is associated with cardiovascular and total mortality. METHODS The longitudinal associations between baseline s-klotho and FGF23 concentrations and mortality were evaluated in 2948 participants of the Ludwigshafen Risk and Cardiovascular Health Study (LURIC), referred for coronary angiography. RESULTS Mean age of participants was: 63 ± 10 years. Patients with diabetes mellitus (n = 1136) had elevated s-klotho: [440 (430-449) versus 414 (406-421) pg/mL, p < 0.001]. S-klotho decreased in parallel to glomerular filtration rate (GFR) and increased in parallel to FGF23. During a median follow-up of 9.9 years, 874 deaths (30%) occurred, 539 (18%) of which were cardiovascular. After adjustment for cardiovascular risk factors, the hazard ratios in the fourth quartile compared to the first quartile of s-klotho were 1.14 (95%CI, 0.94-1.38; p = 0.187) for all-cause mortality and 1.03 (95%CI, 0.80-1.31; p = 0.845) for cardiovascular mortality. Excess mortality prediction by high levels of baseline FGF23 was not modified by adjustment for baseline s-klotho levels. CONCLUSIONS Klotho does not add predictive power to cardiovascular and mortality risk assessment in patients with normal renal function.